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Invited Review: Strategic use of microbial-based probiotics and prebiotics in dairy calf rearing

  • Author Footnotes
    * L. Rostoll Cangiano and T. T. Yohe contributed equally to this work.
    L.R. Cangiano
    Footnotes
    * L. Rostoll Cangiano and T. T. Yohe contributed equally to this work.
    Affiliations
    Department of Animal Biosciences, Animal Science and Nutrition, University of Guelph, Guelph, Ontario, Canada N1G 1Y2
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  • Author Footnotes
    * L. Rostoll Cangiano and T. T. Yohe contributed equally to this work.
    T.T. Yohe
    Footnotes
    * L. Rostoll Cangiano and T. T. Yohe contributed equally to this work.
    Affiliations
    Department of Animal Biosciences, Animal Science and Nutrition, University of Guelph, Guelph, Ontario, Canada N1G 1Y2
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  • M.A. Steele
    Affiliations
    Department of Animal Biosciences, Animal Science and Nutrition, University of Guelph, Guelph, Ontario, Canada N1G 1Y2
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  • D.L. Renaud
    Affiliations
    Department of Population Medicine, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
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  • Author Footnotes
    * L. Rostoll Cangiano and T. T. Yohe contributed equally to this work.

      ABSTRACT

      Purpose

      The objective of this narrative review was to describe the effect of microbial-based products, specifically pro- and prebiotics, on gut health, function, and disease prevention during early life and at weaning in dairy calves.

      Sources

      The main source of data and information compiled for this review was peer-reviewed literature.

      Synthesis

      Diarrhea is responsible for the majority of mortality and morbidity early in life. Pro- and prebiotics have recently been explored as mechanisms to promote gut health and decrease diarrhea in young calves. In addition, the change in calf diet, where there is a transition from a predominantly milk diet to a solid diet in a relatively short period of time, may also provide an opportunity to use microbial-based products.

      Conclusions and Applications

      Based on the current studies that have supplemented calves with pro- and prebiotics, the majority of responses in growth, feed efficiency, and health have either been nonsignificant (39/68, 32/70, and 15/68, respectively) or positive (22/68, 9/70, and 31/68, respectively). The results presented in this review highlight that health and growth were the most positively affected responses to supplementation and that most of the beneficial effects were observed when these products were supplemented during a bout of illness. It appears that pro- and prebiotic supplementation to calves is low risk with potentially positive benefits that are worthy of further investigation. Supplementation of pro- and prebiotics to young ruminants requires further investigation to better understand the underlying mechanisms responsible for the phenotypical responses observed to implement better supplementation strategies.

      Key words

      INTRODUCTION

      Female dairy calves are crucial to the dairy herd and should be reared in a way that maintains good health, welfare, and the ability to produce milk. Similarly, for male dairy calves, opportunities to maximize growth and minimize health challenges are essential. Despite their undoubted importance, significant challenges remain around safely and effectively rearing male and female dairy calves. It is estimated that 5 to 6% of female dairy calves die during the preweaning period on farms in Canada and the United States (
      • Urie N.J.
      • Lombard J.E.
      • Shivley C.B.
      • Kopral C.A.
      • Adams A.E.
      • Earleywine T.J.
      • Olson J.D.
      • Garry F.B.
      Preweaned heifer management on US dairy operations: Part V. Factors associated with morbidity and mortality in preweaned dairy heifer calves..
      ;
      • Winder C.B.
      • Bauman C.A.
      • Duffield T.F.
      • Barkema H.W.
      • Keefe G.P.
      • Dubuc J.
      • Uehlinger F.
      • Kelton D.F.
      Canadian national dairy study: Heifer calf management..
      ). Moreover, an estimated 33% of female dairy calves are treated once during the preweaning period on farms in the United States (
      • Urie N.J.
      • Lombard J.E.
      • Shivley C.B.
      • Kopral C.A.
      • Adams A.E.
      • Earleywine T.J.
      • Olson J.D.
      • Garry F.B.
      Preweaned heifer management on US dairy operations: Part V. Factors associated with morbidity and mortality in preweaned dairy heifer calves..
      ). Male dairy calves face even greater health disorders and diseases, with 4.3 to 9.6% of calves dying on veal farms in Canada and the United States (
      • Pempek J.
      • Trearchis D.
      • Masterson M.
      • Habing G.
      • Proudfoot K.
      Veal calf health on the day of arrival at growers in Ohio..
      ;
      • Renaud D.L.
      • Kelton D.F.
      • LeBlanc S.J.
      • Haley D.B.
      • Duffield T.F.
      Calf management risk factors on dairy farms associated with male calf mortality on veal farms..
      ), and 25 to 87% of calves treated at least once for disease on veal farms in Belgium and Canada (
      • Pardon B.
      • De Bleecker K.
      • Hostens M.
      • Callens J.
      • Dewulf J.
      • Deprez P.
      Longitudinal study on morbidity and mortality in white veal calves in Belgium..
      ;
      • Scott K.
      • Kelton D.F.
      • Duffield T.F.
      • Renaud D.L.
      Risk factors identified on arrival associated with morbidity and mortality at a grain-fed veal facility: A prospective, single cohort study..
      ). Clearly, as mortality and morbidity are used as markers of welfare (
      • Ortiz-Pelaez A.
      • Pritchard D.
      • Pfeiffer D.
      • Jones E.
      • Honeyman P.
      • Mawdsley J.
      Calf mortality as a welfare indicator on British cattle farms..
      ), there is a significant need to address these challenges to protect the long-term sustainability of the dairy, and associated, industries.
      The high diarrhea incidence in calves is an area of concern that should be addressed immediately, as this disease is responsible for the majority of calf mortality and morbidity early in life (
      • Urie N.J.
      • Lombard J.E.
      • Shivley C.B.
      • Kopral C.A.
      • Adams A.E.
      • Earleywine T.J.
      • Olson J.D.
      • Garry F.B.
      Preweaned heifer management on US dairy operations: Part V. Factors associated with morbidity and mortality in preweaned dairy heifer calves..
      ;
      • Scott K.
      • Kelton D.F.
      • Duffield T.F.
      • Renaud D.L.
      Risk factors identified on arrival associated with morbidity and mortality at a grain-fed veal facility: A prospective, single cohort study..
      ). Diarrhea prevention should be emphasized, as calves that require treatment for diarrhea experience reduced growth, increased risk of mortality, increased age at first calving, and reduced first lactation milk production (
      • Waltner-Toews D.
      • Martin S.W.
      • Meek A.H.
      • McMillan I.
      Dairy calf management, morbidity, and mortality in Ontario Holstein herds. I. The data..
      ;
      • Svensson C.
      • Hultgren J.
      Associations between housing, management, and morbidity during rearing and subsequent first lactation milk production of dairy cows in southwest Sweden..
      ;
      • Windeyer M.C.
      • Leslie K.E.
      • Godden S.M.
      • Hodgins D.C.
      • Lissemore K.D.
      • LeBlanc S.J.
      Factors associated with morbidity, mortality, and growth of dairy heiger calves up to 3 months of age..
      ). Traditionally, oral antimicrobials are used to prevent diarrhea; however, the demonstrated variable efficacy of oral antimicrobials and concerns surrounding antimicrobial resistance make this an unsustainable option (
      • Smith G.
      Antimicrobial decision making for enteric diseases of cattle..
      ). Hence, alternative measures should be sought to combat this disease.
      The past decade has been marked by great advances in our understanding of how the gut microbiota can affect gut health and disease. It is now becoming clear that the gut microbial community interacts closely with the host to influence intestinal physiology and the development of the immune system (
      • Mazmanian S.K.
      • Liu C.H.
      • Tzianabos A.O.
      • Kasper D.L.
      An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system..
      ;
      • Peterson D.A.
      • McNulty N.P.
      • Guruge J.L.
      • Gordon J.I.
      IgA response to symbiotic bacteria as a mediator of gut homeostasis..
      ). The presence of specific bacteria with health outcomes are commonly reported in young mammal gastrointestinal research. For example, the prevalence of fecal Bifidobacterium and Lactobacillus has been shown to be a reliable indicator of infant gut health (
      • Yoshioka H.
      • Iseki K.
      • Fujita K.
      Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants..
      ;
      • Harmsen H.J.
      • Wildeboer-Veloo A.C.
      • Raangs G.C.
      • Wagendorp A.A.
      • Klijn N.
      • Bindels J.G.
      • Welling G.W.
      Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods..
      ). Similar microbial biomarkers have been uncovered in calves, namely the prevalence of Faecalibacterium in feces, which resulted in reduced diarrhea incidences and increased BW gains during the first weeks of life (
      • Oikonomou G.
      • Teixeira A.G.
      • Foditsch C.
      • Bichalho M.L.
      • Machado V.S.
      • Bicalho R.C.
      Fecal microbial diversity in pre-weaned dairy calves as described by pyrosequencing of metagenomic 16S rDNA. Associations of Faecalibacterium species with health and growth..
      ). In addition, Bifidobacterium, and several genera from the Bifidobacteriaceae family, have been found to be more prevalent in healthy Holstein calves compared with diarrheic calves (
      • Gomez D.E.
      • Arroyo L.G.
      • Costa M.C.
      • Viel L.
      • Weese J.S.
      Characterization of the fecal bacterial microbiota of healthy and diarrheic dairy calves..
      ). The factors that can alter the gut microbial community in the early life of the calf to benefit health are of great interest. The external factors that have been shown to induce these changes include diet, maternal factors, environment, and antibiotic treatment (
      • Malmuthuge N.
      • Griebel P.J.
      • Guan L.L.
      The gut microbiome and its potential role in the development and function of the newborn calf gastrointestinal tract..
      ). However, it is important to note that the host—especially the immune defense of the host—plays a substantial role in sculpting the gut microbiota and adaptive responses to gut health challenges and, thus, should not be overlooked.
      Although there is a paucity of information about microbial colonization during the birthing process, there has been some characterization of how colostrum, milk, and solid feed affect the gut microbiota of calves.
      • Malmuthuge N.
      • Chen Y.
      • Liang G.
      • Goonewardene L.A.
      • Guan L.L.
      Heat-treated colostrum feeding promotes beneficial bacteria colonization in the small intestine of neonatal calves..
      noted that colostrum accelerates bacterial colonization in the small intestine. Delaying colostrum feeding by 12 h has been shown to reduce the prevalence of Bifidobacteria and Lactobacillus (beneficial bacteria) in the colon of dairy calves (
      • Fischer A.J.
      • Song Y.
      • He Z.
      • Haines D.M.
      • Guan L.L.
      • Steele M.A.
      Effect of delaying colostrum feeding on passive transfer and intestinal bacterial colonization in neonatal male Holstein calves..
      ). After colostrum feeding, during the preweaning period, milk accounts for a large proportion of bacterial substrates provided in the diet, and as such, the source of milk provided can alter bacterial colonization. Specifically, when calves are fed waste milk, which may contain residual levels of antimicrobials, lower levels of Clostridales and Bacteroidales are found in the feces, and gut microbial imbalances occur more often (
      • Maynou G.
      • Migura-Garcia L.
      • Subirats J.
      • Chester-Jones H.
      • Ziegler D.
      • Bach A.
      • Terre M.
      Impact of milk-feeding programs on fecal bacteria population and antimicrobial resistance genes in Escherichia coli isolated from feces in preweaned calves..
      ;
      • Van Vleck Pereira R.V.V.
      • Lima S.
      • Siler J.D.
      • Foditsch C.
      • Warnick L.D.
      • Bicalho R.C.
      Ingestion of milk containing very low concentration of antimicrobials: Longitudinal effect on fecal microbiota composition in preweaned calves..
      ). The transition from milk feeding to solid feed during weaning is marked by some of the most dramatic anatomic and metabolic adaptations (
      • Baldwin R.L.
      • McLeod K.R.
      • Klotz J.L.
      • Heitmann R.N.
      Rumen development, intestinal growth and hepatic metabolism in the pre- and postweaning ruminant..
      ) in addition to large changes in the gut microbiome. In the case of the rumen, bacteria belonging to the Bacteroidetes phylum decreased and bacteria belonging to Proteobacteria and Firmicutes increased during weaning, demonstrating the effect that the solid feed transition can exert on the rumen microbiome (
      • Li R.W.
      • Connor E.E.
      • Li C.
      • Baldwin VI, R.L.
      • Sparks M.E.
      Characterization of the rumen microbiota of pre-ruminant calves using metagenomics tools..
      ;
      • Meale S.J.
      • Li S.C.
      • Azevedo P.
      • Derakhshani H.
      • DeVries T.J.
      • Plaizier J.C.
      • Steele M.A.
      • Khafipour E.
      Weaning age influences the severity of gastrointestinal microbiome shifts in dairy calves..
      ).
      It has been widely characterized in infants and laboratory animals that the gut microbiome has greater plasticity in early life and microbial exposure and perturbations can have consequences related to health and development later in life. The same is thought to occur in calves, as the supplementation of prebiotics (

      Marquez, C. J. 2014. Calf intestinal health: Assessment and dietary interventions for its improvement. PhD Thesis. Univ. Illinois at Urbana-Champaign, Champaign, IL.

      ) and probiotics (
      • Abe F.
      • Ishibashi N.
      • Shimamura S.
      Effect of administration of bifidobacteria and lactic acid bacteria to newborn calves and piglets..
      ) exert the greatest effects in the first weeks of life. This could be directly related to the instability of their microbial communities, whereas later in life the microbiome is stable and more difficult to influence (
      • Malmuthuge N.
      • Griebel P.J.
      • Guan L.L.
      The gut microbiome and its potential role in the development and function of the newborn calf gastrointestinal tract..
      ). Hence, manipulating the gut microbiome, which is a key factor influencing gut health (
      • Bischoff S.C.
      Gut health’: A new objective in medicine?.
      ), early in life could become an option to improve calf health through the use of microbial-based products (
      • Malmuthuge N.
      • Guan L.L.
      Understanding the gut microbiome of dairy calves: Opportunities to improve early-life gut health..
      ). Specifically, pro- and prebiotics have recently been explored to promote gut health and decrease diarrhea in young calves. In addition, the change in calf diet, where there is a transition from a predominantly milk diet to a solid diet composed of rapidly fermentable carbohydrates, may also provide an opportunity to use microbial-based products. This strategy could aid in mitigating exposure of the developing rumen to harsh conditions and may help to prevent calves from experiencing events that negatively affect health and growth during and after weaning.
      The objective of this narrative review is to describe the effect of microbial-based products, specifically pro- and prebiotics, on gut health, function, and disease prevention during early life and at weaning in dairy calves.

      PROBIOTICS

      Probiotics are defined as live strains of strictly selected microorganisms which, when administered in adequate amounts, confer a health benefit (e.g., decrease in diarrhea incidence) on the host (
      • Markowiak P.
      • Śliżewska K.
      Effects of probiotics, prebiotics, and synbiotics on human health..
      ). Probiotics can refer to specific bacterial or fungal strains, microbial cultures, enzyme preparations, culture extracts, or a combination (
      • Yoon I.K.
      • Stern M.D.
      Influence of direct-fed microbials on ruminal microbial fermentation and performance of ruminants: A review..
      ). Young preruminants can be supplemented with probiotics in milk or starter feed to promote gut health, stimulate earlier solid feed consumption, and improve growth. The most commonly used probiotics fed to young calves are live yeast, mainly Saccharomyces cerevisiae (SC), yeast cultures of SC (
      • Alugongo G.M.
      • Xiao J.X.
      • Chung Y.H.
      • Dong S.Z.
      • Li S.L.
      • Yoon I.
      • Wu Z.H.
      • Cao Z.J.
      Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Performance and health..
      ), and bacterial-based probiotics, such as Lactobacillus spp., Enterococcus spp., and Bacillus spp. (
      • Uyeno Y.
      • Shigemori S.
      • Shimosato T.
      Effect of probiotics/prebiotics on cattle health and productivity..
      ).

      Live Yeast and Yeast Culture

      Yeast are single-celled microorganisms and members of the fungi kingdom. The most extensively used probiotic strain of yeast for farm animals is SC. There are several yeast products in the market, including live yeast (LY) and yeast cultures (YC). Live yeast products are fermentable living yeast that have been dried and typically contain at least 10 × 109 LY cells per gram, and YC are products of yeast fermentation and include the media they are grown in (

      AAFCO (Association of American Feed Control Officials Inc.). 2013 Official Publication. Pages 450–451. Assoc. Am. Feed Control Offic., Champaign, IL.

      ). It is important to note that even though YC is classified as a probiotic, it also contains cell-wall components and cell constituents such us β-glucans and oligosaccharides, which are considered prebiotics in nature and possess various biological functions that contribute to the effects exerted by LY (

      Spring, P., C. Wenk, K. A. Dawson, and K. E. Newman. 2000. The effects of dietary mannaoligosaccharides on cecal parameters and the concentrations of enteric bacteria in the ceca of salmonella-challenged broiler chicks. Poult. Sci. 79:205–211. 10.1093/ps/79.2.205.

      ;
      • Davis M.E.
      • Maxwell C.V.
      • Erf G.F.
      • Brown D.C.
      • Wistuba T.J.
      Dietary supplementation with phosphorylated mannans improves growth response and modulates immune function of weanling pigs..
      ).

      Effects on Growth and Performance

      The effects of supplementing LY and YC on DMI are summarized in Table 1, based on a total of 17 studies that measured DMI. Six of the studies showed an increase in starter intake, whereas 11 showed no differences. With respect to growth performance, responses to supplementation follow a similar pattern to that observed for DMI, and the effects are summarized in Figure 1. The inconsistency in growth and DMI response might be attributed to different strains, yeast products (LY or YC), health status of the animals, route of delivery (milk vs. starter feed), or insufficient replicates to show performance responses (
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      ).
      Table 1Summary of growth, health, and gut development responses in calf studies utilizing different probiotics based on yeast culture or live yeast
      Yeast
      YC = yeast culture; SC = Saccharomyces cerevisiae; SCB = Saccharomyces cerevisiae boulardii; LY = live yeast.
      Effects in response to
      Either positive (+) or negative (−) effects are noted with magnitude of change explained here: + = P ≥ 0.05 but ≤0.10, ++ = P ≤ 0.05, and +++ = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      RemarkReference
      Weight

      gain
      Feed

      efficiency
      HealthGut

      development
      YC++NSNSNSFed in starter feed.
      • Lesmeister K.E.
      • Heinrichs A.J.
      • Gabler M.T.
      Effects of supplemental yeast (Saccharomyces cerevisiae) culture on rumen development, growth characteristics, and blood parameters in neonatal dairy calves..
      SC++NS++n/aFed in starter. Increased starter intake. Fewer days with diarrhea.
      • Galvão K.N.
      • Santos J.E.P.
      • Coscioni A.
      • Villaseñor M.
      • Sischo W.M.
      • Berge A.C.B.
      Effect of feeding live yeast products to calves with failure of passive transfer on performance and patterns of antibiotic resistance in fecal Escherichia coli..
      YCNSNSn/a+Fed in starter feed. Improved rumen development.
      • Kaldmäe H.
      • Suurmets H.
      • Järveots T.
      • Suuroja T.
      • Kärt O.
      Effects of supplemental yeast (Saccharomyces cerevisiae) culture on rumen development and growth in calves..
      YCNSNS++n/aFed grain feed. Reduced incidence of diarrhea and mortality rates. Tendency to improve neutrophil function.
      • Magalhães V.J.A.
      • Susca F.
      • Lima F.S.
      • Branco A.F.
      • Yoon I.
      • Santos J.E.P.
      Effect of feeding yeast culture on performance, health, and immunocompetence of dairy calves..
      SC and SCBNSNSNSn/aOral administration in sterile water twice daily.
      • Pinos-Rodríguez J.M.
      • Robinson P.H.
      • Ortega M.E.
      • Berry S.L.
      • Mendoza G.
      • Bárcena R.
      Performance and rumen fermentation of dairy calves supplemented with Saccharomyces cerevisiae1077 or Saccharomyces boulardii 1079..
      LYNSNS++n/aLY product fed in starter feed. Improved fecal scores.
      • Hill S.R.
      • Hopkins B.A.
      • Davidson S.
      • Bolt S.M.
      • Diaz D.E.
      • Brownie C.
      • Brown T.
      • Huntington G.B.
      • Whitlow L.W.
      The addition of cottonseed hulls to the starter and supplementation of live yeast or mannanoligosaccharide in the milk for young calves..
      YC++NSn/an/aYC fed in starter feed
      • Zhou G.
      • Zhen Y.G.
      • Yan Z.G.
      • Li Z.Q.
      • Wang G.H.
      • Wan K.J.
      Study on the effects of yeast culture on the digestibility and growing development in calves..
      YCNSNSn/a+Fed in starter feed. Improved microbial cellulolytic activity.
      • Hučko B.
      • Bampidis V.A.
      • Kodeš A.
      • Christodoulou V.
      • Mudřik Z.
      • Poláková K.
      • Plachý V.
      Rumen fermentation characteristics in pre-weaning calves receiving yeast culture supplements..
      YCNSNS++n/aFed in starter feed. Improved humoral response to vaccine challenge. Low replication to assess growth performance.
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      YC++NS++++Fed in both MR
      MR = milk replacer.
      and starter. Reduction in diarrhea. Improved rumen development and reduced pathogen intestinal colonization.
      • Brewer M.T.
      • Anderson K.L.
      • Yoon I.
      • Scott M.F.
      • Carlson S.A.
      Amelioration of salmonellosis in pre-weaned dairy calves fed Saccharomyces cerevisiae fermentation products in feed and milk replacer..
      YCNSNSNSn/aSCB yeast culture fed with starter.
      • Huuskonen A.
      • Pesonen M.
      Does yeast (Saccharomyces cerevisiae) supplementation in calf starter modify feed intake and liveweight gain of dairy bull calves?.
      SCBNSNSNSn/aFed in MR. Low incidence of diarrhea.
      • He Z.X.
      • Ferlisi B.
      • Eckert E.
      • Brown H.E.
      • Aguilar A.
      • Steele M.A.
      Supplementing a yeast probiotic to pre-weaning Holstein calves: Feed intake, growth and fecal biomarkers of gut health..
      YCn/an/an/a+++Fed in starter. Increased rumen papillae length and increased villus height in all segments of the gastrointestinal tract.
      • Xiao J.X.
      • Alugongo G.M.
      • Chung R.
      • Dong S.Z.
      • Li S.L.
      • Yoon I.
      • Wu Z.H.
      • Cao Z.J.
      Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Ruminal fermentation, gastrointestinal morphology, and microbial community..
      YCNSNS++Fed in MR or MR and starter.

      Increased starter intake when fed in both MR and starter.
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      SCB+NS++n/aFed in MR. Lower incidence of severe diarrhea, and reduction of diarrhea treatments.
      • Villot C.
      • Ma T.
      • Renaud D.L.
      • Ghaffari M.H.
      • Gibson D.J.
      • Skidmore A.
      • Chevaux E.
      • Guan L.L.
      • Steele M.A.
      Saccharomyces cerevisiaeboulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves..
      YCNSNSNSn/aFed in starter. No effects on gut permeability in diarrheic calves.
      • Pisoni L.
      • Relling A.E.
      The effects of supplementing yeast fermentation products on gut permeability, hormone concentration, and growth in newborn dairy calves..
      1 YC = yeast culture; SC = Saccharomyces cerevisiae; SCB = Saccharomyces cerevisiae boulardii; LY = live yeast.
      2 Either positive (+) or negative (−) effects are noted with magnitude of change explained here: + = P ≥ 0.05 but ≤0.10, ++ = P ≤ 0.05, and +++ = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      3 MR = milk replacer.
      Figure 1
      Figure 1Summary of difference in ADG response between control and yeast-supplemented calves. Significant difference between control and prebiotic-supplemented calves from each study is indicated by * (P ≤ 0.05), with the average ADG difference across all studies indicated by the dotted line.
      The most significant effects of supplementation of yeast products during the preweaning phase have been reported when included in the diet of animals during stressful periods, promoting optimal maturation of the rumen microbiota and reducing risk of pathogen colonization (
      • Chaucheyras-Durand F.
      • Durand H.
      Probiotics in animal nutrition and health..
      ). Specifically, calves supplemented with a YC in starter (
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      ) or milk replacer (MR;
      • Brewer M.T.
      • Anderson K.L.
      • Yoon I.
      • Scott M.F.
      • Carlson S.A.
      Amelioration of salmonellosis in pre-weaned dairy calves fed Saccharomyces cerevisiae fermentation products in feed and milk replacer..
      ) that were orally challenged with Salmonella enterica had greater starter intake, ADG, and improved fecal consistency than control calves. Furthermore, calves supplemented with Saccharomyces cerevisiae boulardii (SCB) in MR, a subspecies of SC, had no drop in ADG when experiencing diarrhea compared with control calves that experienced a severe drop in growth performance during a diarrheic episode (
      • Villot C.
      • Ma T.
      • Renaud D.L.
      • Ghaffari M.H.
      • Gibson D.J.
      • Skidmore A.
      • Chevaux E.
      • Guan L.L.
      • Steele M.A.
      Saccharomyces cerevisiaeboulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves..
      ). When the same SCB strain was fed to healthy calves, no effects were observed on growth performance (
      • He Z.X.
      • Ferlisi B.
      • Eckert E.
      • Brown H.E.
      • Aguilar A.
      • Steele M.A.
      Supplementing a yeast probiotic to pre-weaning Holstein calves: Feed intake, growth and fecal biomarkers of gut health..
      ). In addition, calves with failed transfer of passive immunity supplemented with SC in the starter also had improved performance compared with control calves (
      • Galvão K.N.
      • Santos J.E.P.
      • Coscioni A.
      • Villaseñor M.
      • Sischo W.M.
      • Berge A.C.B.
      Effect of feeding live yeast products to calves with failure of passive transfer on performance and patterns of antibiotic resistance in fecal Escherichia coli..
      ).
      Yeast products have been found to aid in preventing microbial imbalances and enhance microbial activity in young ruminants. In a study with gnotobiotic lambs,
      • Chaucheyras-Durand F.
      • Fonty G.
      Influence of a probiotic yeast (Saccharomyces cerevisiae CNCM I-1077) on microbial colonization and fermentation in the rumen of newborn lamb..
      showed that inoculation with SC increased cellulolytic bacteria and fibrolytic enzymes, influenced the establishment of ciliated protozoa in the rumen, reduced lactate synthesis, and enhanced lactate utilization in vitro. This suggests that SC may stabilize rumen pH, an important factor for cellulolytic bacteria to thrive in the early rumen conditions. Several new studies have reinforced the concept that LY and YC supplementation can improve rumen development. Specifically, these studies have found that supplementing YC in MR or starter feed leads to an increase in Butyrivibrio and decreased Prevotella richness in rumen fluid, which resulted in increased butyrate production, papillae length (
      • Xiao J.X.
      • Alugongo G.M.
      • Chung R.
      • Dong S.Z.
      • Li S.L.
      • Yoon I.
      • Wu Z.H.
      • Cao Z.J.
      Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Ruminal fermentation, gastrointestinal morphology, and microbial community..
      ), and rumen weight (
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      ). However, others found that the supplementation of YC had no effect on rumen development or rumen pH (
      • Lesmeister K.E.
      • Heinrichs A.J.
      • Gabler M.T.
      Effects of supplemental yeast (Saccharomyces cerevisiae) culture on rumen development, growth characteristics, and blood parameters in neonatal dairy calves..
      ;
      • Xiao J.X.
      • Alugongo G.M.
      • Chung R.
      • Dong S.Z.
      • Li S.L.
      • Yoon I.
      • Wu Z.H.
      • Cao Z.J.
      Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Ruminal fermentation, gastrointestinal morphology, and microbial community..
      ). The differences observed between studies might be attributed to the type of yeast product fed, LY versus YC. In addition, the starter composition, specifically its fiber content, may influence results because diet composition affects the capacity of yeast products to modify rumen microbiota and, specifically, to stimulate fibrolytic bacteria (
      • Callaway E.S.
      • Martin S.A.
      Effects of a Saccharomyces cerevisiae culture on ruminal bacteria that utilize lactate and digest cellulose..
      ). Furthermore, one important factor to consider is the route of delivery of the product because it is more likely to have an effect on rumen function when delivered in the starter, as opposed to milk, which will bypass the rumen into the abomasum (
      • Hill S.R.
      • Hopkins B.A.
      • Davidson S.
      • Bolt S.M.
      • Diaz D.E.
      • Brownie C.
      • Brown T.
      • Huntington G.B.
      • Whitlow L.W.
      The addition of cottonseed hulls to the starter and supplementation of live yeast or mannanoligosaccharide in the milk for young calves..
      ).

      Effects on Health

      The most consistent response of yeast supplementation is associated with a reduction in the incidence and severity of diarrhea. Calves with failed transfer of passive immunity supplemented with SC had fewer days with diarrhea (
      • Galvão K.N.
      • Santos J.E.P.
      • Coscioni A.
      • Villaseñor M.
      • Sischo W.M.
      • Berge A.C.B.
      Effect of feeding live yeast products to calves with failure of passive transfer on performance and patterns of antibiotic resistance in fecal Escherichia coli..
      ). Furthermore, calves supplemented with YC had better fecal and overall health scores (
      • Magalhães V.J.A.
      • Susca F.
      • Lima F.S.
      • Branco A.F.
      • Yoon I.
      • Santos J.E.P.
      Effect of feeding yeast culture on performance, health, and immunocompetence of dairy calves..
      ;
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      ;
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      ), reduced rates of mortality and diarrhea cases, and a tendency to reduce the presence of a fever (
      • Magalhães V.J.A.
      • Susca F.
      • Lima F.S.
      • Branco A.F.
      • Yoon I.
      • Santos J.E.P.
      Effect of feeding yeast culture on performance, health, and immunocompetence of dairy calves..
      ). In addition, supplementation of SCB in MR was associated with a lower incidence of severe diarrhea and a tendency to reduce antibiotic treatments (
      • Villot C.
      • Ma T.
      • Renaud D.L.
      • Ghaffari M.H.
      • Gibson D.J.
      • Skidmore A.
      • Chevaux E.
      • Guan L.L.
      • Steele M.A.
      Saccharomyces cerevisiaeboulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves..
      ). Clearly, these beneficial effects on health result in increased profitability, even without improvements in growth performance, due to a reduction of rearing costs (
      • Magalhães V.J.A.
      • Susca F.
      • Lima F.S.
      • Branco A.F.
      • Yoon I.
      • Santos J.E.P.
      Effect of feeding yeast culture on performance, health, and immunocompetence of dairy calves..
      ).
      Supplementation of YC and LY have been shown to reduce diarrhea by preventing pathogenic bacteria from binding to intestinal epithelial cells or by modulating gut mucosal immunity (
      • Davis M.E.
      • Maxwell C.V.
      • Erf G.F.
      • Brown D.C.
      • Wistuba T.J.
      Dietary supplementation with phosphorylated mannans improves growth response and modulates immune function of weanling pigs..
      ;
      • Wang Z.
      • Guo Y.
      • Yuan J.
      • Zhang B.
      Effect of dietary b-1,3/1,6-glucan supplementation on growth performance, immune response and plasma prostglandin E2, growth hormone and ghrelin in weaning piglets..
      ). In addition, supplementation of YC has been shown to improve intestinal development with increased villus height and villus height-to-crypt ratio in all segments of the small intestine (
      • Xiao J.X.
      • Alugongo G.M.
      • Chung R.
      • Dong S.Z.
      • Li S.L.
      • Yoon I.
      • Wu Z.H.
      • Cao Z.J.
      Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Ruminal fermentation, gastrointestinal morphology, and microbial community..
      ), and increased villi length and crypt depth in the ileum (
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      ). The majority of the gut has only one layer of cells that separates the lumen of the intestine, and supplementation with YC could improve gut barrier integrity, leading to reduced infiltration of toxic luminal antigens and bacteria (
      • Kvidera S.K.
      • Dickson M.J.
      • Abuajamieh M.
      • Snider D.B.
      • Fernandez M.V.S.
      • Johnson J.S.
      • Keating A.F.
      • Gorden P.J.
      • Green H.B.
      • Schoenberg K.M.
      • Baumgard L.H.
      Intentionally induced intestinal barrier dysfunction causes inflammation, affects metabolism, and reduces productivity in lactating Holstein cows..
      ;
      • Liehr M.
      • Mereu A.
      • Pastor J.J.
      • Quintela J.C.
      • Staats S.
      • Rimbach G.
      • Ipharraguerre I.R.
      Olive oil bioactives protect pigs against experimentally-induced chronic inflammation independently of alterations in gut microbiota..
      ). However, in a recent study conducted by
      • Pisoni L.
      • Relling A.E.
      The effects of supplementing yeast fermentation products on gut permeability, hormone concentration, and growth in newborn dairy calves..
      , calves supplemented with YC showed no improvement in gut barrier function, possibly due to high diarrhea incidence during this particular study. Supplementation of SCB to calves from birth to one week of life has recently been shown to enhance production and release of secretory IgA in the ileum and colon with no effects on immune function at the systemic level (
      • Villot C.
      • Chen Y.
      • Pedgerachny K.
      • Chaucheyras-Durand F.
      • Chevaux E.
      • Skidmore A.
      • Guan L.L.
      • Steele M.A.
      Early supplementation of Saccharomyces cerevisiae boulardii CNCM I-1079 in newborn dairy calves increases IgA production in the intestine at 1 week of age..
      ). Secretory IgA contributes to the establishment of a healthy microbiota, shaping commensal microbiota, while limiting pathogen growth (
      • Pabst O.
      • Cerovic V.
      • Hornef M.
      Secretory IgA in the coordination of establishment and maintenance of the microbiota..
      ;
      • Mantis N.J.
      • Rol N.
      • Corthésy B.
      Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut..
      ). In a similar study with veal calves, the supplementation of SCB in milk increased butyric acid–producing bacteria and Lactobacillus, along with a reduction of Colinsella, a bacterium previously correlated with increased intestinal permeability (
      • Villot C.
      • Ma T.
      • Renaud D.L.
      • Ghaffari M.H.
      • Gibson D.J.
      • Skidmore A.
      • Chevaux E.
      • Guan L.L.
      • Steele M.A.
      Saccharomyces cerevisiaeboulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves..
      ). Furthermore, control diarrheic calves tended to have a greater relative abundance of Escherichia-Shigella. Last, supplementation of a YC has been shown to affect immune function at a systemic level, with improved humoral responses to a vaccination challenge (
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      ) and greater leukocyte counts and leukocyte-to-neutrophil counts following supplementation (
      • Harris T.L.
      • Liang Y.
      • Sharon K.P.
      • Sellers M.D.
      • Yoon I.
      • Scott M.F.
      • Carroll J.A.
      • Ballou M.A.
      Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium..
      ). Furthermore, neutrophil function was observed to be slightly improved (
      • Magalhães V.J.A.
      • Susca F.
      • Lima F.S.
      • Branco A.F.
      • Yoon I.
      • Santos J.E.P.
      Effect of feeding yeast culture on performance, health, and immunocompetence of dairy calves..
      ).
      Taken together, supplementation of yeast products has the ability to modulate gut microbial composition and enhance gut humoral immunity, effects that ultimately translate into a reduction in diarrhea and improvements in growth performance (
      • Abu-Tarboush H.M.
      • Al-Saiady M.Y.
      • Keir El-Din A.H.
      Evaluation of diet containing lactobacilli on performance, fecal coliform, and lactobacilli of young dairy calves..
      ;
      • Villot C.
      • Ma T.
      • Renaud D.L.
      • Ghaffari M.H.
      • Gibson D.J.
      • Skidmore A.
      • Chevaux E.
      • Guan L.L.
      • Steele M.A.
      Saccharomyces cerevisiaeboulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves..
      ).

      Bacterial-Based Probiotics

      Bacterial-based probiotics (BBP) are widely used in preweaned calves, mainly to improve gut health, reduce diarrhea, and improve growth (Table 2). Some commonly used BBP bacterium are Lactobacillus spp., Bifidobacterium spp., Bacillus spp., and Enterococcus spp. Supplementation of BBP have been shown to limit pathogen invasion by providing a stable, nutrient-rich environment for gut microbiota, thereby enhancing host digestive efficiency and mucosal immunity (
      • Uyeno Y.
      • Shigemori S.
      • Shimosato T.
      Effect of probiotics/prebiotics on cattle health and productivity..
      ;
      • Ma T.
      • Suzuki Y.
      • Guan L.L.
      Dissect the mode of action of probiotics in affecting host-microbial interactions and immunity in food producing animals..
      ).
      Table 2Summary of growth, health, and gut development responses in calf studies using different bacteria-based probiotics
      Lactic acid–producing bacteriaEffects in response to
      Either positive (+) or negative (−) effects are noted with magnitude of change explained here: ++ = P ≤ 0.05 and +++ = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      RemarkReference
      Weight

      gain
      Feed

      efficiency
      HealthGut

      development
      Multistrain LAB
      Multistrain LAB = probiotic consisting of a combination of Lactobacillus species.
      ++NS+++n/aFour experiments were performed with a multistrain Lactobacillus probiotic.
      • Timmerman H.M.
      • Mulder L.
      • Everts H.
      • Van Espen D.C.
      • Van Der Wal E.
      • Klaassen G.
      • Rouwers S.M.G.
      • Hartemink R.
      • Rombouts F.M.
      • Beynen A.C.
      Health and growth of veal calves fed milk replacers with or without probiotics..
      Multistrain LAB+++NS+++n/a3 lactic acid–bacteria strains.
      • Frizzo L.S.
      • Soto L.P.
      • Zbrun M.V.
      • Bertozzi E.
      • Sequeira G.
      • Armesto R.R.
      • Rosmini M.R.
      Lactic acid bacteria to improve growth performance in young calves fed milk replacer and spray-dried whey powder..
      Multistrain LABNSNSNSn/aFollow-up study with the same 3 lactic acid bacteria, no effects found.
      • Frizzo L.S.
      • Soto L.P.
      • Zbrun M.V.
      • Signorini M.L.
      • Bertozzi E.
      • Sequeira G.
      • Armesto R.R.
      • Rosmini M.R.
      Effect of lactic acid bacteria and lactose on growth performance and intestinal microbial balance of artificially reared calves..
      Multispecies BBP
      Multispecies BBP = probiotic consisting of a combination of more than one species of bacteria.
      n/an/a+++n/aMeta-analysis composed of 15 different experiments and 965 calves.
      • Signorini M.L.
      • Soto L.P.
      • Zbrun M.V.
      • Sequeira G.J.
      • Rosmini M.R.
      • Frizzo L.S.
      Impact of probiotic administration on the health and fecal microbiota of young calves: A meta-analysis of randomized controlled trials of lactic acid bacteria..
      Multistrain LABNS++++n/aMultispecies probiotic: Lactobacillus plantarum + Bacillus subtilis.
      • Zhang R.
      • Zhou M.
      • Tu Y.
      • Zhang N.F.
      • Deng K.D.
      • Ma T.
      • Diao Q.Y.
      Effect of oral administration of probiotics on growth performance, apparent nutrient digestibility and stress-related indicators in Holstein calves..
      Lactobacillus rhamnosus+++NS++++Increase VFA production and microbial diversity.
      • Zhang L.
      • Jiang X.
      • Liu X.
      • Zhao X.
      • Liu S.
      • Li Y.
      • Zhang Y.
      Growth, health, rumen fermentation, and bacterial community of Holstein calves fed Lactobacillus rhamnosus GG during the preweaning stage..
      Multispecies BBPNSn/a++n/aMultispecies probiotic bolus for the treatment of diarrhea.
      • Renaud D.L.
      • Kelton D.F.
      • Weese J.S.
      • Noble C.
      • Duffield T.F.
      Evaluation of a multispecies probiotic as a supportive treatment for diarrhea in dairy calves: A randomized clinical trial..
      Multispecies BBP+++n/an/an/aMultispecies probiotic. 96 heifer calves fed with automated feeder.
      • Cantor M.C.
      • Stanton A.L.
      • Combs D.K.
      • Costa J.H.C.
      Effect of milk feeding strategy and lactic acid probiotics on growth and behavior of dairy calves fed using an automated feeding system..
      Multistrain LAB++n/aNSn/aImproved final BW.
      • Bayatkouhsar J.
      • Tahmasebi A.M.
      • Naserian A.A.
      • Mokarram R.R.
      • Valizadeh R.
      Effects of supplementation of lactic acid bacteria on growth performance, blood metabolites and fecal coliform and lactobacilli of young dairy calves..
      Multispecies BBPn/an/a++n/aImproved cellular immunity.
      • Qadis A.Q.
      • Goya S.
      • Ikuta K.
      • Yatsu M.
      • Kimura A.
      • Nakanishi S.
      • Sato S.
      Effects of a bacteria-based probiotic on ruminal pH, volatile fatty acids and bacterial flora of Holstein calves..
      Bacillus spp.n/an/a++n/aBacillus-based probiotic provided in electrolytes to scouring calves. Improved cellular and innate immunity.
      • Novak K.N.
      • Davis E.
      • Wehnes C.A.
      • Shields D.R.
      • Coalson J.A.
      • Smith A.H.
      • Rehberger T.G.
      Effect of supplementation with an electrolyte containing a Bacillus-based direct-fed microbial on immune development in dairy calves..
      Lactobacillus acidophilusn/an/an/a++Improved gut bacterial community structure, reducing pathogenic load.
      • Fomenky B.E.
      • Do D.N.
      • Talbot G.
      • Chiquette J.
      • Bissonnette N.
      • Chouinard Y.P.
      • Lessard M.
      • Ibeagha-Awemu E.M.
      Direct-fed microbial supplementation influences the bacteria community composition of the gastrointestinal tract of pre- and post-weaned calves..
      Multispecies BBP++++NSn/aImproved milk intake, ADG, and feed efficiency.
      • Soto L.P.
      • Zbrun M.V.
      • Frizzo L.S.
      • Signorini M.L.
      • Sequeira G.J.
      • Rosmini M.R.
      Effects of bacterial inoculants in milk on the performance of intensively reared calves..
      Multispecies BBPNSNSNSn/a
      • Riddell J.B.
      • Gallegos A.J.
      • Harmon D.L.
      • Mcleod K.R.
      Addition of a Bacillus based probiotic to the diet of preruminant calves: Influence on growth, health, and blood parameters..
      Faecalibacterium prausnitzii++n/a++n/a
      • Foditsch C.
      • Van Vleck Pereira R.
      • Ganda E.K.
      • Gomez M.S.
      • Marques E.C.
      • Santin T.
      • Bicalho R.C.
      Oral administration of Faecalibacterium prausnitzii decreased the incidence of severe diarrhea and related mortality rate and increased weight gain in preweaned dairy heifers..
      Multispecies BBPNSNS++n/aJersey calves challenged with Salmonella Typhimurium. Reduction in inflammatory markers.
      • Liang Y.
      • Hudson R.E.
      • Ballou M.A.
      Supplementing neonatal Jersey calves with a blend of probiotic bacteria improves the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge..
      1 Either positive (+) or negative (−) effects are noted with magnitude of change explained here: ++ = P ≤ 0.05 and +++ = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      2 Multistrain LAB = probiotic consisting of a combination of Lactobacillus species.
      3 Multispecies BBP = probiotic consisting of a combination of more than one species of bacteria.

      Effects on Growth and Performance

      As observed for yeast supplementation, BBP supplementation resulted in inconsistent growth responses; however, in studies where positive growth responses were observed, this result usually occurred when calves experienced high diarrhea incidences (
      • Timmerman H.M.
      • Mulder L.
      • Everts H.
      • Van Espen D.C.
      • Van Der Wal E.
      • Klaassen G.
      • Rouwers S.M.G.
      • Hartemink R.
      • Rombouts F.M.
      • Beynen A.C.
      Health and growth of veal calves fed milk replacers with or without probiotics..
      ;
      • Frizzo L.S.
      • Soto L.P.
      • Zbrun M.V.
      • Bertozzi E.
      • Sequeira G.
      • Armesto R.R.
      • Rosmini M.R.
      Lactic acid bacteria to improve growth performance in young calves fed milk replacer and spray-dried whey powder..
      ;
      • Zhang L.
      • Jiang X.
      • Liu X.
      • Zhao X.
      • Liu S.
      • Li Y.
      • Zhang Y.
      Growth, health, rumen fermentation, and bacterial community of Holstein calves fed Lactobacillus rhamnosus GG during the preweaning stage..
      ; Table 2). Of the 11 studies evaluating the growth performance of BBP supplementation in preweaned calves, 5 showed a significant positive effect on ADG (Figure 2), whereas the remaining studies showed no effect. In a study conducted by
      • Frizzo L.S.
      • Soto L.P.
      • Zbrun M.V.
      • Signorini M.L.
      • Bertozzi E.
      • Sequeira G.
      • Armesto R.R.
      • Rosmini M.R.
      Effect of lactic acid bacteria and lactose on growth performance and intestinal microbial balance of artificially reared calves..
      , supplementation during the preweaning period of a probiotic composed of 3 lactic acid–producing bacteria (LAB) strains of bovine origin (Lactobacillus casei DSPV 318 T, Lactobacillus salivarius DSPV 315 T, and Pediococcus acidilactici DSPV 006 T) improved starter consumption and stimulated earlier starter consumption, resulting in enhanced growth performance. However, in a follow-up study evaluating the same multistrain probiotic, no differences were observed in growth parameters, demonstrating that the effects of probiotic supplementation are highly variable depending on environmental factors, pathogen load, and animal stress (
      • Frizzo L.S.
      • Soto L.P.
      • Zbrun M.V.
      • Signorini M.L.
      • Bertozzi E.
      • Sequeira G.
      • Armesto R.R.
      • Rosmini M.R.
      Effect of lactic acid bacteria and lactose on growth performance and intestinal microbial balance of artificially reared calves..
      ). In a multi-experimental study supplementing a combination of 5 Lactobacillus strains and Enterococcus faecium during the preweaning period, improved growth occurred during the first 2 wk of life, when animals experienced the highest incidence of digestive and respiratory disorders (
      • Timmerman H.M.
      • Mulder L.
      • Everts H.
      • Van Espen D.C.
      • Van Der Wal E.
      • Klaassen G.
      • Rouwers S.M.G.
      • Hartemink R.
      • Rombouts F.M.
      • Beynen A.C.
      Health and growth of veal calves fed milk replacers with or without probiotics..
      ), emphasizing that probiotic supplementation works best during periods of high stress.
      Figure 2
      Figure 2Summary of difference in ADG response between control calves and calves supplemented with lactic acid–producing bacteria. Significant difference between control and prebiotic-supplemented calves from each study is indicated by * (P ≤ 0.05), with the average ADG difference across all studies indicated by the dotted line.
      Although most have underscored the role of BBP on gut health, some reports have demonstrated an effect on modulation of rumen function. Lactobacillus rhamnosus supplementation for 6 wk during the preweaning period resulted in greater microbial diversity in the rumen, altering the dominant bacteria order and relative abundance of bacterial families present in ruminal fluid (
      • Zhang L.
      • Jiang X.
      • Liu X.
      • Zhao X.
      • Liu S.
      • Li Y.
      • Zhang Y.
      Growth, health, rumen fermentation, and bacterial community of Holstein calves fed Lactobacillus rhamnosus GG during the preweaning stage..
      ). As a result, total VFA production and microbial protein concentration were increased, and ruminal pH was reduced, compared with control calves. However, it is important to note that the improvements in rumen function might stem from increased starter intake rather than a direct effect of BBP on rumen development.

      Effects on Health

      In a meta-analysis conducted by
      • Signorini M.L.
      • Soto L.P.
      • Zbrun M.V.
      • Sequeira G.J.
      • Rosmini M.R.
      • Frizzo L.S.
      Impact of probiotic administration on the health and fecal microbiota of young calves: A meta-analysis of randomized controlled trials of lactic acid bacteria..
      including 15 trials and 965 calves, supplementation of LAB reduced the relative risk of diarrhea compared with control calves, although significant variability between studies was observed. Most of the variability observed was due to the type of milk fed to calves (whole milk or MR), with most of the positive responses coming from studies where calves were fed whole milk. The variability in response depending on the source of milk might be attributed to difference in pathogen load between MR and whole milk (
      • Selim S.A.
      • Cullor J.S.
      Number of viable bacteria and presumptive antibiotic residues in milk fed to calves on commercial dairies..
      ). In addition, the response was dependent on the type of inoculum, with only multistrain inocula having a positive effect on diarrhea levels.
      Some evidence demonstrates that the supplementation of BBP to calves with diarrhea could result in positive effects, as calves dosed with a multispecies bolus of Pediococcus acidilactici, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum had a faster resolution of diarrhea than calves that only received a placebo (
      • Renaud D.L.
      • Kelton D.F.
      • Weese J.S.
      • Noble C.
      • Duffield T.F.
      Evaluation of a multispecies probiotic as a supportive treatment for diarrhea in dairy calves: A randomized clinical trial..
      ). Furthermore,
      • Zhang L.
      • Jiang X.
      • Liu X.
      • Zhao X.
      • Liu S.
      • Li Y.
      • Zhang Y.
      Growth, health, rumen fermentation, and bacterial community of Holstein calves fed Lactobacillus rhamnosus GG during the preweaning stage..
      observed that supplementation of Lactobacillus rhamnosus was able to reduce fecal scores in preweaned Holstein calves. Several mechanisms have been proposed to explain the effects of BBP on resolution of diarrhea; however, their mode of action is not fully understood and most of the studies have been conducted with nonruminant animals. Furthermore, many of the effects are dependent on the specific bacterium family and strain used (
      • Newbold C.J.
      • Wallace R.J.
      • Chen X.B.
      • McIntosh F.M.
      Different strains of Saccharomyces cerevisiae differ in their effects on ruminal bacterial numbers in vitro and in sheep..
      ), and a combination of different bacteria can result in additive effects. The proposed mechanisms can be divided into 3 main categories: (1) direct interaction with host cells, (2) inhibition of pathogen growth, and (3) modulation of the host immune responses.
      Bacteria-based probiotics have been shown to directly interact with the host, modulating the gut immune response, leading to increased mucin production by goblet cells, enhancing barrier function by increasing tight junctions and promoting regulation of the inflammatory response (
      • Aragon G.
      • Graham D.B.
      • Borum M.
      • Doman D.B.
      Probiotic therapy for irritable bowel syndrome..
      ;

      Cazzola, M., T. A. Tompkins, and M. G. Matera. 2010 Immunomodulatory impact of a synbiotic in T(h)1 and T (h)2 models of infection. Ther. Adv. Respir. Dis. 4:259–270. 10.1177/1753465810379009.

      ;
      • Wang Q.
      • Lv L.
      • Jiang H.
      • Wang K.
      • Yan R.
      • Li Y.
      • Ye J.
      • Wu J.
      • Wang Q.
      • Bian X.
      • Yang L.
      • Jiang X.
      • Xie J.
      • Lu Y.
      • Shen J.
      • Li L.
      Lactobacillus helveticus R0052 alleviates liver injury by modulating gut microbiome and metabolome in d-galactosamine-treated rats..
      ). Lactic acid–producing bacteria can decrease gut pH by production of lactic acid, creating a more favorable condition for commensal microorganisms. Furthermore, BBP can produce and release antimicrobial peptides, such as bacteriocins in the gut lumen, or out-compete pathogens for nutrients or adhesion sites, thereby decreasing the risk of pathogen infections (
      • Isolauri E.
      • Sütas Y.
      • Kankaanpää P.
      • Arvilommi H.
      • Salminen S.
      Probiotics: Effects on immunity..
      ;
      • La Ragione R.M.
      • Woodward M.J.
      Competitive exclusion by Bacillus subtilis spores of Salmonella enterica serotype enteritidis and Clostridium perfringens in young chickens..
      ;
      • Servin A.L.
      Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens..
      ). Most of these findings come from monogastric or rodent models but might explain the phenotypic responses observed in LAB-supplemented calves.
      Last, the health benefits of LAB supplementation might not be only constrained to the lower gut, as LAB supplementation has been reported to modulate systemic immune function, improving humoral and cell-mediated immunity as indicated by increased T and B cell activity and lower cortisol levels in blood (
      • Qadis A.Q.
      • Goya S.
      • Ikuta K.
      • Yatsu M.
      • Kimura A.
      • Nakanishi S.
      • Sato S.
      Effects of a bacteria-based probiotic on ruminal pH, volatile fatty acids and bacterial flora of Holstein calves..
      ;
      • Zhang R.
      • Zhou M.
      • Tu Y.
      • Zhang N.F.
      • Deng K.D.
      • Ma T.
      • Diao Q.Y.
      Effect of oral administration of probiotics on growth performance, apparent nutrient digestibility and stress-related indicators in Holstein calves..
      ). In a recent study conducted by
      • Liang Y.
      • Hudson R.E.
      • Ballou M.A.
      Supplementing neonatal Jersey calves with a blend of probiotic bacteria improves the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge..
      , calves challenged with Salmonella Typhimurium and fed a BBP blend of Lactobacillus casei and Enterococcus faecium strains had reductions in blood inflammatory markers and a reduction in rectal temperature when compared with control calves that did not receive the probiotic blend. These results showing that BBP supplementation can affect cell function in distant tissues outside the gastrointestinal tract are promising; however, more studies are required to better understand how probiotic–host interaction at the gut mucosal surface translate into systemic modulation of immune function of the growing calf.

      Conclusion

      Probiotic supplementation seems to offer some beneficial effects that promote animal growth while reducing digestive disorders. However, we observed significant variability among studies, and it appears that most of the beneficial effects are observed when supplemented during stressful conditions. Part of the variation between studies can be attributed to differences in environmental and management factors between studies such as the type of milk fed (whole milk vs. MR), pasteurization, and the incidence of disease and pathogen load on the farm (
      • Klein-Jöbstl D.
      • Iwersen M.
      • Drillich M.
      Farm characteristics and calf management practices on dairy farms with and without diarrhea: A case-control study to investigate risk factors for calf diarrhea..
      ). Furthermore, even if BBP and yeast supplementation had similar effects in terms of diarrhea resolution and growth parameters, the underlying mechanisms of action seem to differ. Further investigation is needed in young ruminants to understand the phenotypical responses observed to better formulate and target probiotic supplementation strategies. Yeast supplementation showed improvements in starter intake, possibly as a function of improved fiber digestion, and mild improvement in rumen development in early life. Furthermore, the route of delivery seems to be critical and most of the effects on starter intake are observed when fed in starter rather than in milk. This suggests that it might be advantageous to include them in feeding programs to promote starter intake, especially when animals are weaned early. In the case of BBP supplementation, most of the effects observed appear to be postruminal, having marked effects on lower gut health and reducing diarrhea cases.
      Last, the mode of action of BBP might be species and strain specific; therefore, supplementation of multispecies and multistrain BBP typically result in improved beneficial effects on the host due to a combination of their different effects. Further research is needed to better formulate probiotic products that can harvest the different metabolic activities of multispecies and multistrain probiotics to the benefit of the host.

      PREBIOTICS

      Prebiotics are defined as substrates that are selectively used by host microorganisms, conferring a health benefit to the host (
      • Markowiak P.
      • Śliżewska K.
      Effects of probiotics, prebiotics, and synbiotics on human health..
      ). Compared with probiotics, prebiotics are nonviable substrates that serve as nutrients for healthy microbes (e.g., LAB and Bifidobacteria) and can be used to defend against pathogens and modulate the immune system (
      • Gibson G.R.
      • Hutkins R.
      • Sanders M.E.
      • Prescott S.L.
      • Reimer R.A.
      • Salminen S.J.
      • Scott K.
      • Stanton C.
      • Swanson K.S.
      • Cani P.D.
      • Verbeke K.
      • Reid G.
      Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics..
      ). In young ruminants, prebiotics have been shown to have effects on growth, feed efficiency (FE), and health. The most commonly used prebiotics fed to calves are oligosaccharides (OS), which comprise the major prebiotic group, and β-glucans. Unlike probiotics, the mechanisms by which prebiotics exert their effect have been relatively unexplored in ruminant models. However, potential mechanisms have been suggested in monogastrics, including changes in intestinal microbiota, immunomodulation, nutrient absorption effects, and pathogen inhibition (
      • Markowiak P.
      • Śliżewska K.
      Effects of probiotics, prebiotics, and synbiotics on human health..
      ). It is worth noting that although “prebiotics” has been a term used for the past few decades, the definition of what constitutes a prebiotic has evolved. In recent years, there has been an effort to better characterize metabolites and cell-wall components derived from either living or nonliving microbes with particular interest in the term “postbiotic” (reviewed by
      • Aguilar-Toala J.E.
      • Garcia-Varela R.
      • Garcia H.S.
      • Mata-Haro V.
      • Gonzalez-Cordova A.F.
      • Vallejo-Cordoba B.
      • Hernandez-Mendoza A.
      Postbiotics: An evolving term within the functional foods field..
      ). For the sake of clarity and familiarity with the subject, we have decided to use the term “prebiotic” throughout this review with the knowledge that other definitions may also be appropriate for these compounds.

      Fructooligosaccharides

      Fructooligosaccharides (FOS) are a family of OS consisting of one glucose molecule linked to several fructose molecules via β-(2–1) or β-(2–6) bonds. Some variations of FOS include inulin and short-chain FOS (scFOS), which are found in vegetables, such as onions and Jerusalem artichokes, or produced via transfructosylation of sucrose via β-fructosidase, respectively (

      Wang, J., P. Sporns, and N. H. Low. 1999. Analysis of food oligosaccharides using MALDI-MS: Quantification of fructooligosaccharides. J. Agric. Food Chem. 47:1549–1557. 10.1021/jf9809380.

      ;

      Singh, S. P., J. S. Jadaun, L. K. Narnoliya, and A. Pandey. 2017. Prebiotic oligosaccharides: Special focus on fructooligosaccharides, its biosynthesis and bioactivity. Appl. Biochem. Biotechnol. 183:613–635. 10.1007/s12010-017-2605-2.

      ). The use of FOS as a prebiotic is similar to other prebiotics, as it has been shown to support growth of LAB (
      • Sghir A.
      • Chow J.M.
      • Mackie R.I.
      Continuous culture selection of bifidobacteria and lactobacilli from human faecal samples using fructooligosaccharide as selective substrate..
      ;
      • Menne E.
      • Guggenbuhl N.
      • Roberfroid M.
      Fn-type chicory inulin hydrolysate has a prebiotic effect in humans..
      ). However, FOS has the unique ability to prevent the adhesion of E. coli and Salmonella to the intestinal epithelium (

      Hartemink, R., K. M. Van Laere, and F. M. Rombouts. 1997. Growth of enterobacteria on fructo-oligosaccharides. J. Appl. Microbiol. 83:367–374. 10.1046/j.1365-2672.1997.00239.x.

      ;

      Benyacoub, J., F. Rochat, K. Y. Saudan, I. Rochat, N. Antille, C. Cherbut, T. von der Weid, E. J. Schiffrin, and S. Blum. 2008. Feeding a diet containing a fructooligosaccharide mix can enhance Salmonella vaccine efficacy in mice. J. Nutr. 138:123–129. 10.1093/jn/138.1.123.

      ) and has been shown to reduce E. coli growth when added to a coculture with LAB (
      • Vongsa R.A.
      • Minerath R.A.
      • Busch M.A.
      • Tan J.
      • Koenig D.W.
      In vitro evaluation of nutrients that selectively confer a competitive advantage to lactobacilli..
      ).

      Effects on Growth and Performance

      The effects of supplementing FOS on growth are summarized in Table 3. Four of the 7 studies that measured growth showed an increase in growth, whereas 3 showed no differences (Figure 3). With respect to FE, 2 of the 4 studies measuring FE observed an improvement in calves supplemented with FOS (or a FOS variation) compared with controls, whereas a decrease in FE was also found in another study (Table 3). There is a lack of data throughout these studies measuring the effects of FOS on LAB or other potential beneficial bacteria throughout the gut; however, differing results were found with respect to gut development.

      Grand, E., F. Respondek, C. Martineau, J. Detilleux, and G. Bertrand. 2013. Effects of short-chain fructooligosaccharides on growth performance of preruminant veal calves. J. Dairy Sci. 96:1094–1101. 10.3168/jds.2011-4949.

      fed scFOS at 6 g/d and found a tendency for increased fecal butyrate concentrations compared with controls, which may be a sign of enhanced gut development (

      Gorka, P., Z. M. Kowalski, R. Zabielski, and P. Guilloteau. 2018. Invited review: Use of butyrate to promote gastrointestinal tract development in calves. J. Dairy Sci. 101:4785–4800. 10.3168/jds.2017-14086.

      ). Conversely,

      Masanetz, S., N. Wimmer, C. Plitzner, E. Limbeck, W. Preissinger, and M. W. Pfaffl. 2010. Effects of inulin and lactulose on the intestinal morphology of calves. Animal 4:739–744. 10.1017/S1751731109991728.

      found tendencies for shorter villi in the jejunum and less proliferation in the ileum of calves supplemented with 2% inulin in their MR, suggesting decreased intestinal development compared with control calves. Interestingly, both

      Masanetz, S., N. Wimmer, C. Plitzner, E. Limbeck, W. Preissinger, and M. W. Pfaffl. 2010. Effects of inulin and lactulose on the intestinal morphology of calves. Animal 4:739–744. 10.1017/S1751731109991728.

      and

      Grand, E., F. Respondek, C. Martineau, J. Detilleux, and G. Bertrand. 2013. Effects of short-chain fructooligosaccharides on growth performance of preruminant veal calves. J. Dairy Sci. 96:1094–1101. 10.3168/jds.2011-4949.

      observed an improvement in FE, which suggests that regardless of gut development, the inclusion of FOS in the diet may allow more energy to be absorbed, contributing to more efficient calf growth.
      Table 3Summary of growth, health, and gut development responses in calf studies using different prebiotic supplements
      Prebiotics used
      The term listed is how the prebiotic was described in the manuscript, but the grouping in the table is based on structure similarities. CO = cellooligosaccharides; scFOS = short-chain fructooligosaccharides; GOS = galactooligosaccharides; CWS = condensed whey solubles that are created enzymatically and contain a variety of di- and oligosaccharide compounds (e.g., galactosyl-lactose); MOS = mannanoligosaccharides; YCW = yeast cell wall (described as mannanoligosaccharide product in the paper); MFOS = mannan and fructooligosaccharides; BC = β-cyclodextrin; SRB = heat-stabilized rice bran; BG = β-glucans.
      Effects in response to
      Either positive (+) or negative (−) effects are noted with magnitude of change explained here: 1 = P ≥ 0.05 but ≤0.10, 2 = P ≤ 0.05, and 3 = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      RemarkReference
      Weight

      gain
      Feed

      efficiency
      HealthGut

      development
      Oligosaccharides
      CO++++NSn/aFeed efficiency was improved after weaning.
      • Hasunuma T.
      • Kawashima K.
      • Nakayama H.
      • Murakami T.
      • Kanagawa H.
      • Ishii T.
      • Akiyama K.
      • Yasuda K.
      • Terada F.
      • Kushibiki S.
      Effect of cellooligosaccharide or synbiotic feeding on growth performance, fecal condition and hormone concentrations in Holstein calves..
      CONSn/an/an/a

      Uyeno, Y., K. Kawashima, T. Hasunuma, W. Wakimoto, M. Noda, S. Nagashima, K. Akiyama, M. Tabata, and S. Kushibiki. 2013. Effects of cellooligosaccharide or a combination of cellooligosaccharide and live Clostridium butyricum culture on performance and intestinal ecology in Holstein calves fed milk or milk replacer. Livest. Sci. 153:88–93. 10.1016/j.livsci.2013.02.005.

      CO+n/an/an/aBeef calves weaned between 3 and 4 mo.
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      scFOS+n/an/an/a
      • Kaufhold J.
      • Hammon H.M.
      • Blum J.W.
      Fructo-oligosaccharide supplementation: Effects on metabolic, endocrine and hematological traits in veal calves..
      Inulin+, NSNS, NS++, ++n/a, n/a2 experiments were performed where FOS was fed in milk replacer.

      Quigley, J. D., 3rd, C. J. Kost, and T. A. Wolfe. 2002. Effects of spray-dried animal plasma in milk replacers or additives containing serum and oligosaccharides on growth and health of calves. J. Dairy Sci. 85:413–421. 10.3168/jds.S0022-0302(02)74089-7.

      InulinNS+n/a–, –Inulin calves tended to have decreased jejunal villus lengths and proliferative ileal cells.

      Masanetz, S., N. Wimmer, C. Plitzner, E. Limbeck, W. Preissinger, and M. W. Pfaffl. 2010. Effects of inulin and lactulose on the intestinal morphology of calves. Animal 4:739–744. 10.1017/S1751731109991728.

      scFOSNS+n/an/a

      Grand, E., F. Respondek, C. Martineau, J. Detilleux, and G. Bertrand. 2013. Effects of short-chain fructooligosaccharides on growth performance of preruminant veal calves. J. Dairy Sci. 96:1094–1101. 10.3168/jds.2011-4949.

      Inulin, serum proteins++++, – –+++n/aFeed efficiency was increased in FOS calves in wk 1 but decreased in wk 2–4.

      Pineda, A., M. A. Ballou, J. M. Campbell, F. C. Cardoso, and J. K. Drackley. 2016. Evaluation of serum protein-based arrival formula and serum protein supplement (gammulin) on growth, morbidity, and mortality of stressed (transport and cold) male dairy calves. J. Dairy Sci. 99:9027–9039. 10.3168/jds.2016-11237.

      scFOSNSn/an/an/a

      Pantophlet, A. J., M. S. Gilbert, J. J. G. C. van den Borne, W. J. J. Gerrits, M. G. Priebe, and R. J. Vonk. 2016. Insulin sensitivity in calves decreases substantially during the first 3 months of life and is unaffected by weaning or fructo-oligosaccharide supplementation. J. Dairy Sci. 99:7602–7611. 10.3168/jds.2016-11084.

      Inulin+++n/an/an/a
      • Jonova S.
      • Ilgaza A.
      • Grinfelde I.
      • Zolovs M.
      Impact of the flour of Jerusalem artichoke on the production of methane and carbon dioxide and growth performance in calves..
      Galactosyl-lactose++++n/a

      Quigley, J. D., 3rd, J. J. Drewry, L. M. Murray, and S. J. Ivey. 1997. Body weight gain, feed efficiency, and fecal scores of dairy calves in response to galactosyl-lactose or antibiotics in milk replacers. J. Dairy Sci. 80:1751–1754. 10.3168/jds.S0022-0302(97)76108-3.

      GOS– – –n/a– – –++Jejunal villus length and colon crypt depth were increased in GOS calves.

      Castro, J. J., A. Gomez, B. A. White, H. J. Mangian, J. R. Loften, and J. K. Drackley. 2016. Changes in the intestinal bacterial community, short-chain fatty acid profile, and intestinal development of preweaned Holstein calves. 1. Effects of prebiotic supplementation depend on site and age. J. Dairy Sci. 99:9682–9702. 10.3168/jds.2016-11006.

      CWSNS– –+++n/aG:F was reduced after weaning in CWS-fed calves, whereas mean fecal scores after weaning were decreased in CWS calves.

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      MOSNSn/a+++n/a
      • Heinrichs A.J.
      • Jones C.M.
      • Heinrichs B.S.
      Effects of mannan oligosaccharide or antibiotics in neonatal diets on health and growth of dairy calves..
      MOSNS–, – –NSn/a
      • Terre M.
      • Calvo M.A.
      • Adelantado C.
      • Kocher A.
      • Bach A.
      Effects of mannan oligosaccharides on performance and microogranism fecal counts of calves following an ehnahced-growth feeding program..
      MOSNSNS++NSJersey calves had increased BW in wk 9; both Jersey and Holstein calves had decreased mean fecal scores.
      • Hill S.R.
      • Hopkins B.A.
      • Davidson S.
      • Bolt S.M.
      • Diaz D.E.
      • Brownie C.
      • Brown T.
      • Huntington G.B.
      • Whitlow L.W.
      The addition of cottonseed hulls to the starter and supplementation of live yeast or mannanoligosaccharide in the milk for young calves..
      MOSNSn/a++n/a

      Morrison, S. J., S. Dawson, and A. F. Carson. 2010. The effects of mannan oligosaccharide and streptococcus faecium addition to milk replacer on calf health and performance. Livest. Sci. 131:292–296. 10.1016/j.livsci.2010.04.002.

      MOSNSn/a++n/aMean fecal score was decreased in MOS-supplemented calves during wk 1.
      • da Silva J.T.
      • Bittar C.M.M.
      • Ferreira L.S.
      Evaluation of mannan-oligosaccharides offered in milk replacers or calf starters and their effect on performance and rumen development of dairy calves..
      MOS+++++++++n/aCrossbred Holstein calves were used.
      • Ghosh S.
      • Mehla R.K.
      Influence of dietary supplementation of prebiotics (mannanoligosaccharide) on the performance of crossbred calves..
      MOS++n/an/an/aIncreased ADG in wk 7 and 8 of trial.

      Roodposhti, P. M., and N. Dabiri. 2012. Effects of probiotic and prebiotic on average daily gain, fecal shedding of Escherichia coli, and immune system status in newborn female calves. Asian Australas. J. Anim. 25:1255–1261. 10.5713/ajas.2011.11312.

      MOS+NS++n/a
      • Heinrichs A.J.
      • Heinrichs B.S.
      • Jones C.M.
      Fecal and saliva IgA secretion when feeding a concentrated mannan oligosaccharide to neonatal dairy calves..
      MOSNSNSNSn/a
      • Kara C.
      • Cihan H.
      • Temizel M.
      • Catik S.
      • Meral Y.
      • Orman A.
      • Yibar A.
      • Gencoglu H.
      Effects of supplemental mannanoligosaccharides on growth performance, faecal characteristics and health in dairy calves..
      MOS, probiotics, fibrolytic enzymesNSNS+++n/a

      Marcondes, M. I., T. R. Pereira, J. C. Chagas, E. A. Filgueiras, M. M. Castro, G. P. Costa, A. L. Sguizzato, and R. D. Sainz. 2016. Performance and health of Holstein calves fed different levels of milk fortified with symbiotic complex containing pre- and probiotics. Trop. Anim. Health Prod. 48:1555–1560. 10.1007/s11250-016-1127-1.

      YCWNSNS++n/aMean fecal score was decreased in YCW-supplemented calves during wk 3.

      Froehlich, K. A., K. W. Abdelsalam, C. Chase, J. Koppien-Fox, and D. P. Casper. 2017. Evaluation of essential oils and prebiotics for newborn dairy calves. J. Anim. Sci. 95:3772–3782. 10.2527/jas.2017.1601

      MOSNSn/an/a+++Rumen papillae and jejunal villus lengths were increased in MOS calves.

      Alves Costa, N., A. P. Pansani, C. H. de Castro, D. Basile Colugnati, C. H. Xaxier, K. C. Guimaraes, L. Antas Rabelo, V. Nunes-Souza, L. F. Souza Caixeta, and R. Nassar Ferreira. 2019. Milk restriction or oligosaccharide supplementation in calves improves compensatory gain and digestive tract development without changing hormone levels. PLoS One. 14:e0214626. 10.1371/journal.pone.0214626.

      MFOSNSn/an/aNS

      Alves Costa, N., A. P. Pansani, C. H. de Castro, D. Basile Colugnati, C. H. Xaxier, K. C. Guimaraes, L. Antas Rabelo, V. Nunes-Souza, L. F. Souza Caixeta, and R. Nassar Ferreira. 2019. Milk restriction or oligosaccharide supplementation in calves improves compensatory gain and digestive tract development without changing hormone levels. PLoS One. 14:e0214626. 10.1371/journal.pone.0214626.

      Unknown or other
      BCNSn/aNSn/a

      Castro-Hermida, J. A., Y. Gonzalez-Losada, F. Freire-Santos, M. Mezo-Menendez, and E. Ares-Mazas. 2001. Evaluation of beta-cyclodextrin against natural infections of cryptosporidiosis in calves. Vet. Parasitol. 101:85–89. 10.1016/s0304-4017(01)00505-2.

      Commercial productNSNSNSn/aIt contained fermentation products of Lactobacillus gasseri OLL2716 and Propionibacterium freudenreichii ET-3.
      • Heinrichs A.J.
      • Jones C.M.
      • Elizondo-Salazar J.A.
      • Terrill S.J.
      Effects of a prebiotic supplement on health of neonatal dairy calves..
      LactuloseNSNSn/a++, +Lactulose calves had increased jejunal villus lengths and tended to have more proliferative ileal cells.

      Masanetz, S., N. Wimmer, C. Plitzner, E. Limbeck, W. Preissinger, and M. W. Pfaffl. 2010. Effects of inulin and lactulose on the intestinal morphology of calves. Animal 4:739–744. 10.1017/S1751731109991728.

      Commercial productNS+NSn/a

      Quezada-Mendoza, V. C., A. J. Heinrichs, and C. M. Jones. 2011. The effects of a prebiotic supplement (prebio support) on fecal and salivary iga in neonatal dairy calves. Livest. Sci. 142:222–228. 10.1016/j.livsci.2011.07.015.

      SRBNSn/an/a
      • Velasquez-Munoz A.
      • Manriquez D.
      • Paudyal S.
      • Han H.
      • Callan R.
      • Ryan E.P.
      • Pinedo P.
      Effect of prebiotic supplementation with stabilized rice bran in milk of pre-weaned organic Holstein calves..
      Polysaccharides
      BG, ascorbic acidNSNSn/an/a

      Eicher, S. D., I. V. Wesley, V. K. Sharma, and T. R. Johnson. 2010. Yeast cell-wall products containing beta-glucan plus ascorbic acid affect neonatal bos taurus calf leukocytes and growth after a transport stressor. J. Anim. Sci. 88:1195–1203. 10.2527/jas.2008-1669.

      BG
      A hydrolyzed yeast product was used in this study containing 10–12% β-glucan.
      NSNS++n/aMean fecal score was decreased in BG-supplemented calves during wk 3.
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      Kraft pulpNSn/an/an/aBeef calves weaned between 3 and 4 mo.
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      BG– – –n/an/a

      McDonnell, R. P., J. V. O’Doherty, B. Earley, A. M. Clarke, and D. A. Kenny. 2019. Effect of supplementation with n-3 polyunsaturated fatty acids and/or beta-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods. J. Anim. Sci. Biotechnol. 10:7. 10.1186/s40104-019-0317-x.

      1 The term listed is how the prebiotic was described in the manuscript, but the grouping in the table is based on structure similarities. CO = cellooligosaccharides; scFOS = short-chain fructooligosaccharides; GOS = galactooligosaccharides; CWS = condensed whey solubles that are created enzymatically and contain a variety of di- and oligosaccharide compounds (e.g., galactosyl-lactose); MOS = mannanoligosaccharides; YCW = yeast cell wall (described as mannanoligosaccharide product in the paper); MFOS = mannan and fructooligosaccharides; BC = β-cyclodextrin; SRB = heat-stabilized rice bran; BG = β-glucans.
      2 Either positive (+) or negative (−) effects are noted with magnitude of change explained here: 1 = P ≥ 0.05 but ≤0.10, 2 = P ≤ 0.05, and 3 = P ≤ 0.01. An NS denotes no change, and an n/a denotes the variable was not measured.
      3 A hydrolyzed yeast product was used in this study containing 10–12% β-glucan.
      Figure 3
      Figure 3Summary of difference in ADG response between control and prebiotic-supplemented calves. Significant difference between control and prebiotic-supplemented calves from each study is indicated by * (P ≤ 0.05), with the average ADG difference across all studies indicated by the dotted line.

      Effects on Health

      Only 2 studies measured the health effects of feeding FOS, with both reporting positive results (Table 3).

      Quigley, J. D., 3rd, C. J. Kost, and T. A. Wolfe. 2002. Effects of spray-dried animal plasma in milk replacers or additives containing serum and oligosaccharides on growth and health of calves. J. Dairy Sci. 85:413–421. 10.3168/jds.S0022-0302(02)74089-7.

      , who fed FOS with bovine serum sprayed on MR, reported a tendency for reductions in fecal scores, scouring days, days offering electrolytes, and antibiotic treatments compared with control calves.

      Pineda, A., M. A. Ballou, J. M. Campbell, F. C. Cardoso, and J. K. Drackley. 2016. Evaluation of serum protein-based arrival formula and serum protein supplement (gammulin) on growth, morbidity, and mortality of stressed (transport and cold) male dairy calves. J. Dairy Sci. 99:9027–9039. 10.3168/jds.2016-11237.

      found lower mortality, fewer antibiotic treatments, and lower mean fecal scores in inulin-supplemented compared with control calves. Interestingly,

      Pineda, A., M. A. Ballou, J. M. Campbell, F. C. Cardoso, and J. K. Drackley. 2016. Evaluation of serum protein-based arrival formula and serum protein supplement (gammulin) on growth, morbidity, and mortality of stressed (transport and cold) male dairy calves. J. Dairy Sci. 99:9027–9039. 10.3168/jds.2016-11237.

      also saw a decrease in respiratory scores in inulin-supplemented calves. It is difficult to interpret immune parameter data when it is not coupled with health records; however, 2 studies evaluated the immunity of calves supplemented with FOS.
      • Kaufhold J.
      • Hammon H.M.
      • Blum J.W.
      Fructo-oligosaccharide supplementation: Effects on metabolic, endocrine and hematological traits in veal calves..
      supplemented FOS in whole milk or MR and observed an increase in total leukocytes during wk 12 and an increase in eosinophils during wk 13 in blood compared with control calves. As recent evidence has demonstrated, eosinophils communicate in both the innate and adaptive immune system (

      Wen, T., and M. E. Rothenberg. 2016. The regulatory function of eosinophils. Microbiol. Spectr. 4. 10.1128/microbiolspec.MCHD-0020-2015.

      ); thus, the increase in eosinophils may improve the calf’s ability to respond if an infection occurs.

      Masanetz, S., W. Preissinger, H. H. Meyer, and M. W. Pfaffl. 2011. Effects of the prebiotics inulin and lactulose on intestinal immunology and hematology of preruminant calves. Animal 5:1099–1106. 10.1017/S1751731110002521.

      found that calves supplemented with 2% inulin had a decreased number of thrombocytes and an increase in the gene PECAM1, which is important for transmigration of leukocytes (

      Wakelin, M. W., M. J. Sanz, A. Dewar, S. M. Albelda, S. W. Larkin, N. Boughton-Smith, T. J. Williams, and S. Nourshargh. 1996. An anti-platelet-endothelial cell adhesion molecule-1 antibody inhibits leukocyte extravasation from mesenteric microvessels in vivo by blocking the passage through the basement membrane. J. Exp. Med. 184:229–239. 10.1084/jem.184.1.229.

      ).
      The utility of FOS based on the current data seems to support the role of FOS as an effective prebiotic for growth, FE, and health in calves. While certain studies observed no differences, which would suggest utilizing FOS is unnecessary, it is worth noting that the true benefit of FOS (or other prebiotics) may not be recognized until a calf is in a state of distress or illness, which has not been the focus of many studies utilizing FOS in calf diets.

      Galactooligosaccharides

      Galactooligosaccharides (GOS) are created from lactose and contain repeating galactose molecules via β-(1–3) and β-(1–4) linkages. More specifically, GOS are typically created at scale from β-galactosidase–treated whey permeate that has been filtered from whey leftovers during cheese manufacturing (

      Vera, C., A. Cordova, C. Aburto, C. Guerrero, S. Suarez, and A. Illanes. 2016. Synthesis and purification of galacto-oligosaccharides: State of the art. World J. Microbiol. Biotechnol. 32:197. 10.1007/s11274-016-2159-4.

      ). Galactosyl-lactose (GL) is similar to GOS in structure, in that it is a trisaccharide containing 2 galactose and 1 glucose molecule. The usefulness of GOS stems from its similarity to OS found in milk, which has been shown to promote beneficial bacteria in the lower gut (
      • Malmuthuge N.
      • Chen Y.
      • Liang G.
      • Goonewardene L.A.
      • Guan L.L.
      Heat-treated colostrum feeding promotes beneficial bacteria colonization in the small intestine of neonatal calves..
      ), and thus, it is used as a prebiotic in calf diets.

      Effects on Growth and Performance

      Mixed results on growth and FE were found in the 3 studies that evaluated GOS/GL products. One study found an increase in growth and tendency for improved FE (

      Quigley, J. D., 3rd, J. J. Drewry, L. M. Murray, and S. J. Ivey. 1997. Body weight gain, feed efficiency, and fecal scores of dairy calves in response to galactosyl-lactose or antibiotics in milk replacers. J. Dairy Sci. 80:1751–1754. 10.3168/jds.S0022-0302(97)76108-3.

      ), whereas the others found either decreased growth (

      Castro, J. J., A. Gomez, B. A. White, H. J. Mangian, J. R. Loften, and J. K. Drackley. 2016. Changes in the intestinal bacterial community, short-chain fatty acid profile, and intestinal development of preweaned Holstein calves. 1. Effects of prebiotic supplementation depend on site and age. J. Dairy Sci. 99:9682–9702. 10.3168/jds.2016-11006.

      ) or FE (

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      ) in supplemented calves (Table 3).

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      fed a condensed whey soluble (CWS) product to calves before and after weaning, which increased di- and oligosaccharide concentrations (including GL), and increased starter and total DMI overall. However, these differences did not translate to higher levels of growth and supplemented calves had reduced FE postweaning. The exact amount of GOS fed in the CWS in

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      is unclear, but it appears that

      Quigley, J. D., 3rd, J. J. Drewry, L. M. Murray, and S. J. Ivey. 1997. Body weight gain, feed efficiency, and fecal scores of dairy calves in response to galactosyl-lactose or antibiotics in milk replacers. J. Dairy Sci. 80:1751–1754. 10.3168/jds.S0022-0302(97)76108-3.

      fed the lowest amount of a GOS supplement (GL) at 1% DM of MR, whereas the other studies likely fed the GOS at 3.35% DM or greater, which could indicate that high levels of GOS may have a negative effect on calf growth. However,

      Castro, J. J., A. Gomez, B. A. White, H. J. Mangian, J. R. Loften, and J. K. Drackley. 2016. Changes in the intestinal bacterial community, short-chain fatty acid profile, and intestinal development of preweaned Holstein calves. 1. Effects of prebiotic supplementation depend on site and age. J. Dairy Sci. 99:9682–9702. 10.3168/jds.2016-11006.

      did measure an increase in jejunal villi length and colon crypt depth in GOS-supplemented calves, suggesting an overall improvement in intestinal health, despite decreased growth, even when GOS was supplemented at higher levels.

      Effects on Health

      Of the studies that evaluated health, 2 found that health was improved in supplemented calves (

      Quigley, J. D., 3rd, J. J. Drewry, L. M. Murray, and S. J. Ivey. 1997. Body weight gain, feed efficiency, and fecal scores of dairy calves in response to galactosyl-lactose or antibiotics in milk replacers. J. Dairy Sci. 80:1751–1754. 10.3168/jds.S0022-0302(97)76108-3.

      ;

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      ), whereas one reported negative results (

      Castro, J. J., A. Gomez, B. A. White, H. J. Mangian, J. R. Loften, and J. K. Drackley. 2016. Changes in the intestinal bacterial community, short-chain fatty acid profile, and intestinal development of preweaned Holstein calves. 1. Effects of prebiotic supplementation depend on site and age. J. Dairy Sci. 99:9682–9702. 10.3168/jds.2016-11006.

      ; Table 3).

      Castro, J. J., A. Gomez, B. A. White, H. J. Mangian, J. R. Loften, and J. K. Drackley. 2016. Changes in the intestinal bacterial community, short-chain fatty acid profile, and intestinal development of preweaned Holstein calves. 1. Effects of prebiotic supplementation depend on site and age. J. Dairy Sci. 99:9682–9702. 10.3168/jds.2016-11006.

      found increased LAB in the colon of GOS-fed calves compared with control; however, this difference was short lived and did not translate to improvements in intestinal health, as GOS calves in this study had an increased number of days with diarrhea. It should be noted that the authors suggested the cause of diarrhea to be osmotic in nature instead of health related. In contrast,

      Quigley, J. D., 3rd, J. J. Drewry, L. M. Murray, and S. J. Ivey. 1997. Body weight gain, feed efficiency, and fecal scores of dairy calves in response to galactosyl-lactose or antibiotics in milk replacers. J. Dairy Sci. 80:1751–1754. 10.3168/jds.S0022-0302(97)76108-3.

      observed that calves supplemented with GL experienced fewer days with diarrhea, and

      Senevirathne, N. D., J. L. Anderson, and L. Metzger. 2019. Growth performance, nutrient utilization, and health of dairy calves supplemented with condensed whey solubles. J. Dairy Sci. 102:8108–8119. 10.3168/jds.2019-16314.

      found lower mean fecal scores after weaning in GL-fed calves, which suggests an improved intestinal microbial community able to prevent pathogens from causing diarrhea.
      While there have been suggested benefits of colostral and milk OS in both ruminants and nonruminants (
      • ten Bruggencate S.J.
      • Bovee-Oudenhoven I.M.
      • Feitsma A.L.
      • van Hoffen E.
      • Schoterman M.H.
      Functional role and mechanisms of sialyllactose and other sialylated milk oligosaccharides..
      ;
      • Malmuthuge N.
      • Chen Y.
      • Liang G.
      • Goonewardene L.A.
      • Guan L.L.
      Heat-treated colostrum feeding promotes beneficial bacteria colonization in the small intestine of neonatal calves..
      ;

      Song, Y., N. Malmuthuge, F. Li, and L. L. Guan. 2019. Colostrum feeding shapes the hindgut microbiota of dairy calves during the first 12 h of life. FEMS Microbiol. Ecol. 95. 10.1093/femsec/fiy203.

      ), the effects of GOS/GL in calf diets are conflicting. Evidence of GOS/GL altering microbial populations and subsequently improving calf growth and health is lacking and warrants further investigation.

      Mannanoligosaccharides

      Mannanoligosaccharides (MOS) are derivatives of the cell walls of S. cerevisiae and are known to contain repeating mannose units via α-(1–2) and α-(1–3) linkages. It is the most commonly used prebiotic and has been shown to competitively bind pathogenic bacteria (

      Spring, P., C. Wenk, K. A. Dawson, and K. E. Newman. 2000. The effects of dietary mannaoligosaccharides on cecal parameters and the concentrations of enteric bacteria in the ceca of salmonella-challenged broiler chicks. Poult. Sci. 79:205–211. 10.1093/ps/79.2.205.

      ; reviewed in
      • Spring P.
      • Wenk C.
      • Connolly A.
      • Kiers A.
      A review of 733 published trials on Biol.-Mos, a mannan-oligosaccharide, and Actigen, a second generation mannose rich fraction, on farm and companion animals..
      ), highlighting the positive role MOS can exert in calf diets.

      Effects on Growth and Performance

      Of the 13 studies that evaluated the effect of MOS supplementation on growth, 3 found a measurable improvement in growth in MOS-supplemented calves, whereas the other studies noted no difference compared with control calves (Table 3). With respect to FE, one study found a positive effect on FE, one study found a negative effect on FE, and 5 studies found no difference between MOS-supplemented and control calves (Table 3). An increase in DMI was only observed in 2 studies (
      • Heinrichs A.J.
      • Jones C.M.
      • Heinrichs B.S.
      Effects of mannan oligosaccharide or antibiotics in neonatal diets on health and growth of dairy calves..
      ;
      • Terre M.
      • Calvo M.A.
      • Adelantado C.
      • Kocher A.
      • Bach A.
      Effects of mannan oligosaccharides on performance and microogranism fecal counts of calves following an ehnahced-growth feeding program..
      ), where there was an increase in starter intake without improved growth in MOS-supplemented calves, ultimately leading to decreased FE. Although no differences in intake or growth were noted in calves fed MOS in milk, an increase in rumen papillae length and jejunal villi height was found (

      Alves Costa, N., A. P. Pansani, C. H. de Castro, D. Basile Colugnati, C. H. Xaxier, K. C. Guimaraes, L. Antas Rabelo, V. Nunes-Souza, L. F. Souza Caixeta, and R. Nassar Ferreira. 2019. Milk restriction or oligosaccharide supplementation in calves improves compensatory gain and digestive tract development without changing hormone levels. PLoS One. 14:e0214626. 10.1371/journal.pone.0214626.

      ). The increased intestinal villi height was likely the result of enhanced growth of the intestinal epithelium due to an increase in substrate availability from bacteria utilizing MOS. However, it is unclear how MOS supplementation led to ruminal papillae differences observed by

      Alves Costa, N., A. P. Pansani, C. H. de Castro, D. Basile Colugnati, C. H. Xaxier, K. C. Guimaraes, L. Antas Rabelo, V. Nunes-Souza, L. F. Souza Caixeta, and R. Nassar Ferreira. 2019. Milk restriction or oligosaccharide supplementation in calves improves compensatory gain and digestive tract development without changing hormone levels. PLoS One. 14:e0214626. 10.1371/journal.pone.0214626.

      .

      Effects on Health

      Improved health seems the most consistent response for calves supplemented with MOS. Of the 10 studies to assess health, 8 found a positive effect of MOS supplementation and the other 2 found no differences compared with controls (Table 3).
      • Heinrichs A.J.
      • Jones C.M.
      • Heinrichs B.S.
      Effects of mannan oligosaccharide or antibiotics in neonatal diets on health and growth of dairy calves..
      found a greater probability of normal fecal scores, a decrease in diarrhea severity, and faster recovery to normal fecal consistency in MOS-supplemented calves. Fecal scores were also lower in MOS-supplemented Holstein calves in other studies (
      • Hill S.R.
      • Hopkins B.A.
      • Davidson S.
      • Bolt S.M.
      • Diaz D.E.
      • Brownie C.
      • Brown T.
      • Huntington G.B.
      • Whitlow L.W.
      The addition of cottonseed hulls to the starter and supplementation of live yeast or mannanoligosaccharide in the milk for young calves..
      ;

      Morrison, S. J., S. Dawson, and A. F. Carson. 2010. The effects of mannan oligosaccharide and streptococcus faecium addition to milk replacer on calf health and performance. Livest. Sci. 131:292–296. 10.1016/j.livsci.2010.04.002.

      ;
      • Ghosh S.
      • Mehla R.K.
      Influence of dietary supplementation of prebiotics (mannanoligosaccharide) on the performance of crossbred calves..
      ;
      • Heinrichs A.J.
      • Heinrichs B.S.
      • Jones C.M.
      Fecal and saliva IgA secretion when feeding a concentrated mannan oligosaccharide to neonatal dairy calves..
      ).

      Marcondes, M. I., T. R. Pereira, J. C. Chagas, E. A. Filgueiras, M. M. Castro, G. P. Costa, A. L. Sguizzato, and R. D. Sainz. 2016. Performance and health of Holstein calves fed different levels of milk fortified with symbiotic complex containing pre- and probiotics. Trop. Anim. Health Prod. 48:1555–1560. 10.1007/s11250-016-1127-1.

      fed a blend of MOS, probiotics, and fibrolytic enzymes and also observed lower fecal scores. These results might not be completely attributable to the MOS, but nevertheless demonstrate the potential synergistic effects of pro- and prebiotics that should be further explored. It has been suggested that MOS may help prevent attachment of pathogenic species in the lower gut (

      Spring, P., C. Wenk, K. A. Dawson, and K. E. Newman. 2000. The effects of dietary mannaoligosaccharides on cecal parameters and the concentrations of enteric bacteria in the ceca of salmonella-challenged broiler chicks. Poult. Sci. 79:205–211. 10.1093/ps/79.2.205.

      ), although 2 studies noted no differences in E. coli, Clostridium perfringens, or Cryptospordium spp. fecal counts between control or MOS-supplemented calves (
      • Terre M.
      • Calvo M.A.
      • Adelantado C.
      • Kocher A.
      • Bach A.
      Effects of mannan oligosaccharides on performance and microogranism fecal counts of calves following an ehnahced-growth feeding program..
      ;
      • Kara C.
      • Cihan H.
      • Temizel M.
      • Catik S.
      • Meral Y.
      • Orman A.
      • Yibar A.
      • Gencoglu H.
      Effects of supplemental mannanoligosaccharides on growth performance, faecal characteristics and health in dairy calves..
      ).

      Froehlich, K. A., K. W. Abdelsalam, C. Chase, J. Koppien-Fox, and D. P. Casper. 2017. Evaluation of essential oils and prebiotics for newborn dairy calves. J. Anim. Sci. 95:3772–3782. 10.2527/jas.2017.1601

      measured a lower mean fecal score during wk 3 in calves supplemented with 2 g/d of a yeast cell-wall product containing MOS, and
      • da Silva J.T.
      • Bittar C.M.M.
      • Ferreira L.S.
      Evaluation of mannan-oligosaccharides offered in milk replacers or calf starters and their effect on performance and rumen development of dairy calves..
      also measured a lower mean fecal score during wk 1 in calves supplemented MOS in their MR. There was little assessment of the immune response in calf studies utilizing MOS; however, a single study noted no differences in leukocytes or IgG levels in the blood, demonstrating that the immune system of calves was not altered due to MOS supplementation (

      Roodposhti, P. M., and N. Dabiri. 2012. Effects of probiotic and prebiotic on average daily gain, fecal shedding of Escherichia coli, and immune system status in newborn female calves. Asian Australas. J. Anim. 25:1255–1261. 10.5713/ajas.2011.11312.

      ).
      Compared with the other prebiotics used in calf studies, MOS has a clear and consistent benefit on health (mainly digestive health), which suggests that it is worth including in calf diets. This value is further highlighted by
      • Ghosh S.
      • Mehla R.K.
      Influence of dietary supplementation of prebiotics (mannanoligosaccharide) on the performance of crossbred calves..
      , who calculated an improvement in feed cost per kilogram gain for calves supplemented with MOS. Overall, these results underpin the benefit of MOS to calf growth and health, although how MOS exerts these beneficial effects still needs to be elucidated.

      β-Glucans

      There are many variations of β-glucans (BG), with the main sources coming from plant and fungal cell walls. β-Glucans are polysaccharides of glucose that differ in their arrangement of β-glycosidic bonds [e.g., baker’s yeast: β-(1–3) and β-(1–6), cellulose: β-(1–4), or cereal grains: β-(1–3) and β-(1–4)] and are used in food, cosmetic, and health products for humans, as well as feed additives for livestock animals (

      Zhu, F., B. Du, and B. Xu. 2016. A critical review on production and industrial applications of beta-glucans. Food Hydrocoll. 52:275–288. 10.1016/j.foodhyd.2015.07.003.

      ). In this review, we found it difficult to interpret and synthesize results from research studies that used BG, as it originates from a multitude of different sources. However, the studies discussed provided information on the source of BG, which helped to compare results between studies. While BG may be controversial to include as a prebiotic for ruminants, it has demonstrated prebiotic effects in humans (reviewed by
      • Roberfroid M.
      • Gibson G.R.
      • Hoyles L.
      • McCartney A.L.
      • Rastall R.
      • Rowland I.
      • Wolvers D.
      • Watzl B.
      • Szajewska H.
      • Stahl B.
      • Guarner F.
      • Respondek F.
      • Whelan K.
      • Coxam V.
      • Davicco M.J.
      • Leotoing L.
      • Wittrant Y.
      • Delzenne N.M.
      • Cani P.D.
      • Neyrinck A.M.
      • Meheust A.
      Prebiotic effects: Metabolic and health benefits..
      ) and other nonruminants (
      • Snart J.
      • Bibiloni R.
      • Grayson T.
      • Lay C.
      • Zhang H.
      • Allison G.E.
      • Laverdiere J.K.
      • Temelli F.
      • Vasanthan T.
      • Bell R.
      • Tannock G.W.
      Supplementation of the diet with high-viscosity beta-glucan results in enrichment for lactobacilli in the rat cecum..
      ;
      • Pieper R.
      • Jha R.
      • Rossnagel B.
      • Van Kessel A.G.
      • Souffrant W.B.
      • Leterme P.
      Effect of barley and oat cultivars with different carbohydrate compositions on the intestinal bacterial communities in weand piglets..
      ;
      • Cox C.M.
      • Sumners L.H.
      • Kim S.
      • McElroy A.P.
      • Bedford M.R.
      • Dalloul R.A.
      Immune responses to dietary β-glucan in broiler chicks during an Eimeria challenge..
      ), which may explain the few studies that have investigated BG in calves that have undeveloped rumens and have a metabolism more similar to that of a nonruminant early in life. As this field of research advances, a more appropriate definition of a prebiotic may not include BG for ruminants, but at present, we have included studies that have used BG sourced from both microbiota and plants in calf diets.

      Effects on Growth and Performance

      The effects of BG on growth and FE are highlighted in Table 3, with a total of 4 studies measuring these parameters. The results were mixed, with no differences found in 3 studies and, in a single study, a substantial decrease in growth was observed in BG-supplemented calves. It should be noted that both

      Eicher, S. D., I. V. Wesley, V. K. Sharma, and T. R. Johnson. 2010. Yeast cell-wall products containing beta-glucan plus ascorbic acid affect neonatal bos taurus calf leukocytes and growth after a transport stressor. J. Anim. Sci. 88:1195–1203. 10.2527/jas.2008-1669.

      and
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      supplemented calves with BG from the yeast cell wall and
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      used kraft pulp, whereas

      McDonnell, R. P., J. V. O’Doherty, B. Earley, A. M. Clarke, and D. A. Kenny. 2019. Effect of supplementation with n-3 polyunsaturated fatty acids and/or beta-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods. J. Anim. Sci. Biotechnol. 10:7. 10.1186/s40104-019-0317-x.

      demonstrated negative effects in growth by supplementing BG containing 10% laminarin [β-(1–3) and β-(1–6)-glucopyranose bonds] and 8% fucoidan [typically α-(1–3)-fucopyranose or α-(1–3) and α-(1–4) fucopyranose], which are extracted from brown algae (
      • Kadam S.U.
      • O’Donnell C.P.
      • Rai D.K.
      • Hossain M.B.
      • Burgess C.M.
      • Walsh D.
      • Tiwari B.K.
      Laminarin from Irish brown seaweeds Ascophyllum nodosum and Laminaria hyperborea: Ultrasound assisted extraction, characterization and bioactivity..
      ;

      Luthuli, S., S. Wu, Y. Cheng, X. Zheng, M. Wu, and H. Tong. 2019. Therapeutic effects of fucoidan: A review on recent studies. Mar. Drugs. 17. 10.3390/md17090487.

      ). An explanation for this difference between BG from the yeast cell wall or kraft pulp and brown algae may be due to an aversion to the taste of brown algae, which was demonstrated by

      Erickson, P. S., S. P. Marston, M. Gemmel, J. Deming, R. G. Cabral, M. R. Murphy, and J. I. Marden. 2012. Short communication: Kelp taste preferences by dairy calves. J. Dairy Sci. 95:856–858. 10.3168/jds.2011-4826.

      , who noted calves preferred a textured starter compared with the same starter mixed with brown algae meal. In addition,

      McDonnell, R. P., J. V. O’Doherty, B. Earley, A. M. Clarke, and D. A. Kenny. 2019. Effect of supplementation with n-3 polyunsaturated fatty acids and/or beta-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods. J. Anim. Sci. Biotechnol. 10:7. 10.1186/s40104-019-0317-x.

      noted a decrease in starter DMI throughout the trial, which taken together, suggest BG from brown algae may not be a suitable choice for promoting weight gain.

      Effects on Health

      Similar to growth, there were mixed results between studies in terms of health. Of the 3 studies that reported health data, one found improved health measures (
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      ), another found no differences (
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      ), and the other found a tendency for greater mean fecal scores in BG calves throughout the trial (

      McDonnell, R. P., J. V. O’Doherty, B. Earley, A. M. Clarke, and D. A. Kenny. 2019. Effect of supplementation with n-3 polyunsaturated fatty acids and/or beta-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods. J. Anim. Sci. Biotechnol. 10:7. 10.1186/s40104-019-0317-x.

      ; Table 3). With respect to immune function,

      Eicher, S. D., I. V. Wesley, V. K. Sharma, and T. R. Johnson. 2010. Yeast cell-wall products containing beta-glucan plus ascorbic acid affect neonatal bos taurus calf leukocytes and growth after a transport stressor. J. Anim. Sci. 88:1195–1203. 10.2527/jas.2008-1669.

      found that although general health scores were not measured in the study, leukocyte phagocytosis of Staphylococcus aureus was decreased. Moreover, the percentage of calves that were positive for Escherichia coli O157:H7 on d 7 was greater in calves supplemented with the 2% BG or 70% BG product compared with control calves. Furthermore,

      McDonnell, R. P., J. V. O’Doherty, B. Earley, A. M. Clarke, and D. A. Kenny. 2019. Effect of supplementation with n-3 polyunsaturated fatty acids and/or beta-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods. J. Anim. Sci. Biotechnol. 10:7. 10.1186/s40104-019-0317-x.

      found a decrease in cell-mediated and humoral immune responses in the BG and noted greater plasma haptoglobin in BG calves.
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      also noted increased haptoglobin in BG-supplemented (hydrolyzed yeast containing 10–12% BG) calves; however, this could have been due to a response that occurred after the vaccine challenge. Several positive effects, however, were noted by
      • Kim M.H.
      • Seo J.K.
      • Yun C.H.
      • Kang S.J.
      • Ko J.Y.
      • Ha J.K.
      Effects of hydrolyzed yeast supplementation in calf starter on immune responses to vaccine challenge in neonatal calves..
      . Specifically, an increased production of total serum IgA (both bacterial-specific and viral-specific IgA) as well as increased neutrophils, neutrophil:lymphocyte ratio, and serum lactoferrin in calves challenged with a live bacterial and viral vaccine and supplemented with BG in a starter. This suggests that the BG in the starter boosted the immune response to the vaccine, potentially conferring additional protection against disease. Similarly,
      • Eicher S.D.
      • Patterson J.A.
      • Rostagno M.H.
      β-Glucan plus ascorbic acid in neonatal calves modulates immune functions with and without Salmonella enterica serovar Dublin..
      fed MR with 70% BG from a SC extract and found a tendency for increased gene expression of toll-like receptor 4 (TLR4) and interleukin-12 (IL12) in the lung of BG-supplemented calves, suggesting that calves fed BG had improved responses to a potential infection in the lung.
      Taken together, the growth and health results of studies utilizing BG in calves were inconclusive but suggest that BG used from yeast cell wall or kraft pulp is more effective than BG from brown algae based on growth, health, and immune measurements taken.

      Cellooligosaccharides

      The group of cellooligosaccharides (CO) are similar to BG in that they are composed of repeating units of β-(1–4)-glucopyranose, but they differ in length, where OS (including CO) have shorter chain lengths of glucose monomers—typically in the 3 to 10 range. Unlike BG that occur naturally and are extracted from the cell wall of plants or fungi, CO are prepared via acid hydrolysis of isolated cellulose and have been shown to promote the growth of LAB (
      • Kontula P.
      • von Wright A.
      • Mattila-Sandholm T.
      Oat bran beta-gluco- and xylo-oligosaccharides as fermentative substrates for lactic acid bacteria..
      ).

      Effects on Growth and Performance

      The effect of CO on growth and FE is more promising than BG, as 2 of the 3 studies observed a positive effect on growth, and one found improved FE (Table 3). The study by

      Uyeno, Y., K. Kawashima, T. Hasunuma, W. Wakimoto, M. Noda, S. Nagashima, K. Akiyama, M. Tabata, and S. Kushibiki. 2013. Effects of cellooligosaccharide or a combination of cellooligosaccharide and live Clostridium butyricum culture on performance and intestinal ecology in Holstein calves fed milk or milk replacer. Livest. Sci. 153:88–93. 10.1016/j.livsci.2013.02.005.

      was the only study that found CO supplementation did not improve growth or FE; however, an increase in fecal numbers of the butyric acid–producing Clostridium coccoides-Eubacterium rectale group and fecal butyrate was found in CO-supplemented calves, which may have resulted in enhanced gut development (

      Gorka, P., Z. M. Kowalski, R. Zabielski, and P. Guilloteau. 2018. Invited review: Use of butyrate to promote gastrointestinal tract development in calves. J. Dairy Sci. 101:4785–4800. 10.3168/jds.2017-14086.

      ). Whereas

      Uyeno, Y., K. Kawashima, T. Hasunuma, W. Wakimoto, M. Noda, S. Nagashima, K. Akiyama, M. Tabata, and S. Kushibiki. 2013. Effects of cellooligosaccharide or a combination of cellooligosaccharide and live Clostridium butyricum culture on performance and intestinal ecology in Holstein calves fed milk or milk replacer. Livest. Sci. 153:88–93. 10.1016/j.livsci.2013.02.005.

      demonstrated the role of CO as a fermentation substrate for cellulolytic bacteria in the lower gut,
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      demonstrated the role of CO fermentation in the rumen of beef calves, where ruminal short-chain fatty acids were increased during weaning at 4 mo of age and subsequently had a tendency for increased ADG after weaning compared with control calves.
      • Hasunuma T.
      • Kawashima K.
      • Nakayama H.
      • Murakami T.
      • Kanagawa H.
      • Ishii T.
      • Akiyama K.
      • Yasuda K.
      • Terada F.
      • Kushibiki S.
      Effect of cellooligosaccharide or synbiotic feeding on growth performance, fecal condition and hormone concentrations in Holstein calves..
      did not measure gut development but found a tendency for increased insulin-like growth factor-1 (IGF-1), which has been shown to be an important somatotropic axis hormone involved in calf growth (

      Blum, J. W., T. H. Elsasser, D. L. Greger, S. Wittenberg, F. de Vries, and O. Distl. 2007. Insulin-like growth factor type-1 receptor down-regulation associated with dwarfism in Holstein calves. Domest. Anim. Endocrinol. 33:245–268. 10.1016/j.domaniend.2006.05.007.

      ).

      Effects on Health

      Unlike growth measurements, no differences were found with respect to total fecal score or days experiencing diarrhea in CO-supplemented calves when compared with controls in
      • Hasunuma T.
      • Kawashima K.
      • Nakayama H.
      • Murakami T.
      • Kanagawa H.
      • Ishii T.
      • Akiyama K.
      • Yasuda K.
      • Terada F.
      • Kushibiki S.
      Effect of cellooligosaccharide or synbiotic feeding on growth performance, fecal condition and hormone concentrations in Holstein calves..
      , whereas general health was not assessed by

      Uyeno, Y., K. Kawashima, T. Hasunuma, W. Wakimoto, M. Noda, S. Nagashima, K. Akiyama, M. Tabata, and S. Kushibiki. 2013. Effects of cellooligosaccharide or a combination of cellooligosaccharide and live Clostridium butyricum culture on performance and intestinal ecology in Holstein calves fed milk or milk replacer. Livest. Sci. 153:88–93. 10.1016/j.livsci.2013.02.005.

      or
      • Kido K.
      • Tejima S.
      • Haramiishi M.
      • Uyeno Y.
      • Ide Y.
      • Kurosu K.
      • Kushibiki S.
      Provision of beta-glucan prebiotics (cellooligosaccharides and kraft pulp) to calves from pre- to post-weaning period on pasture..
      ; Table 3).
      Utilizing CO as a supplement in calf diets showed positive signs for calf growth, while health and microbial measurements were not affected. The source of cellulose used to synthesize CO was not discussed in any study included, but like BG, the source of the prebiotic used may have underlying effects that we are unable to observe presently. Studies utilizing CO in calf diets seem to provide their biggest effect via promoting microbial fermentation and subsequent short-chain fatty acids that promote gut and overall calf growth.

      Other Prebiotic Compounds

      Studies have used proprietary products or prebiotics that have not been well-defined in the literature, but given that they were discussed as prebiotics, they have been included in this review. Some of the examples listed in Table 3 are not well described, and others, like lactulose (disaccharide containing galactose and fructose) and β-cyclodextrin [BC; an OS that has 7 glucose units joined in a cyclic α-(1–4) manner] have been included as they do not fit well in other categories. Ultimately, they have been included in this review because they are believed to act in a prebiotic manner and have been used in calf studies.

      Effects on Growth and Performance

      Only one study in this category showed a positive response, which was a tendency to increase FE in calves (

      Quezada-Mendoza, V. C., A. J. Heinrichs, and C. M. Jones. 2011. The effects of a prebiotic supplement (prebio support) on fecal and salivary iga in neonatal dairy calves. Livest. Sci. 142:222–228. 10.1016/j.livsci.2011.07.015.

      ; Table 3).

      Masanetz, S., N. Wimmer, C. Plitzner, E. Limbeck, W. Preissinger, and M. W. Pfaffl. 2010. Effects of inulin and lactulose on the intestinal morphology of calves. Animal 4:739–744. 10.1017/S1751731109991728.

      fed lactulose at 2% of the MR diet and found a tendency for calves to have more proliferative ileal cells, which suggests lactulose promoted intestinal growth; however, this did not translate to overall growth. The lack of replication using these products in calves may explain the lack of growth response in the other studies and suggests further investigation is required to accurately assess these compounds as prebiotic supplements in calf diets.

      Effects on Health

      Similar to growth and performance measures, there was a minimal effect on health, with only one study observing a negative effect (Table 3). The one negative result was observed by
      • Velasquez-Munoz A.
      • Manriquez D.
      • Paudyal S.
      • Han H.
      • Callan R.
      • Ryan E.P.
      • Pinedo P.
      Effect of prebiotic supplementation with stabilized rice bran in milk of pre-weaned organic Holstein calves..
      , who fed a compound believed to have prebiotic properties, heat stabilized rice bran (SRB), at 10% caloric intake/d for 28 d. The authors demonstrated a reduced number of days to first moderate diarrhea event, and an increased number of days were needed to recover from a diarrhea event in the supplemented group. The authors posited that the diarrhea occurring in SRB calves was the result of increased osmolality due to lack of digestion of SRB in MR. Increased fecal IgA may suggest an enhanced humoral immunity, which was found by
      • Heinrichs A.J.
      • Jones C.M.
      • Elizondo-Salazar J.A.
      • Terrill S.J.
      Effects of a prebiotic supplement on health of neonatal dairy calves..
      , who fed a proprietary prebiotic product; however, no differences in health observations or lymphocyte populations were noted. The authors speculated that the excellent health of the calves used in the study may have prevented any noticeable differences and suggests that prebiotics might be more appropriate for unhealthy calves.

      Castro-Hermida, J. A., Y. Gonzalez-Losada, F. Freire-Santos, M. Mezo-Menendez, and E. Ares-Mazas. 2001. Evaluation of beta-cyclodextrin against natural infections of cryptosporidiosis in calves. Vet. Parasitol. 101:85–89. 10.1016/s0304-4017(01)00505-2.

      administered BC to calves orally, and although no differences in diarrhea incidences were observed, there was a decrease in Cryptosporidium oocyst shedding in the feces of calves administered BC.

      Masanetz, S., W. Preissinger, H. H. Meyer, and M. W. Pfaffl. 2011. Effects of the prebiotics inulin and lactulose on intestinal immunology and hematology of preruminant calves. Animal 5:1099–1106. 10.1017/S1751731110002521.

      , who supplemented lactulose, measured a decrease in immune activation via decreased IL2RA and tumor necrosis factor gene expression in the lower gut compared with control calves.
      Taken together, the prebiotic results in this section demonstrate no promising effects on calf health or growth. Considering the large body of evidence underpinning lactulose as a positive prebiotic in monogastrics, there may be some usefulness in ruminants that has not yet been explored. The other compounds did not prove useful either, but as previously mentioned, lack of repetition or utilizing stressful or challenging situations may potentially explain why positive effects were not identified in this review.

      Conclusion

      When considering the prebiotic studies evaluated as part of this review, it seems clear that there are no prebiotics boasting substantial evidence of positive effects on calf growth, health, or immune status. There is more evidence to support the use of MOS in calf diets compared with other compounds, but it is worth noting that the majority of studies have been conducted using MOS. In addition, the mechanisms of action for these prebiotics is severely understudied, with the main connection to any positive health benefit currently being “prebiotics promote growth of beneficial bacteria.” Although this statement is true, there are also cellular-level mechanisms involving epigenetic regulation and leukocyte activity that might play critical roles. Future work should look beyond growth and observable health parameters to focus on how and why compounds, such as OS, improve gut development and immune response. Furthermore, future work should also address when is the most appropriate time to use a prebiotic compound to receive the maximum return on investment (e.g., either prevention or treatment of a gastrointestinal illness).

      FUTURE RESEARCH

      Research synthesis is a fundamental component of science, with systematic reviews and meta-analyses becoming more common approaches to synthesize research in animal science. However, incomplete reporting in primary studies is a common finding that limits the ability of these systematic reviews to answer relevant questions (
      • Ali Naqvi S.
      • Nobrega D.B.
      • Ronksley P.E.
      • Barkema H.W.
      Effectiveness of precalving treatment on postcalving udder health in nulliparous dairy heifers: A systematic review and meta-analysis..
      ;
      • Winder C.B.
      • Miltenburg C.L.
      • Sargeant J.M.
      • LeBlanc S.J.
      • Haley D.B.
      • Lissemore K.D.
      • Godkin M.A.
      • Duffield T.F.
      Effects of local anesthetic or systemic analgesia on pain associated with cautery disbudding in calves: A systematic review and meta-analysis..
      ). Specifically, in a meta-analysis evaluating microbial-based products, 18 out of 32 trials were excluded due to lack of information needed to conduct the analysis (
      • Signorini M.L.
      • Soto L.P.
      • Zbrun M.V.
      • Sequeira G.J.
      • Rosmini M.R.
      • Frizzo L.S.
      Impact of probiotic administration on the health and fecal microbiota of young calves: A meta-analysis of randomized controlled trials of lactic acid bacteria..
      ). A study completed in 2019 also found that many areas of experimental design were not reported or incompletely described in many dairy science articles (
      • Winder C.B.
      • Churchill K.J.
      • Sargeant J.M.
      • LeBlanc S.J.
      • O’Connor A.M.
      • Renaud D.L.
      Invited Review: Completeness of reporting of experiments REFLECTing on a year of animal trials in the Journal of Dairy Science..
      ). Hence, there is a need to adhere to reporting guidelines for authors, reviewers, and editors, such as the Reporting Guidelines for Randomized Controlled Trials for Livestock and Food Safety (REFLECT), which was developed through consensus of experts to improve reporting in livestock trials (
      • Sargeant J.M.
      • O’Connor A.M.
      • Gardner I.A.
      • Dickson J.S.
      • Torrence M.E.
      • Dohoo I.R.
      • Lefebvre S.L.
      • Morley P.S.
      • Ramirez A.
      • Snedeker K.
      The REFLECT statement: Reporting guidelines for randomized controlled trials in livestock and food safety: Explanation and elaboration..
      ). Improved reporting will ultimately allow for a better understanding of the efficacy of pro- and prebiotics and increase the value of the work that is being conducted.
      In addition to following REFLECT principles, ensuring proper and consistent sample collection and analysis is essential to making proper comparisons between studies investigating mode of action. In particular, when researchers pursue the underlying mode of action of microbial-based solutions, the intensity of the sampling becomes more complex. To gain more insight into how the probiotics and prebiotics change the microbiome and host, many researchers have adopted “omic” approaches and next-generation sequencing. Although these approaches have been insightful, a large degree of variability exists in sample collection, processing, and laboratory analysis. With respect to assessing the changes in the microbial community of the gut, the locations and types (fluid digesta, solid digesta, attached to digestive tract) of samples in the literature are inconsistent. This is commonly shown in medical research, where the preparation, handling, and storage of human gut samples significantly affects the results (
      • Gorzelak M.A.
      • Gill S.K.
      • Tasnim N.
      • Ahmadi-Vand Z.
      • Jay M.
      • Gibson D.L.
      Methods for improving human gut microbiome data by reducing variability through sample processing and storage of stool..
      ). Once the sample has been taken, the extraction method, clone library construction, DNA sequencing procedures, and data analysis pipelines are all different between studies. Adding to this problem is the overarching lack of existing databases to identify microorganisms and function of unclassified reads that still exist in cattle and calves (
      • Malmuthuge N.
      • Griebel P.J.
      • Guan L.L.
      The gut microbiome and its potential role in the development and function of the newborn calf gastrointestinal tract..
      ). Although new sequencing technologies boast great potential to improve our knowledge about microbial-based solutions in calves, consistency between research groups will be the key to making swift progress in this field. Moreover, to fully uncover how probiotic and prebiotic technologies can positively affect health and performance, researchers must look beyond characterization of the microbial community. The effect on the host—especially immune function—needs to be considered in studies investigating mode of action. More studies need to evaluate host–microbial interaction with integrated omic approaches to characterize the host and the microbes (
      • Ma T.
      • Suzuki Y.
      • Guan L.L.
      Dissect the mode of action of probiotics in affecting host-microbial interactions and immunity in food producing animals..
      ).

      APPLICATIONS

      It is worth noting that based on the study results included in this review, there have been limited negative responses in growth (2/68), FE (4/70), health (3/68) and gut development (2/70). Growth, FE, and gut development responses to pro- and prebiotic supplementation resulted in marginal positive responses (22/68, 9/70, and 11/70, respectively), with many results demonstrating a nonsignificant effect (39/68, 32/70, and 3/70, respectively). With respect to health, many studies (31/68) had positive responses and only 15 out of 68 did not show a difference. Taken together, it appears that using pro- and prebiotics in calf diets demonstrates the most beneficial effects on calf health, with growth being the next area most positively affected. Without formal, rigorous statistical testing, it would be inappropriate to make conclusions from these response proportions, but they do suggest that pro- and prebiotics should be further studied in calves to determine the most appropriate times for supplementation. As discussed earlier and signified by the large number of positive health responses, one time to study may be when the disease burden is high. There is a lack of data on whether it is most beneficial to supplement calves with pro- and prebiotics prophylactically or therapeutically, and future studies should investigate these areas further. Specifically, studies using models of experimentally induced enteric infections could provide useful information regarding timing and duration of pro- and prebiotic supplementation. Also, although rarely addressed in the literature and not in this review, proper mixing and administration of pro- and prebiotic supplements is an important consideration that should be addressed in future studies to confirm consumption. Last, although health may be the most positively affected response in the current data, there may be subsequent positive effects on growth, as calves will not have to partition energy for immune responses or have a reduction in feed intake.

      ACKNOWLEDGMENTS

      The authors are grateful for the funding support provided by Alberta Milk (Edmonton, AB, Canada), SaskMilk (Regina, SK, Canada), BC Dairy Association (Burnaby, BC, Canada), Dairy Farmers of Manitoba (Winnipeg, MB, Canada), Trouw Nutrition (Guelph, ON, Canada), Bayer Animal Health (Mississauga, ON, Canada), the Natural Sciences and Engineering Research Council of Canada (Ottawa, ON), Lallemand (Montreal, QC, Canada), and Westgen (Abbotsford, BC, Canada).

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