Role of the Microbiome in Early Development of the Bovine Gastrointestinal Tract. Dr. Philip Griebel

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1 Role of the Microbiome in Early Development of the Bovine Gastrointestinal Tract Dr. Philip Griebel Vaccine & Infectious Disease Organization School of Public Health University of Saskatchewan Saskatoon, Saskatchewan Canada

2 Overview Bovine Mucosal Immune System Neonatal Mucosal Immune System Development Microbial Colonization During Birth Regional Development of Microbial Populations Interactions Between Microbiome and Mucosal Development Interaction between Colostrum and Microbiome Summary

3 Bovine GALT at Birth Continuous ileal PP 1-3 m Discrete (jejunual) PP PP D D F IF F

4 Peyer s Patch (PP) Development No. of PP No. of Follicles Species Ileal Jejunal Ileal Jejunal Cattle Pig Dog Horse Single m Single m Single m Several m Fetal Develop ,000 10,000 Present ,000 9,000 Present N.D N.D Present N.D. N.D. Present Human Several ,000-20,000 Present Sacculus Rabbit 1-10 N.D. N.D. Absent Rotundus Mouse Absent N.D.- Not Determined Extensive fetal GALT development in the absence of commensal microflora Fetal GALT is functional in the absence of commensal microflora (Gerdts et al. 2002) Griebel P and Hein W

5 How Does GALT Function Change Following Birth? mirnas play a major role in regulating gene expression (mrna) Many mirnas are involved in regulating immune function genes Analyzing mirna expression provides an index of changing tissue function Jejunum Ileum The first 7 days after life are a very dynamic developmental period in the small intestine Liang G et al, 2014

6 Relative abundance of Bacterial Phyla (%) Bacterial Colonization Begins During Birth 100% 90% Phyla 80% 70% 60% 50% 40% 30% 20% 10% 0% Animal ID Approximately S rdna copies/g tissue and contents present in GIT at 30 minutes after birth Malmuthuge N et al, 2014; Malmuthuge N et al, 2015

7 Relative abundance of bacterial families (%) Pioneer Species in GIT are Highly Diverse 100% Family 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Animal ID Highly diverse bacterial populations contribute to GIT colonization Marked variance in microbiome of each calf despite common birth environment Malmuthuge N et al, 2014; Malmuthuge et al, 2015

8 Regional Development of Commensal Communities A 10 to 100-fold increase in bacterial abundance throughout the GIT within 3 weeks An age-dependent decrease in mucosa-associated bacterial abundance An age-dependent change in regional bacterial abundance Malmuthuge N et al

9 Microbiome Interaction with Mucosal Development Ru Copy number of total bacteria MJ Copy number of Bifidobacterium spp MJ Copy number of Lactobacillus spp MJ Copy number of total bacteria DO D7 D21 D42 IL Copy number of Bifidobacterium spp IL Copy number of Lactobacillus spp IL Copy number of total bacteria Figure 6. Number of mirnas with significant correlations between their expression and the copy number of microbial 16S rrna gene Expression of few mirnas correlated with microbiome during the first week of life Expression of many more mirnas correlated with microbiome at 3 weeks of age Correlations between microbiome and mirna expression still apparent at 6 weeks of age Liang et al, 2014

10 % Absorption g / 100 ml Colostrum Has A Major Impact On Gut Development Protein Concentration Ig g/100 ml IgG1 3-4 IgM IgA Intestinal Absorption Hour post-partum Vet Clin North Am Food Anim Pract, (1): p Vet Clin North Am Food Anim Pract, (1): p Advances in Dairy Technology, Vol 19, : p

11 Colostral Components and Activity Colostrum contains immunoglobulins for passive transfer of immunity to the neonate Colostrum contains nutrient and non-nutrient factors that affect gut maturation Colostrum contains growth factors, hormones, and cytokines that directly stimulate epithelial cell growth and differentiation. Does colostrum alter development of gut microbiome?

12 Colostrum Increases Total Microbiome Abundance Fresh (FC) and heat-treated (HC) colostrum increase intestinal bacterial 100-fold within 12 h after birth when compared to calves receiving no colostrum Malmuthuge et al, 2015

13 Colostrum Increases Beneficial Bacterial Abundance Heat-treated (HC) colostrum increase the proportion of Bifidobacterium spp. within 6 h after birth when compared to calves receiving no colostrum Malmuthuge et al, 2015

14 Colostrum Suppresses Growth of Potential Pathogens Heat-treated (HC) colostrum decreases the proportion of E. coli present in both intestinal contents and associated with mucosal epithelium within 6 h after birth Malmuthuge et al, 2015

15 Summary Rapid developmental changes occur in the bovine small intestine during the first three weeks of life Significant correlations between total bacterial number and genus and the expression of mirnas regulating immune function. This interaction varies among GIT regions. Age-dependent evolution of regionally distinct microbial communities throughout the GIT Colostrum has a profound effect on gut microbiome development within the first 24 h of life Colostrum enhances development of beneficial bacteria and suppresses potential pathogens

16 Health Management Implications Each calf is colonized by a unique microbiome reflecting both maternal and environmental microbiome. Enteric pathogens present in the dam or the environment may colonize the intestine during birthing. Early feeding of colostrum is important for not only passive transfer of maternal immunity but also functions as a prebiotic to promote growth of beneficial bacteria. This beneficial effect is seen with heat-treated colostrum. Growth and development of the small intestine and mucosal immune system is directly affected by the microbiome and this development is most rapid during the first three weeks of life. Colostrum feeding and biosecurity during the first 24 h post-partum may have along-term impacts on gut health. Gut health has direct effects on calf growth and immune function.

17 Acknowledgements University of Saskatchewan Patricia Gonzalez Chandru Charavarymath George Mutwiri Patrick Fries Steward Walker University of Edmonton Leluo Guan Nilusha Malmuthuge Guanxiang Liang Meiju Li Natasa Arsic Donna Dent Sherri Tetland Erin Scruten Funding ALMA, CIHR, NSERC, Sask. ADF