Interactions Between Gut Microbial Composition, Mucosal Immunity and Metabolism

While evidence that the intestinal microbiome contributes to host health and disease has rapidly developed, the causal mechanisms that link these microbes to disease are largely elusive. The goal of this project was to explore the complex crosstalk between the microbiome and the immune system using genetically defined mouse models under defined environmental conditions. We first aimed to identify how early-life perturbations in the microbiome alter the immune landscape of gut-associated lymphoid tissue (GALT), as well as extra-intestinal influences conferred by these perturbations. We investigated how oral administration of the antibiotic vancomycin from weaning until early adulthood affects the microbial ecosystem, intestinal immunity and serum metabolic profiles in C57BL/6 mice. Vancomycin treatment significantly altered gut microbiome composition, affected T cell and innate-like lymphocyte (ILC) populations in the small intestine, and increased levels of intestinal and serum IgA. We also report that vancomycin treatment altered serum cytokine and metabolic profiles, demonstrating that gut microbial perturbation can have extra-intestinal effects. The second focus of this project was to understand how biological sex participates in the trialogue between the immune system, metabolism, and the microbiome. We used the “four core genotypes” (FCG) mouse model which generates XX or XY gonadal females, and XX or XY gonadal males to dissect the independent and collective roles of sex hormones and sex chromosomes on these processes. We observed that during puberty, both sex chromosomes and sex hormones affect the composition of cecal microbial taxa that subsequently develops in adult mice. Gonadal sex had a broad effect on serum metabolites and bile acids, and androgens influenced gut microbial composition and immune cell population frequencies in males. Collectively, the data presented in this thesis uncover new insights into the relationship between gut microbial composition and intestinal immunity. We comprehensively immunophenotyped the GALT and demonstrated how microbial perturbation effects intestinal-associated immune subsets, highlighting a major source of control on immunity in extra-intestinal sites. Further, these data emphasize the importance of considering sex as a biological variable in analysis of microbiome-immune-metabolic interactions and reveal potential mechanisms that may influence sex differences in immune and metabolic diseases.

Department dc:contributor.department

Immunology

Year dc:date.issued

2020

Author dc:creator

• Israelian, Nyrie Elise

Advisor dc:contributor.advisor

• Danska, Jayne

• antibiotics
• Immunology
• microbiome
• microbiota
• Sex differences

Handle dc:identifier.uri

http://hdl.handle.net/1807/126026

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/126026