The gut microbiome: A key regulator of mucosal tolerance, barrier function, and vaccine response

In multicellular organisms, the gastrointestinal tract serves as the largest interface between the internal body and the external environment. In mammals, the gastrointestinal (GI) tract intestine is home to a diverse and dynamic microbial community, continuously exposing the mucosal epithelium to a broad spectrum of microorganisms, cellular components, and metabolites. Through coevolution with the intestinal microbiota, mammals have developed a highly specialized mucosa that not only facilitates digestion and nutrient absorption but also maintains a balanced relationship with symbiotic and mutualistic microorganisms and as well as commensals while safeguarding the body from pathogens. The human GI tract harbors an astonishingly complex and diverse array of microorganisms, with recent estimates suggesting the presence of approximately 100 trillion microbial cells. The immense size and diversity of the gut microbiota make it a cornerstone of human health, influencing both physiological and pathological processes throughout the body. The gut microbiota is not only highly diverse, comprising hundreds to potentially thousands of bacterial species or strains, but it is also highly responsive to a variety of factors, such as diet, environment, and host genetics. This microbial complexity plays a vital role in host metabolism, immune system development, and protection against pathogenic microbes, underscoring the intricate symbiotic relationship between the host and its microbial inhabitants. To better understand the role of the microbiota in maintaining gut health and their links to disease, the use of gnotobiotic mouse models colonized with defined microbiota, such as the Altered Schaedler Flora (ASF), offers a reductionistic system to study these interactions. This dissertation examines the role of microbial communities in modulating the integrity of the intestinal barrier, highlighting the critical role of microbiota in both maintaining epithelial homeostasis and shaping immune responses in the context of immunization. Additionally, this work delves into the complex relationship between microbiota composition and mucosal tolerance, emphasizing how these interactions shape the immune environment within the intestinal tissue. The second chapter investigates the impact of microbial diversity on intestinal permeability, revealing that reduced microbial diversity in ASF mice impairs epithelial barrier integrity. A key objective was to explore the restoration of impaired permeability in ASF mice via fecal microbiota transplantation (FMT) from conventionally-reared mice, underscoring the therapeutic potential of microbiota modulation for restoring barrier function. The findings highlight that reduced microbial diversity in ASF mice leads to significant alterations in intestinal barrier function, particularly in the ileum, with concurrent mitochondrial damage. Chapter three examines how the complexity of the microbiota influences the immune response to SARS-CoV-2 spike protein vaccination. Using the ASF mouse model, we demonstrate that ASF mice, despite having a simplified microbiota, exhibit enhanced initial antibody responses to vaccination, particularly in female C3H/HeN mice. This response is characterized by increased TLR2 and TLR4 ligand levels and a robust Th1-type immune activation. However, while sex and microbiota composition significantly affect early immune responses, these factors did not influence long-term immunity. These findings suggest that targeted microbiota modulation could optimize vaccine efficacy, particularly for diverse populations. The final chapter delves into the mechanisms of mucosal tolerance to the gut microbiota, focusing on the role of IL10 in regulating immune responses to resident microbial antigens. Immunization with whole-cell lysates (WCL) derived from ASF bacteria reveals genotype- and IL10-dependent differences in immune responses. In IL10-deficient mice, a broader range of ASF strains triggers heightened immune activation, suggesting that IL10 is crucial for maintaining tolerance. Additionally, immunization with specific ASF strains confers protection against DSS-induced colitis, highlighting the therapeutic potential of self-microbial immunization in inflammatory bowel diseases (IBD). To conclude, the research described in this dissertation provides new understanding of how the gut microbiota influences intestinal health and immune function, with particular emphasis on its role in maintaining epithelial integrity, modulating immune responses, and contributing to mucosal tolerance. Through the exploration of microbial diversity, its impact on intestinal permeability, and its interaction with immune systems in the context of vaccination and disease, this work highlights the potential for microbiota-targeted therapies. The findings suggest that microbial modulation, particularly through fecal microbiota transplantation or immunization with self-microbial antigens, may offer novel therapeutic approaches for restoring intestinal barrier function and managing inflammatory diseases like IBD. As we continue to unravel the complex relationships between the host and its microbiota, this research paves the way for further exploration of microbiome-based strategies to optimize immune health and disease prevention.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

dissertation

Discipline thesis:degree_discipline

Immunology

Department dc:contributor.department

Department of Veterinary Microbiology and Preventive Medicine

Grantor

Iowa State University

Year dc:date.issued

2025

Author dc:creator

• Parvinroo, Shadi

Advisors dc:contributor.advisor

• Wannemuehler, Micheal J
• Jergens, Albert E
• Kohut, Marian
• Kopper, Jammie
• Phillips, Gregory J

Language dc:language.iso

en

DOI

https://doi.org/10.31274/td-20251215-343

OAI identifier oai:identifier

oai:dr.lib.iastate.edu:20.500.12876/kv7kNqRv