Humans and other mammals are colonized by a plethora of microorganisms at the time of birth. The constellation of microorganisms that inhabit the gut is key in the development of the host immune system. It is increasingly clear that early events in development of the colonic microbiota influence host immunity, nutrition, and susceptibility to disease, yet specific mechanistic insights on these processes remain limited. Inflammatory bowel disease (IBD) and colonic malignancy are heterogeneous diseases that emerge as a result of a complex interplay of host genetic and environmental factors, including the composition and function of the gut microbiota. Bacteroides fragilis represents up to 2.5% of the human gut microbiota and is often found in neonates within the first month of life. A subset of Bacteroides fragilis strains termed enterotoxigenic B. fragilis (ETBF) secretes B. fragilis toxin (BFT), a metalloprotease that causes inflammatory damage of the intestinal epithelium. ETBF has been found as strongly associated to the pathogenesis of colonic disease, yet also colonizes up to 20% of asymptomatic humans, suggesting that these individuals may carry a potential long- term health risk as part of their stable gut microbiome. The primary goal of this proposal is to examine the effects of early life acquisition of ETBF on the immune system, based on the hypothesis that ETBF can dramatically alter T cell specific responses. These studies will benefit from the use of a novel model of B. fragilis vertical transmission in which the temporal and genetic determinants of initial niche colonization by B. fragilis can be evaluated in neonatal mice. Through a comprehensive genetically- and temporally-dissected analysis of antigen-specific T cell responses to ETBF during neonatal colonization, this study aims at defining fundamental principles that underlie ETBF-mediated disease through analysis of luminal antigen sampling and BFT-dependent modulation of immune response. We will also explore the possibility that ETBF allows for other members of the microbiota to access the lamina propria niche, further disrupting development of the immune system. Overall, our proposed studies will provide mechanistic insights of early life effects of BFT on the immune system, emphasizing the impact on tolerance to Bacteroides-specific and other colonic luminal antigens.
The proposed project is relevant to public health because alterations of the gut microbiota are increasingly recognized as a hallmark of human inflammatory diseases, yet there is a gap in knowledge of how interactions between host and microbes affect outcomes of health and disease. Understanding the effects of enterotoxigenic Bacteroides fragilis pathogenesis on the immune system during early life is expected to inform an understanding of novel targeted probiotic interventions to mitigate disease.
