Early-Life Enterotoxigenic Bacteroides fragilis Acquisition and Colorectal Cancer Risk

About This Grant

PROJECT SUMMARY Bacteroides fragilis, which comprises up to 2.5% of the human microbiota, is often acquired within the first month of life. While non-toxigenic B. fragilis (NTBF) is considered a symbiont in humans, enterotoxigenic B. fragilis (ETBF) produces the B. fragilis toxin (BFT), which causes pro-inflammatory damage to the intestinal epithelium and has been associated with colorectal cancer (CRC) development. Since the human microbiota composition becomes stable during early development, the link between early colonization by ETBF and CRC risk requires further investigation to develop preventive therapeutics. To address this, our lab has developed a vertical transmission model to study ETBF colonization in neonatal mice and to assess the impact of the developing microbiota on the host. Using this model, we have demonstrated that BFT facilitates lamina propria (LP) niche acquisition through goblet cell-associated passages (GAPs) during the pre-weaning period. Additionally, neonatal ETBF colonization persists into adulthood and induces crypt elongation and goblet cell hyper- differentiation in colonic tissue. Based on the localization of ETBF in the LP niche beneath the colonic crypt base, as well as its role in BFT-dependent colonic tissue remodeling, I hypothesize that BFT directly influences epithelial stem cell fate signaling by positioning itself beneath the colon crypt base, contributing to CRC progression. To investigate this hypothesis, I will use a neonatal colonization model (vertical transmission model) to study early-life ETBF colonization and advanced microscopic techniques to capture the earliest CRC precursors in ApcMin/+ mice upon neonatal ETBF colonization. Focusing on in vivo studies, I will explore how BFT-mediated ETBF LP colonization modulates crypt cell fate signaling and also assess how early-life ETBF colonization affects CRC susceptibility. This research strategy will provide insights at both the molecular level and the clinical level into how ETBF colonization influences colonic crypt base stem cells and CRC susceptibility. The successful completion of this proposal will address an unexplored gap in ETBF-host epithelial cell interaction in the colon tissue and provide mechanistic insights into the interplay between early-colonizer microbiota and disease risk. Together, these studies will pave a way to investigate microbiome-based therapeutic interventions to prevent CRC.