Understanding the Impact of Xenobiotic Metabolism on the Gut Microbiome and Resilience against Gastrointestinal Pathogens

Abstract The gut microbiome plays a key role in maintaining intestinal homeostasis and serves as a critical barrier against invading microorganisms through competition, chemical antagonism, and immune modulation. However, external factors such as exposure to xenobiotics (including non-antibiotic drugs, pesticides, plasticizers) can influence the resilience of the gut microbiome and its susceptibility to infections. Recent studies have demonstrated the impact of xenobiotics on the gut microbiome, with increasing evidence suggesting that non-antibiotic xenobiotic exposure can alter microbial composition, potentially facilitating pathogen expansion. This is especially concerning for gastrointestinal pathogens such as Salmonella enterica and Vibrio cholerae, where chemical pollution is often found as a confounding exposure factor. Although multiple studies have shown the influence of xenobiotics on microbiome composition, there remains a major knowledge gap in the mechanistic understanding of how these exposures shape microbial metabolism that controls resilience to invading pathogens. My research program aims to fill this gap by investigating how xenobiotics and their biotransformation products affect the gut microbiome's composition, metabolism, specialized metabolite production, and ultimately resilience against invading bacteria. Using a synthetic microbiome model and our functional metabolomics tools, we will assess the inhibitory effects of xenobiotics, and their biotransformation products on commensal bacteria and pathogens. Additionally, we will explore the long-term effects of xenobiotic exposure by evolving commensal bacteria to investigate cross-resistance to antibiotics, and their impact on pathogen colonization. Ultimately, these experiments aim to uncover mechanistic insights into bacterial antagonism under xenobiotic stress and explore how adaptive responses within microbial communities influence the resilience towards invading pathogens. Together, this project will provide new insights into how xenobiotic pressures shape microbial ecosystems and pathogen resilience, with translational implications for future microbiome-based therapeutics.