Impacts of non-antibiotic medications on microbiome-mediated protection against intestinal pathogens

PROJECT SUMMARY Antibiotic usage disrupts intestinal homeostasis and is associated with an increased risk of infections in humans. Recent evidence suggests that non-antibiotic prescription medications can change microbiome composition, but how drug-microbiome interactions impact the risk of gastrointestinal (GI) disease is unexplored. To address this gap in knowledge, we analyzed health records, including hospitalization, drug prescription data, and pharmacy claims, for over 1 million anonymized individuals spanning 15 years to identify medications associated with increased risk of GI infection. We identified expected associations, including anti-infectives and immunosuppressive agents, that increase infection risk. Notably, we also identified unexpected associations: other prescription medications that elevate infection risk to a similar degree as antibiotics and immunosuppressants but do not fall into either of these drug classes. The central hypothesis of this proposal is that treatment with non-antibiotic prescription medications disrupts the microbiome to increase the risk of intestinal infections. We established a mouse model of Salmonella enterica subsp. Typhimurium (S. Tm) infection for two of these drugs (the cardiac drug digoxin and the anticonvulsant clonazepam), and demonstrated that drug administration increases infection risk and also alters microbiome composition. In our initial (proof-of- concept) studies, we established that the impact of digoxin on infection risk is transmissible via the microbiome. Specifically, digoxin decreases the abundance of a key group of immunomodulatory bacteria (segmented filamentous bacteria; SFB) in the mouse gut, and restoring the abundance of these bacteria rescues mice from increased infection susceptibility. Notably, clonazepam also increases infection risk, but in an SFB-independent manner. Building on this work, in Aim 1 of this proposal, I will 1) determine how digoxin alters SFB levels in the mouse gut and 2) examine whether human microbiome variability alters digoxin effects on the microbiome and S. Tm infection. I will use a similar approach in Aim 2 to examine whether clonazepam increases pathogen colonization by disrupting the microbiome. Through these aims, I will enrich my experience in mucosal immunology, analysis of large datasets, epidemiological study designs, and mouse models of infection (K99 phase). To enable this training, I have established a mentoring and advisory team consisting of experts in drug- microbiome studies, S. Tm pathogenesis, mucosal immunology, and epidemiological study designs. As I transition into independence, I will build on this unique foundation to define mechanisms of the impacts of prescription medications on the gut microbiome and infection risk (R00 phase). These studies will allow us to understand the effects of these bioactive compounds on the gut microbial communities, which are important in maintaining gut health. The underlying molecular mechanisms discovered by the completion of this study will enable us to develop strategies for mitigating GI diseases using microbiome-mediated interventions.