PROJECT SUMMARY/ABSTRACT There is an increasing level of appreciation in the fields of environmental health sciences and toxicology on the critical role of the gut microbiota on the host response to toxic chemical exposure. The microbiota is known to directly and indirectly influence the extent of toxicity of dietary and environmental chemicals, and has been implicated in a wide-range of diseases including metabolic disorders, cancer, and inflammatory diseases. Careful and rigorous experimentation to determine the mechanism by which the microbiota influences environmental chemical exposure will lead to a more complete understanding of how these chemicals disrupt the host- microbiota interaction and will generate novel insights into the key signaling pathways underlying those perturbations and adverse health outcomes. Importantly, studies of the microbiota and environmental chemicals may provide key insights that will better inform risk assessment that could positively impact human health. In this R35 RIVER proposal, we plan to work across three innovative and complementary themes to address the unifying hypothesis that environmental chemical exposure perturbs the host-gut microbiota interaction to adversely affect health. First, using mouse models, we will explore the idea that early-life exposure to environmental chemicals impacts later life health outcomes (e.g., metabolic disorders, acute and chronic inflammatory bowel disorders) via alterations in the host-gut microbiota axis. Second, we will examine how environmental chemicals impact common commensal microbes of the gastrointestinal tract including their metabolic activities and potential to modulate host physiology. Third, we will explore new pathways involved in microbiota control and influence of host physiologic processes. To achieve these goals, we have assembled a diverse, collaborative, and highly interdisciplinary team consisting of experts in biochemistry, enzymology, immunology, metabolism, microbiology, transcriptional regulation, and toxicology. The Patterson lab has a long history of making unique and seminal discoveries along the host-gut microbiota axis and thus is well-positioned with cutting-edge technology and approaches, experience, innovative ideas, and an open/collaborative environment to advance our understanding of the host-gut microbiota interaction and help to move the field forward. From a translational standpoint, these studies may lead to new protective approaches toward dietary and environmental toxicity through design of new pre/probiotics.

NARRATIVE The gut microbiota can be perturbed by environmental factors including diet composition, xenobiotic exposure (e.g., environmental toxicants, antibiotics) and life-style (smoking, exercise, stress, social interactions); thus, a better understanding of the functional role of microbiome and its regulation of host metabolic responses is an important prerequisite for designing microbiome-specific therapeutic strategies. This study will provide insight into how exposure (including dose and timing) to environmentally relevant toxicants interacts with the host and gut microbiota to affect health. Important outcomes include improved understanding of the gut microbiota in the response to toxic insult and the identification of toxicity levels that can be used to establish possible microbial toxicity endpoints which will likely help to inform hazard identification and risk assessment.