Microbial modulation of endocrine signaling in C. elegans

The rising prevalence of metabolic disorders, such as type 2 diabetes (T2D) contribute to kidney, liver, and cardiovascular diseases, posing a major public health challenge. While poor diet and dysregulated endocrine signaling are known drivers of these disorders, recent studies underscore the critical role of gut microbiota in the development of these conditions. Gut microbiota-derived metabolites, including short-chain fatty acids and secondary bile acids, affect enteroendocrine cells (EECs), which regulate energy balance and glucose metabolism via the gut-brain axis. Patients with T2D often exhibit gut microbial dysbiosis and an increase in opportunistic pathogens. Studies have shown that modifying gut microbiota can enhance hormone secretion from EECs and improve insulin resistance. However, the complex interplay between gut microbiota, host genetics, and life stages underscores the need to better understand the roles of specific microbes and endocrine cells within these networks. The invertebrate model organism C. elegans shares highly conserved physiology with vertebrates, including homologs for insulin and nuclear hormone receptors involved endocrine regulation of glucose and fatty acid metabolism. In its natural environment, C. elegans interacts with diverse microbes that impact its behavior and metabolism through key endocrine processes. Research has demonstrated that microbes influence insulin ligand production, receptor sensitivity, and lipid mobilization in C. elegans. Thus, the proposed project will utilize C. elegans and the natural microbiome collection (CeMbio) to investigate microbial regulation of endocrine signaling with depth and breadth: 1) In-depth, the project will map the genetic circuits connecting commensal bacteria to host endocrine signaling by identifying the enteroendocrine and neuronal signals involved, pinpointing bacterial metabolites that trigger host responses, and characterizing the downstream host effectors that regulate gut colonization. 2) In-breadth: the project will create an open-access database cataloging C. elegans endocrine gene expression in response to individual CeMbio strains and defined microbial communities. This database will apply machine learning to identify bacterial functions that regulate host endocrine signaling, serve as a resource for generating new hypotheses for the research community, and support research training to promote diversity in the STEM workforce. These efforts will deepen the understanding of how the microbiome influences the gut-brain axis and guide the development of microbiome-based interventions to improve human health.