Decoding the role of dietary xenobiotic-active CAZymes in Ruminococcus gnavus: mechanisms, microbiome interactions, and health implications

Objective

The human gut microbiota plays a central role in health and disease, with diet being one of its strongest modulators. While much is known about the microbial enzymes that degrade diet polysaccharides in the human gut, the metabolism of dietary xenobiotics (XB), small bioactive compounds often glycosylated, are poorly understood. Dietary XB deglycosylation by gut bacteria releases metabolites that can influence microbial ecology and host physiology, yet the enzymes driving these transformations are largely unknown. This project will investigate novel XB-active carbohydrate-active enzymes (XB-CAZymes) in the human gut symbiont Ruminococcus gnavus, a strain-diverse species prevalent across populations and strongly associated with inflammatory bowel disease. Through multi-omics, recombinant enzyme production, enzymatic assays, and structural biology, XB-CAZymes will be identified and their mechanisms of action characterised. Functional validation will be carried out using R. gnavus knockout mutants, while advanced in vitro models of the human gut will assess how XB metabolites affect gut barrier integrity and immune responses. R. gnavus isolation and multi-omics analyses of human faecal samples from an existing elderly cohort will provide ecological and interindividual perspectives, linking enzyme function to microbiome variability and health implications. The project will generate fundamental knowledge to refine CAZy classification, uncover biomarkers and therapeutic targets, and identify enzymes with biotechnological potential. Beyond scientific advances, the fellowship will provide the researcher with first-hand expertise in cutting-edge integrative microbiome science, preparing them to lead interdisciplinary research at the interface of diet, microbiota, and health in Europe and internationally.