Deciphering Molecular Mechanisms Underlying Outer Membrane Biogenesis of Human Gut Microbiome Species

Objective

The human gut microbiome profoundly influences health by aiding digestion, defending against pathogens, and producing essential metabolites. While large-scale initiatives have advanced our understanding of microbiome composition and diversity, we still lack fundamental insight into its functional diversity, as many gut species diverge significantly from established model organisms at the genetic and phenotypic levels. This gap limits our ability to design microbiome-targeted therapeutics. Bacteroides, the most abundant genus in the human gut, plays a central role in degrading complex dietary sugars and is thus a prime candidate for therapeutic strategies. A key feature underlying its success in gut colonization and defining characteristic for this phylum is its outer membrane (OM), enriched in surface lipoproteins (twice as many genes compared to E. coli). Lipoproteins come in two flavours: outer membrane proteins (OMPs) and surface-exposed lipoproteins (SELs), which together form a structural scaffold for the OM, and are essential for nutrient acquisition and communication with the host. However, the molecular principles by which Bacteroides traffics and assembles these lipoproteins into a functional OM remain largely unexplored. The Microbi-OM project intends to uncover the mechanisms of OM biogenesis in Bacteroides by dissecting the role of the translocation and assembly module (TAM) complex in lipoprotein surface exposure, (phospho)lipid transport, and coordination with other OM biogenesis pathways. Through high-throughput functional genomics, in situ cross-linking, and proteomics, this project will deliver unprecedented molecular insights into how key gut commensals build and maintain their OM. By expanding the toolkit for studying non-traditional model organisms, Microbi-OM will set the stage for rational microbiome engineering and the development of next-generation therapeutics.