IN and OUT · In with the good, out with the bad: understanding small molecule influx and efflux in gut Bacteroides.

The human gut microbiome can be considered a virtual organ that has a profound influence on many aspects of human health. While very diverse at the species level, the human gut microbiome is dominated by just two bacterial phyla, the Gram-positive Firmicutes and the Gram-negative Bacteroidetes. The Bacteroides genus belongs to the Bacteroidetes phylum and is the most abundant genus within the gut of western world populations. Due to their abundance and their well-characterised ability to break down dietary glycans that are inaccessible to the host, Bacteroides are keystone species that shape the human gut microbiome. However, to thrive within the gut, Bacteroides need to take up many small molecules besides glycans (INFLUX), and noxious compounds such as bile acids and antibiotics need to be removed from the cell (EFFLUX). Both processes are crucial for fitness within the highly competitive environment of the human gut, and depend critically on lipoproteins, channels and transporters residing in the bacterial outer membrane (OM). In this proposal we will identify and characterise OM influx and efflux processes in gut Bacteroides via a pioneering approach including structural biology, proteomics, and metabolomics. Compared to Proteobacteria in which these processes have been studied in detail, OM influx and efflux in the phylogenetically distant Bacteroides is largely terra incognita. However, based on what we do know, it is clear that the OM and OM proteins of Bacteroides are very different from those of well-studied bacterial model systems. By delivering a step-change in our understanding, this project will not only result in groundbreaking new knowledge of the ""ins and outs"" of arguably the most important microbial genus in the gut but should also inform approaches for gut microbiota manipulation to improve human health.""