Targeting the aryl hydrocarbon receptor by gut phenolic metabolites: A strategy towards gut inflammation.

The Aryl Hydrocarbon Receptor (AHR) is a ligand-dependent transcription factor able to control complex transcriptional processes in several cell types, which has been correlated with various diseases, including inflammatory bowel diseases (IBD). Numerous studies have described different compounds as ligands of this receptor, like xenobiotics, natural compounds, and several host-derived metabolites. Dietary (poly)phenols have been studied regarding their pleiotropic activities (e.g., neuroprotective and anti-inflammatory), but their AHR modulatory capabilities have also been considered. However, dietary (poly)phenols are submitted to extensive metabolism in the gut (e.g., gut microbiota). Thus, the resulting gut phenolic metabolites could be key players modulating AHR since they are the ones that reach the cells and may exert effects on the AHR throughout the gut and other organs. This review aims at a comprehensive search for the most abundant gut phenolic metabolites detected and quantified in humans to understand how many have been described as AHR modulators and what could be their impact on inflammatory gut processes. Even though several phenolic compounds have been studied regarding their anti-inflammatory capacities, only 1 gut phenolic metabolite, described as AHR modulator, has been evaluated on intestinal inflammatory models. Searching for AHR ligands could be a novel strategy against IBD.

Specific Eco-evolutionary Contexts in the Mouse Gut Reveal Escherichia coli Metabolic Versatility.

Members of the gut microbiota are thought to experience strong competition for nutrients. However, how such competition shapes their evolutionary dynamics and depends on intra- and interspecies interactions is poorly understood. Here, we test the hypothesis that Escherichia coli evolution in the mouse gut is more predictable across hosts in the absence of interspecies competition than in the presence of other microbial species. In support, we observed that lrp, a gene encoding a global regulator of amino acid metabolism, was repeatedly selected in germ-free mice 2 weeks after mono-colonization by this bacterium. We established that this specific genetic adaptation increased E. coli's ability to compete for amino acids, and analysis of gut metabolites identified serine and threonine as the metabolites preferentially consumed by E. coli in the mono-colonized mouse gut. Preference for serine consumption was further supported by testing a set of mutants that showed loss of advantage of an lrp mutant impaired in serine metabolism in vitro and in vivo. Remarkably, the presence of a single additional member of the microbiota, Blautia coccoides, was sufficient to alter the gut metabolome and, consequently, the evolutionary path of E. coli. In this environment, the fitness advantage of the lrp mutant bacteria is lost, and mutations in genes involved in anaerobic respiration were selected instead, recapitulating the eco-evolutionary context from mice with a complex microbiota. Together, these results highlight the metabolic plasticity and evolutionary versatility of E. coli, tailored to the specific ecology it experiences in the gut.