Chemical modulation of gut bacterial metabolism induces colanic acid and extends the lifespan of nematode and mammalian hosts

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans . In the mouse gut, oral administration of low-dose cephaloridine induced transcription of the capsular polysaccharide synthesis ( cps ) operon responsible for CA biosynthesis in commensal E. coli at 37 °C, and attenuated age-related metabolic changes. We also found that low-dose cephaloridine overcomes the temperature-dependent inhibition of CA biosynthesis and promotes its induction through a mechanism mediated by the membrane-bound histidine kinase ZraS, independently of cephaloridine’s known antibiotic properties. Our work lays a foundation for microbiota-based therapeutics through chemical modulation of bacterial metabolism and highlights the promising potential of leveraging bacteria-targeting drugs in promoting host longevity.