Directed evolution of the Drosophila microbiome improves intestinal health and extends lifespan

The gut microbiome and its bacterially derived metabolites are known to affect many aspects of the host organism's health, including metabolism, immune response, intestinal inflammation, oxidative stress, and even lifespan. Because pathological changes in the gut microbiome and these functions are associated with aging, many have hypothesized that we could protect against aging by generating beneficial changes to the gut microbiome. Here, we directed evolution outside of the host ( ex vivo ) and generated a Drosophila gut microbiome resistant to paraquat, a toxin that causes oxidative stress. Compared to a control microbiome, this paraquat-resistant (PQR) microbiome transplanted back into the Drosophila gut endowed the host with multiple health benefits: increased resistance to dietary paraquat, reduced age-related pathologies in the gut, and extended lifespan. We identified the beneficial species of the PQR microbiome as Lactiplantibacillus plantarum and further identified mutations specific to lifespan-extending isolates linked to greater production of acetate. Directly feeding this short-chain fatty acid, acetate, to Drosophila was sufficient to recapitulate an extended lifespan, similar to that induced by gut colonization of PQR bacteria in the gut. These results serve as a proof of principle that increasing the resistance of the microbiome to oxidative stress via directed ex vivo evolution could serve as a therapeutic strategy to protect against aging.