Microbiota Derived Lactate Activates Production of Reactive Oxygen Species by the Intestinal NADPH Oxidase Nox and Shortens Drosophila Lifespan
&NA; Commensal microbes colonize the gut epithelia of virtually all animals and provide several benefits to their hosts. Changes in commensal populations can lead to dysbiosis, which is associated with numerous pathologies and decreased lifespan. Peptidoglycan recognition proteins (PGRPs) are important regulators of the commensal microbiota and intestinal homeostasis. Here, we found that a null mutation in Drosophila PGRP SD was associated with overgrowth of Lactobacillus plantarum in the fly gut and a shortened lifespan. L. plantarum derived lactic acid triggered the activation of the intestinal NADPH oxidase Nox and the generation of reactive oxygen species (ROS) In turn, ROS production promoted intestinal damage, increased proliferation of intestinal stem cells, and dysplasia. Nox mediated ROS production required lactate oxidation by the host intestinal lactate dehydrogenase, revealing a host commensal metabolic crosstalk that is probably broadly conserved. Our findings outline a mechanism whereby host immune dysfunction leads to commensal dysbiosis that in turn promotes age related pathologies. Graphical Abstract Figure. No caption available. HighlightsPGRP SD mutant is short lived due to dysplasia caused by excessive load of L. plantarumL. plantarum derived lactic acid triggers ROS via the intestinal NADPH oxidase NoxOxidation of lactate by the intestinal lactate dehydrogenase generates NADH for NoxPGRP SD overexpression prevents dysbiosis and extends lifespan &NA; Iatsenko et al. find that flies bearing a mutation in a peptidoglycan recognition protein exhibit dysbiosis and shortened lifespan. In these flies, the unrestricted growth of a commensal bacterium generates excessive lactate, which triggers ROS production in intestinal cells and subsequent dysplasia. This ROS producing pathway is conserved, suggesting relevance of such host microbe metabolic crosstalk in age related pathologies in humans.
Immunity