Recognition of commensal bacterial peptidoglycans definesDrosophilagut homeostasis and lifespan

Abstract

AbstractCommensal microbes in animals have a profound impact on tissue homeostasis, stress resistance, and ageing. We previously showed inDrosophila melanogasterthatAcetobacter persiciis a member of the gut microbiota that promotes ageing and shortens fly lifespan. However, the molecular mechanism by which this specific bacterial species changes lifespan and physiology remains unclear. The difficulty in studying longevity using gnotobiotic flies is the high risk of contamination during ageing. To overcome this technical challenge, we used a bacteria-conditioned diet enriched with bacterial products and cell wall components. Here, we demonstrate that anA. persici-conditioned diet shortens lifespan and increases intestinal stem cell (ISC) proliferation. Feeding adult flies a diet conditioned withA. persici, but not withLactiplantibacillus plantarum, can decrease lifespan but increase resistance to paraquat or oral infection ofPseudomonas entomophila, indicating that the bacterium alters the trade-off between lifespan and host defence. A transcriptomic analysis using fly intestine revealed thatA. persicipreferably induces antimicrobial peptides (AMPs), whileL. plantarumupregulates amidase peptidoglycan recognition proteins (PGRPs). The specific induction of these Imd target genes by peptidoglycans from two bacterial species is due to the stimulation of the receptor PGRP-LC in the anterior midgut for AMPs or PGRP-LE from the posterior midgut for amidase PGRPs. Heat-killedA. persicialso shortens lifespan and increases ISC proliferation via PGRP-LC, but it is not sufficient to alter the stress resistance. Our study emphasizes the significance of peptidoglycan specificity in determining the gut bacterial impact on healthspan. It also unveils the postbiotic effect of specific gut bacterial species, which turns flies into a “live fast, die young” lifestyle.Author SummaryMicrobiota plays a vital role in our health, but it can also have a negative impact on the lifespan of certain model organisms, such as the fruit fly Drosophila melanogaster. Despite its impact, the molecular mechanism behind how gut bacteria limits host lifespan remains unclear. In this study, we investigated the mechanism that one specific species of microbiota shortens lifespan and disrupts gut homeostasis of the aged flies, using a “fermented” fly diet. We found that the specific effects of this bacterium on fly healthspan were due to its capability of stimulating a specific receptor in the gut that recognizes peptidoglycan, a component of bacterial cell wall. Paradoxically, the same bacterium also increases stress resistance and defence against oral infection of a pathogen. Our study provides insight into the mechanisms underlying how certain members of the microbiota can lead to a “life fast, die young” lifestyle.