How does microbiota-born peptidoglycan affect host homeostasis? – Peptimet

A universal feature of organisms with open digestive tracts is colonization of the gastrointestinal tract by a characteristic commensal microbiota. This microbiota, which thrives on the nutrients produced by host’s diet, is shaped by host-specific selective pressures such as the intestinal environment and food preference. In turn, the microbiota manipulates host metabolism by generating essential nutrients and excreting metabolites that serve as a form of interspecies communication. Intestinal bacteria are therefore implicated in setting basal metabolic tone, educating the immune system or even in impacting central functions, such as appetite control and mood. Studies in mice and humans have allowed considerable progress in defining how intestinal bacteria influence human physiology and metabolism. However, the mechanisms underlying microbiota-host communication are extremely complex and remain largely to be elucidated. Because of its less-complex and more-tractable microbiota in comparison to mammals, Drosophila provides a useful model in which to study the governing principles of the host’s metabolic interaction with its microbiota. Our previous results have shown that the universal bacterial cell wall component, peptidoglycan, is one of the key mediator of the dialog between Drosophila and its gut microbiota. Sensing of microbiota-derived PGN by pattern recognition receptor belonging to the PGRP (peptidoglycan recognition receptors) family activates the NF-kB pathway locally in the enterocytes. Activation of this pathway which shares homology with the mammalian Tumor-Necrosis-Factor-??pathway, is essential to produce antimicrobial peptides (AMP) which, in turn, shape gut microbiota. In certain circumstances, the same gut-born PGN can cross the gut epithelium and reaches the insect blood where it acts on organs and tissues that are bathing within it. If the sporadic presence of PGN in the hemolymph is beneficial for the host by inducing AMP production by immune cells, we have shown that higher and longer exposures to PGN have deleterious effects on internal organ physiology and in fine on fly fitness. Indeed, flies with chronic gut bacterial infection present cachexia-like organ wasting which are only due to PGN-dependent improper NF-kB signaling in cells that were not identified, so far. Our latest genetic data demonstrate that the gut-derived PGN is able to reach and to signal to the outer most glial cells forming the blood-brain-barrier. PGN dependent NF-kB activation in these cells induces, in turn, wasting of the energy storing organs such as the fat body, the muscles and the ovaries. If these data demonstrate that PGN is a major regulator of the Gut-Brain communication in eukaryotes, we are still far from understanding how this microbiota derives metabolites affects the physiology of its host.
We propose here to tackle this issue by combining the expertise and know-how of a Drosophilist studying bacteria-host interactions and a microbiologist specialized in peptidoglycan. Both teams, one in flies and the other in mice, are interested in understanding how is microbiota-derived PGN able to reach remote organs and to characterize the impact that PGN sensing has on these peripheral organs. Using PGN labeled by different methods, we will try to follow the PGN trajectory from the gut to the rest of the body. Taking advantage of the genetic tools available in flies, we will dissect the molecular mechanisms by which PGN sensing by the Blood-Brain-Barrier regulated metabolism in energy storing organs and how a deregulation of this process causes cachexia-like organ wasting. We firmly believe that, given the remarkable evolutionary conservation in most immune-metabolic mechanisms, the results generated by this project will be of significant relevance to an in-depth understanding of the dialog between the host and its microbiota in organisms other than Drosophila, and namely in humans.