Microbiota-induced active translocation of peptidoglycan across the intestinal barrier dictates its within-host dissemination

Abstract

Peptidoglycan, the major structural polymer forming the cell wall of bacteria, is an important mediator of physiological and behavioral effects in mammalian hosts. These effects are frequently linked to its translocation from the intestinal lumen to host tissues. However, the modality and regulation of this translocation across the gut barrier has not been precisely addressed. In this study, we characterized the absorption of peptidoglycan across the intestine and its systemic dissemination. We report that peptidoglycan has a distinct tropism for host organs when absorbed via the gut, most notably by favoring access to the brain. We demonstrate that intestinal translocation of peptidoglycan occurs through a microbiota-induced active process. This process is regulated by the parasympathetic pathway via the muscarinic acetylcholine receptors. Together, this study reveals fundamental parameters concerning the uptake of a major microbiota molecular signal from the steady-state gut.

In silico MS/MS prediction for peptidoglycan profiling uncovers novel anti-inflammatory peptidoglycan fragments of the gut microbiota

“…2,3 Soluble peptidoglycan fragments, also known as PGNs or muropeptides, are continuously generated by bacteria during growth and released into the milieu, exerting a broad-range impact on different organisms. 4 In the context of the human gut microbiota, trillions of resident bacteria produce a multitude of PGNs in the gut niche, 5 which can disseminate into host systemic circulation under steadystate conditions, 6 inuencing host biology including autoimmunity, brain development, appetite, and body temperature, as well as efficacies of cancer immunotherapy. [7][8][9][10] Remarkably, subtle structural changes in PGNs can signicantly alter their biological activities in hosts.…”

Noninvasive Analysis of Peptidoglycan from Living Animals

“…Despite the growing appreciation that gut bacterial sacculi (and their peptidoglycan fragments) are bona fide interspecies signaling molecules, , the direct characterization of polymeric sacculi from living organisms has not been extensively evaluated. The Boneca laboratory used radiolabeled sacculi that were labeled in vitro to define the translocation of peptidoglycan into host tissues . Given the vast diversity of the gut microbiota, including a large fraction that has yet to be cultured in vitro, the isolation of sacculi from gut bacterial communities may represent our most reliable access point to polymeric precursors to these peptidoglycan-host signaling molecules.…”

“…Radiolabeled sacculi that were orally administered to mice translocated to the circulatory system and led to subsequent systemic dissemination. 33 Despite the growing appreciation that gut bacterial sacculi (and their peptidoglycan fragments) are bona fide interspecies signaling molecules, 34,35 the direct characterization of polymeric sacculi from living organisms has not been extensively evaluated. The Boneca laboratory used radiolabeled sacculi that were labeled in vitro to define the translocation of peptidoglycan into host tissues.…”

Non-invasive Analysis of Peptidoglycan from Living Animals

“…Radiolabeled sacculi that were orally administered to mice translocated to the circulatory system and led to subsequent systemic dissemination. 28 5 Despite the growing appreciation that gut bacterial sacculi (and its peptidoglycan fragments) are bona fide interspecies signaling molecules, 29 the direct isolation of sacculi from living organisms has not been properly evaluated. Given the vast diversity of the gut microbiota, including a large fraction that has yet to be cultured in vitro, the isolation of sacculi from gut bacterial communities may represent our most reliable access point to polymeric precursors to these peptidoglycan-host signaling molecules.…”

“…Radiolabeled sacculi that were orally administered to mice translocated to the circulatory system and led to subsequent systemic dissemination. 28…”