Bacterial sensing via neuronal Nod2 regulates appetite and body temperature

Abstract

Gut bacteria influence brain functions and metabolism. We investigated whether this influence can be mediated by direct sensing of bacterial cell wall components by brain neurons. In mice, we found that bacterial peptidoglycan plays a major role in mediating gut-brain communication via the Nod2 receptor. Peptidoglycan-derived muropeptides reach the brain and alter the activity of a subset of brain neurons that express Nod2. Activation of Nod2 in hypothalamic inhibitory neurons is essential for proper appetite and body temperature control, primarily in females. This study identifies a microbe-sensing mechanism that regulates feeding behavior and host metabolism.

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

“…Growing evidence suggests a gut-brain axis connecting microbiota peptidoglycan translocation to effects on the brain 10,29,30 . Our data indicate that for studies of peptidoglycan effects on the brain, the route of delivery is a critical factor.…”

“…Intravenously administered peptidoglycan was not detected in the brain, and absence from the brain was even more striking when administered intraperitoneally, since a higher relative abundance of peptidoglycan was observed in the spleen, liver, kidney and fat. Growing evidence suggests a gut-brain axis connecting microbiota peptidoglycan translocation to effects on the brain 10,29,30 . Our data indicate that for studies of peptidoglycan effects on the brain, the route of delivery is a critical factor.…”

“…One such class of MAMP, the bacterial cell wall component peptidoglycan, is well-characterized as a key inflammatory molecule in acute and chronic conditions, and increasingly recognized as an important mediator of steady-state phenomena in the host. These effects are not limited to the gut where the microbiota resides 3 , but include the broader host physiology and behaviors, facilitated by the continuous dissemination of peptidoglycan fragments across the intestinal epithelial barrier 4–10 , for which a variety of mechanisms have been proposed 11 . Nevertheless, a clear understanding of the basic principles governing the absorption and dissemination of microbiota peptidoglycan throughout the host system is lacking.…”

Tea Polyphenols as Prospective Natural Attenuators of Brain Aging

“…Recently, it has been found that hypothalamic neurons can directly sense the structural components of the intestinal bacterial microbiota and control food intake and body temperature [ 129 ]. The researchers knocked out the Nod2 of inhibitory γ-aminobutyric acid neurons in mice and found that peptidoglycan derivative cell wall peptides no longer exerted an inhibitory effect.…”

Non-invasive Fluorescence Imaging of Gut Commensal Bacteria in Live Mice

“…These range from immune dysfunctions (e.g., allergies and numerous autoimmune conditions) to endocrine system disorders (e.g., obesity and diabetes). [2][3][4][5] Very recently, fragments of peptidoglycan (PG) within the bacterial cell wall were shown to play a major role in mediating gut-brain communication by regulating appetite and body temperature in mice 6 and in strongly modulating responses to check-point inhibitors of immunotherapies in mouse tumor models. 7 In the case of severe disruptions to the gut bacterial communities (e.g., colitis caused by Clostridium difficile), it is more straight forward to establish a clear connection and causational link.…”