In:
Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6590 ( 2022-04-15)
Abstract:
Compounds released by the microbiota are found in the bloodstream and can modulate physiological processes in the host, such as immunity, metabolism, and brain functions. Microbial metabolites, including short-chain fatty acids and tryptophan derivatives, regulate many processes through receptors that are widely expressed. However, the structural components of microbes are detected by pattern recognition receptors (PRRs) that signal the presence of viruses, bacteria, or fungi on mucosal surfaces, in tissues, and in cells. Bacterial components have been found to modulate brain activity, and PRRs are associated with brain disorders. Whether brain neurons can directly sense bacterial components and whether bacteria can regulate physiological processes through regulation of brain neurons remains to be demonstrated. RATIONALE Mice that lack neuronal expression of Nod2—a PRR recognizing fragments of the bacterial cell wall termed muropeptides—develop alterations in food intake, nesting behavior, and body temperature control. We used brain imaging to identify regions affected by the oral administration of muropeptides and measured the modulation of neuronal activity by muropeptides. We also developed mice that lack Nod2 expression in subsets of neurons and in regions of the hypothalamus that regulate feeding behavior and body temperature, so as to assess the impact of the gut-brain axis on the regulation of host metabolism. Finally, we used patch-clamp recordings to assess whether neurons directly respond to muropeptides. RESULTS Using reporter mice and in situ hybridization techniques, we found that Nod2 was expressed in neurons of several brain regions including the hypothalamus. Older female mice lacking expression of Nod2 in inhibitory γ-aminobutyric acid transporter–positive (GABAergic) neurons ate more and consequently gained more weight than normal mice. Oral administration of muramyl dipeptide (MDP), a muropeptide ligand of Nod2, reduced feeding but only when activating Nod2 in GABAergic neurons. These mice also showed a reduced propensity to build nests, a behavioral trait related to heat conservation, as well as reduced temperature regulation in response to the circadian rhythm, fasting, and adrenergic stimulation. MDP, administered orally or as muropeptides produced by intestinal bacteria, reached the brain and regulated neurons in diverse brain areas of older female mice, including the arcuate nucleus of the hypothalamus, which is involved in the regulation of feeding behavior and body temperature. The activity of GABAergic neurons of the arcuate nucleus was depressed upon feeding and was similarly depressed upon oral administration of MDP. Infusion of MDP in single neurons and patch-clamp recording of neuron excitability demonstrated that MDP-mediated control of GABAergic neurons was cell-autonomous. We next tested whether the expression of Nod2 in hypothalamic GABAergic neurons was necessary to control food intake and body temperature. Indeed, the ablation of the Nod2 gene in hypothalamic neurons alone using the local injection of a Cre-expressing virus led to weight gain in older mice. Moreover, this treatment altered nest building behavior and body temperature control. The intestinal microbiota is the most probable source of Nod2 ligand in this context, as oral antibiotic treatment abrogated the Nod2-mediated control over feeding. CONCLUSION Our study shows that structural components of the bacterial microbiota can be directly sensed by hypothalamic neurons to regulate feeding behavior, nesting behavior, and body temperature. In this way, intestinal bacteria may be used by the brain as an indirect measure of food intake or as a direct measure of bacterial expansion or death attributable to food intake. In the latter scenario, bacterial expansion or death may be associated with perturbation of intestinal homeostasis or a risk of pathogenesis. Alternatively, resident bacteria may regulate food intake to protect their intestinal niche. Metabolic control via the gut-brain axis. Food consumption induces expansion of the intestinal microbiota. This expansion is followed by an increase in muropeptide release from the gut bacteria. When they reach the brain, these muropeptides target a subset of inhibitory hypothalamic neurons. In older females, activation of neuronal Nod2 receptors by muropeptides decreases neuronal activity, which in turn helps to regulate satiety and body temperature.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abj3986
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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