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A gut sense for a microbial pattern regulates feeding

ABSTRACT: To coexist with its resident microorganisms, the host must have a sense to adjust its behaviour in response to them. In the intestine, a sense for nutrients transduced to the brain through neuroepithelial circuits guides appetitive choices. However, a sense that allows the host to respond in real time to stimuli arising from resident gut microorganisms remains to be uncovered. Here we show that in the mouse colon, the ubiquitous microbial pattern flagellin—a unifying feature across phyla—stimulates Toll-like receptor 5 (TLR5) in peptide YY (PYY)-labelled colonic neuropod cells. This stimulation leads to PYY release onto NPY2R vagal nodose neurons to regulate feeding. Mice lacking TLR5 in these cells eat more and gain more weight than controls. We found that flagellin does not act on the nerve directly. Instead, flagellin stimulates neuropod cells from the colonic lumen to reduce feeding through a gut–brain sensory neural circuit. Moreover, flagellin reduces feeding independent of immune responses, metabolic changes or the presence of gut microbiota. This sense enables the host to adjust its behaviour in response to a molecular pattern from its resident microorganisms. We call this sense at the interface of the biota and the brain the neurobiotic sense.

ORGANISM(S): Mus musculus

PROVIDER: GSE288590 | GEO | 2025/05/08

REPOSITORIES: GEO

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Project description:The healthy gut microbiota is composed of three different functional subgroups, symbionts, commensals and pathobionts. Additionally, infection with pathogenic bacteria can occur. Microbe Associated Molecular Patterns (MAMPs) are expressed by most members of both, microbiota and pathogens and interact with Pattern Recognition Receptors (PRRs), resulting in activation of the innate immune system. It is still unclear whether the interaction of PRRs with MAMPs of different origin, leads to a differential activation of innate immunity and whether thereby, distinction can be made between symbionts, commensals, pathobionts and pathogens. Here we addressed the question whether the interaction of flagellin with Toll-like receptor 5 (TLR5) might be a possible mechanism of the innate immune system to distinguish between the different microbial subgroups and initiate the respective immune response. To characterize distinct cellular immune responses to symbiont or pathogen derived flagellin we run transcriptomics, phosphoproteomics and proteomics of TLR5 overexpressing cells. Responses to different flagellins were characterized by differential kinetics and regulation of protein phosphorylation as well as variant protein expression patterns. In vivo experiments revealed that commensal derived flagellin mediated an inert TLR5 signal, thus not affecting Dextran-Sodium-Sulfate (DSS) induced intestinal inflammation. In vitro pathogenic derived flagellin induced a strong pro-inflammatory TLR5 response and did not ameliorate intestinal inflammation. In contrast, symbiont derived flagellin revealed an intermediate TLR5 activation and clearly ameliorated DSS induced intestinal inflammation thus shifting the host immune response in favor of mucosal immune balance. Bone marrow chimeric mice proofed that CD11c+TLR5+ intestinal lamina propria cells mediate the anti-inflammatory symbiotic effect of flagellin. We suggest that the quality of flagellin-induced TL signal might determine the balance between homeostasis and intestinal inflammation and may help the innate immune system to distinguish between symbionts, commensals, pathobionts and pathogenic microbes. We used microarrays to analyze differential expression of genes between treatments with flagellins of E. coli Nissle (EcN) and Salmonella Typhimurium SL1344 (ST).

Project description:BACKGROUND: The gut microbiome and the host immune system interact synergistically to maintain intestinal health and defend against infections. Toll-like receptor 5 (TLR5), known for recognizing bacterial flagellin, plays a pivotal role in this regulatory network. Despite significant advances in understanding the gut microbiome and TLR5, the precise role of TLR5 in gut health and infection resistance remains unclear. This study aimed to elucidate the role of TLR5 in regulating gut microbiota and metabolites and their impact on resistance to Salmonella infection using a TLR5 intestinal-specific overexpression mouse model. METHODS: Fecal microbiota and metabolite transplantation experiments were conducted using feces from TLR5-overexpressing mice (TLR5+/+ group) and wild-type mice (WT group) into C57 mice, creating four experimental groups: Flora-TLR5-C57, Metabolite-TLR5-C57, Flora-WT-C57 and Metabolite-WT-C57. Mice were infected with Salmonella, and various parameters including survival time, fecal Salmonella load, and alterations in gut microbiota and metabolites were assessed. RESULTS: Despite notable shifts in gut microbiota composition and metabolite profiles induced by TLR5 overexpression, no significant differences in fecal Salmonella load or survival time were observed across the experimental groups. TLR5-overexpressing mice exhibited an enrichment of beneficial bacterial taxa and significant changes in metabolites; however, these alterations did not correlate with enhanced resistance to Salmonella infection. CONCLUSION: Our findings suggest that while TLR5 overexpression significantly modifies gut microbiota and metabolite profiles, these changes do not directly enhance resistance to Salmonella infection. The immune response to Salmonella is multifaceted and involves various components beyond the gut microbiota and metabolites. Further research is required to elucidate the detailed molecular pathways through which TLR5 influences infection outcomes and to explore potential combined therapeutic strategies for enhancing host defenses against enteric pathogens.

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A gut sense for a microbial pattern regulates feeding

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