A New Gut Sense: How Microbial Cues May Quickly Shape Appetite

Imagine you’re about to eat, and then your appetite simply fades. What might have happened?

One possibility involves microorganisms living in the gut. The intestinal microbiota can engage gut–brain neural circuits, but the molecular mechanisms mediating these interactions remain incompletely understood. In an in vivo study published in Nature, researchers determined how a bacterial protein delivered directly into the colon could stimulate nerve activity and influence appetite.

Bacteria carry distinctive molecular patterns that may act like an “identification card.” In this case, researchers focused on flagellin, a protein that forms the tail-like propeller (a flagellum) present and used for motility in many bacteria, including the harmless gut commensals. For this study, however, the authors used purified flagellin from Salmonella typhimurium, a common cause of food poisoning.

To translate these potential “ID checks” into a quick gut-brain message, the gut seems to rely on a type of epithelial sensor cell called a neuropod cell. A subset of neuropod cells in the distal ileum and colon (where microbial density is highest) produce PYY (peptide YY), a hormone linked to reduced appetite and increased feelings of fullness. Researchers found that these cells were also enriched in genes encoding pattern-recognition receptors, including Toll-like receptor 5 (TLR5), known to recognize flagellin.

To test whether this pathway regulates feeding, the authors generated mice with TLR5 selectively deleted in PYY-labelled gut cells (neuropod). These mice ate more and gained more weight than controls, consistent with a weakened “brake” on food intake.

Next, the researchers tested whether this pathway is fast enough to influence appetite on short timescales. Introducing flagellin into the colon triggered a rapid increase in activity of the vagal nerve, the main communication highway between gut and brain, producing a short-term reduction in food intake.

Flagellin did not act directly on vagal nerve endings. Instead, the response relied on the involvement of neuropod cells. These cells don’t only signal by releasing hormones into the bloodstream, they can also communicate quickly with nerves. Acting as “interpreters,” they sensed flagellin via TLR5 and then signaled to vagal neurons using PYY. Blocking a PYY-detecting receptor on vagal neurons abolished the response.

Finally, the researchers tested whether this circuit changes feeding in a way consistent with satiety. After overnight fasting, intracolonic delivery of flagellin resulted in a reduced food intake among mice, detectable within 20 min and lasting up to 3 hours, and the effect required both the neuropod-cell TLR5 sensor and the vagal PYY-detecting receptor.

These results provide insight into the molecular pathways underlying gut–brain circuit for rapid sensing of a microbial pattern. As the flagellin used here was derived from a pathogen, it remains to be tested whether flagellins from nonpathogenic/commensal bacteria similarly produce an effect. Possible next steps include testing other microbial features or microbiome compositions, and whether comparable sensing exists in humans.

For gut health, the broader significance is less about the body’s answer to one specific flagellin and more about the discovery of this new, “neurobiotic sense”. It suggests microbial cues in the colon might influence the body not only through slow inflammation or metabolites, but also through a fast sensory pathway that could shape eating behavior.

The gut, it seems, may be listening to its microbes more directly, and rapidly, than we once assumed, underscoring the microbiote’s potential impact on brain-linked behaviors.