Newly discovered "sixth sense" plays a vital role in human behavior and appetite

The human gut and the human brain share a hotline that scientists have been mapping for decades. Nutrients such as sugar and fat trigger signals that travel from the digestive tract to nerve centers in a flash, guiding everything from cravings to satiety.

Yet the thought that the brain might also monitor the trillions of microbes living in the colon sounded almost science fiction – until now.

New evidence shows that chemical chatter from resident bacteria can hit the nervous system in real time, shaping behaviors, such as how much we eat, within minutes.

These findings sketch out a neurobiotic “sixth sense” that sits alongside taste and smell, one that keeps tabs on microscopic neighbors before they cause trouble or waste precious calories.

How the brain monitors the gut

Most gut microbes cluster in the colon, where they break down leftovers and spin out vitamins that our bodies cannot make on their own. While they work, they shed fragments of protein that swirl through the intestinal stew.

One of the most common of these bits is flagellin, the building block of the spinning tails many bacteria use for propulsion.

Flagellin has long been known to trip immune alarms, but the speed of immune responses is measured in hours, not seconds. A faster line of communication had to exist if the brain were to react during a meal rather than after it.

Researchers at Duke University School of Medicine have now traced such a line to neuropod cells – rare sensory cells embedded in the colon’s lining.

Fewer than one in a thousand epithelial cells qualifies as a neuropod, yet those spies plug directly into fibers of the vagus nerve, the major information highway connecting gut and brain.

Tiny sensors with big influence

Neuropod cells in the small intestine are already famous for tasting nutrients. The new work shows that their cousins in the colon carry a receptor named Toll-like receptor 5 (TLR5), best known from immune cells that watch for bacterial flagellin.

When flagellin docks on TLR5, the neuropod releases peptide YY (PYY), a hormone that presses the brakes on appetite, and fires an electrical burst into the vagus nerve.

In laboratory dishes, roughly one-quarter of isolated neuropods erupted with calcium sparks – an unmistakable sign of activation – within seconds of flagellin appearing. Block TLR5 and the flashes vanish.

“We were curious whether the body could sense microbial patterns in real time and not just as an immune or inflammatory response, but as a neural response that guides behavior in real time,” said Bohórquez, a professor of medicine and neurobiology at Duke University School of Medicine and senior author of the study.

Flagellin and the vagus nerve

To see whether this microscopic relay mattered in a living animal, the scientists threaded a hair-thin tube into the colons of mice and dripped in purified flagellin. Within moments, electrodes on the neck picked up a surge of activity in the vagus nerve.

The mice, which had fasted overnight, hesitated before taking their first bite and ate noticeably less during the next hour. The effect faded after about three hours – just long enough for the gut to clear its latest load of nutrients.

When the same experiment was run on mice genetically engineered to lack TLR5 only in neuropod cells, the nerve stayed quiet and the animals kept eating.

Over time, these mice gained weight even though their hormones, blood sugar, and gut inflammation stayed normal. Removing a single receptor from a tiny population of cells had quietly lifted a brake on food intake.

Dissecting the gut-brain pathway

The steps in the circuit line up like dominoes: flagellin binds TLR5 on a neuropod cell, the cell releases PYY, PYY hits Y2 receptors on nearby vagus endings, and the electrical pulse races to appetite centers in the brainstem.

Interfering at any point – blocking TLR5, preventing PYY release, or silencing Y2 receptors – cuts the signal. The speed of the response, measured in fractions of a second, sets it apart from hormonal cues such as leptin or ghrelin, which rise and fall over hours.

By responding swiftly, the gut can keep a running tally of microbial activity and adjust intake before the next mouthful.

“Looking ahead, I think this work will be especially helpful for the broader scientific community to explain how our behavior is influenced by microbes,” said Bohórquez.

“One clear next step is to investigate how specific diets change the microbial landscape in the gut. That could be a key piece of the puzzle in conditions like obesity or psychiatric disorders.”

Neuropods, flagellin, and appetite

The discovery slots gut bacteria alongside nutrients, stretch receptors, and hormones as direct contributors to appetite control.

Because the neuropod pathway works locally in the colon and talks to the brain through existing nerves, it might one day be targeted without systemic side effects.

Drugs that mimic flagellin’s signal, or dietary tweaks that favor bacteria whose flagellins hit TLR5 hardest, could help curb overeating in a more natural-feeling way than current appetite suppressants.

Emerging hints suggest the circuit may also converse with emotional centers. The vagus nerve reaches brain regions involved in mood, and PYY has been linked to feelings of calm after meals.

If microbial flagellin can influence those areas too, the microbiome might steer not only how much we eat but how we feel while doing it.

More we learn, less we know

The study used flagellin from Salmonella typhimurium, a species better known for food poisoning than for friendly gut housekeeping. Harmless commensal bacteria sport subtly different flagellins.

Do those variations tweak the neuropod response, dialing appetite up or down depending on which microbes dominate? And does the brain treat all flagellins as the same “slow down” cue, or can it distinguish between benign tourists and rowdy invaders?

Answering those questions will require tools that can swap microbial strains on demand and sensors that report neuropod activity in real animals during normal meals.

As those tools come online, scientists expect to map a fuller picture of how bacterial voices blend with nutritional signals to fine-tune eating behavior.

To sum it all up, gut bacteria can tap a lightning-fast nerve circuit that tells the brain to put the fork down by flashing a protein badge.

This discovery places neuropod cells at the heart of a freshly recognized “neurobiotic sense,” one that keeps the peace between host and microbes meal after meal.

The full study was published in the journal Nature.

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