The “sixth sense” links intestinal microorganisms to the brain in real time

A common bacterial protein can be felt in the colon nature.

The study revealed circuits that connect microorganisms in the gut to the brain, bypassing hormones and immune responses, supporting direct neural communication.

At the heart of the system is the neuropod, a specialized sensory cell that detects flagellin, a protein found in the whip-like tail of many bacteria. These cells use a receptor called TLR5 to send signals through the vagus nerve, suppressing appetite within minutes. Without TLR5, the pathway collapses, causing mice to overeat and gain weight.

The sixth sense of the colon

“We are curious whether the body can sense microbial patterns in real time, not just an immune or inflammatory response,” said Diego Bohórquez, a professor of medicine and neurobiology at Duke University. The team found that colonic neuropods express TLR5, a microbial sensor that is often associated with immune cells. When they encounter flagellin, they release a neurochemistry called PYY, which activates appetite-suppressing neurons in the brain stem.

This effect is both fast and accurate. In one experiment, fasting mice directly used a small dose of flagellin with control mice significantly less. Mice that lacked TLR5 gene modification in the neuropod did not respond this way and gained weight over time.

Real-time behavior control

Unlike the immune system, which takes hours of installation response, this gut brain link runs in seconds. The team used in vivo calcium imaging to show that nearly half of vagus neurons with PYY receptors emitted in response to flagellin, but not nutritional signals such as lipids, revealing a dedicated microbial detection channel.

To confirm that this effect requires neuropods, the researchers used optogenetics to activate or silence these cells. Turning off neuropods during flagellin exposure can eliminate brain response and appetite suppression.

A new platform for microbiome research

This neurobiological sense opens up new ways to think about how the microbiome shapes behavior, independent of inflammation or metabolism. The main findings of the study include:

• Flaglin levels rise after eating, and make a feeling of fullness to the brain through the vagus nerve
• Disable TLR5 only in the neuropod, increasing the size and duration of meals without changing meal frequency
• These effects were observed even in germ-based mice, suggesting that direct sensing (rather than microbial metabolites) can trigger the response

The researchers also established a “crunching master” system to accurately measure the occlusal pattern after microbial stimulation. Mice receiving flagellar enema began to eat and consume less time, even without immune-labeled disease markers.

“A obvious next step is to study how a particular diet changes the microbial landscape in the gut,” Bohórquez said. This could help explain why certain foods or microbiome metastasis is associated with obesity, anxiety, or other brain-related diseases.

Magazine: nature
doi: 10.1038/S41586-025-09301-7

Related