A 'sixth sense' discovered in the gut that helps regulate appetite

All organisms interpret the world through their senses. But science is increasingly clear that the five most popular ones (hearing, sight, touch, smell, and taste) are probably insufficient to address all interactions with the environment around us. New research published in the journal Nature , a showcase of the world's best science, has now discovered a kind of new, hidden sixth sense , located in the gut. Specifically, in a study on mice, scientists at Duke University (United States) have revealed that this sensory system, which they define as "a neurobiotic sense," enables real-time communication between the brain and the microbiome , that immense ecosystem of microorganisms that populates the gut and is capable of modulating health and disease.

For starters, researchers say this sensory infrastructure is used to sense what's happening in the gut , detect nutrients, and guide appetite decisions. But this is likely just the beginning of a longer, yet-to-be-discovered story: scientists hypothesize that this sixth sense could be a platform for a deeper understanding of how the gut detects microbes, how they influence behavior (from eating habits to mood ), and even how the brain might shape the microbiome.

For a long time, says Diego Bohórquez, a researcher at Duke's Gut-Brain Neurobiology Laboratory and lead author of the study, it was thought that the intestine was "a very passive tube that only served to digest and absorb." But that premise left many loose ends. "How the intestine knows what has reached it hadn't been explored. For example, an apple or a glass of milk is a universe of molecules. And the intestine has to recognize and create an immediate representation in order to notify the brain of what has arrived," explains the neuroscientist. His hypothesis was that the brain and the intestine had "a sensory system" to communicate information about what is happening in that microbial ecosystem. Something fast, direct, and independent of the much slower immune or metabolic response that those microbes can provoke.

And he wasn't wrong: after 15 years of research, Bohórquez and his team have managed to document how this new sense operates, allowing the brain to respond in real time to signals from microbes living in the gut. "It's a sensory system in the gut that allows bacteria to influence how much we eat and for how long," he summarizes.

The key transmission belt for this sixth sense is neuropods, tiny sensory cells that line the epithelium of the colon. “Just as the eye, to distinguish the colors blue and red, has neuroepithelial cells—first cousins of neuropods—that detect photons and, through wavelength, help us determine whether something is red or blue, in the intestine we have neuropod cells that, in the case of nutrients, help us quickly detect the molecules we've ingested to guide the brain and determine not only whether we ate a fat or a protein, but also how much more we need to eat,” explains Bohórquez.

Their research goes way back. A few years ago, they had already detected that neuropods were "essential" for the body to differentiate, for example, between sugars and sweeteners and to choose to consume the former, which have a caloric value, over other sweeteners. They called this a "nutrient sense," which helps guide what we eat: neuropods were capable of transforming nutrient signals into messages for the brain. But scientists still didn't understand how the body responded in real time to stimuli emanating from gut microbes.

What they have now discovered with this research is that when we eat , some gut bacteria release proteins called flagellin. Neuropods detect them and, with the help of a receptor (called TLR-5), send a message to the vagus nerve, which is a fundamental communication route between the gut and the brain. The signal that reaches the body's operations center through this channel is a warning that we have eaten enough. "We believe that neuropods detect flagellin and it immediately alerts the brain and sends a signal that it needs to stop eating. It's a form of immediate sensory interface so that the brain can know not only that we ate, but that the bacteria also received enough food," Bohórquez reflects.

To validate their thesis, the scientists subjected a group of mice to an overnight fast and, the next day, administered a dose of flagellin directly into the colon. The response was that the animals ate less. In contrast, the same experiment in another group of genetically manipulated rodents in which the TLR-5 receptor was deactivated resulted in the animals eating more and gaining more weight. “They became obese because they ate a little more and for longer each time. But it took us a long time [to reach the final conclusions] because we had to demonstrate that it wasn't immune or metabolic and that there actually existed a sensory neuronal system to recognize microbial patterns,” says Bohórquez. Their research showed that flagellin, through this neurobiotic circuit, sent signals to the brain to curb appetite. However, when this route was cut off, the message didn't arrive and the mice became obese. This meant there was a direct microbial influence on eating behavior.

Bohórquez argues that, although his research is conducted using animal models, the main ideas are perfectly applicable to humans: "There may be some modifications to the sensory system, but the basic principle is the same."

An ancient sense

His experiments have focused on the flagellin of a specific bacterial genus ( Salmonella ), but the scientist points out that this molecular pattern is conserved in many different species of microorganisms . “ This sensory system is activated even in animals free of microbiota. This means that it is constitutive of the animal, suggesting that it is a very ancient and basic sense for the intestine to recognize these microbial molecular patterns and communicate them to the brain,” Bohórquez adds.

Their discovery, however, is only "the first step" on a grand ladder yet to be explored. "We have just discovered that the intestine, through neuropods, communicates these molecular patterns to the brain. But this opens the possibility that other molecular patterns may be causing specific behavioral changes in the brain," he suggests.

Clàudia Aràjol, a physician in the Digestive System Department at Bellvitge Hospital in Barcelona, also considers this research to be "a very interesting thread to pull on." "It's a fabulous study, with a comprehensive methodology and promising results. It's the beginning of a new path in relation to the role of the microbiome in controlling satiety and weight," says the specialist, who was not involved in the research. Aràjol also highlights the scientists' efforts to clear up all confounding elements (such as potential immunological or metabolic explanations) to demonstrate this sensory system between intestinal microbes and the brain. "We remain to see how it ultimately pans out in humans, but at a clinical level, these results may promote the study of different drugs to modify obesity," she points out.

An immense research landscape is opening up. “We always talk colloquially about how we are what we eat. There's a direct correlation. But here we're already talking about the gut having a sensory system that guides our desires, not just our food needs, because everything else comes from food. Once you're nourished, you can imagine, create, and interact socially,” Bohórquez emphasizes.

The scientist doesn't rule out, in fact, the possibility that new senses could also emerge: "We are a conglomeration of all these sensory systems. Although we are perhaps documenting the sixth or seventh sensory system [taking into account the nutrient sensor detected a few years ago], there must be many more. For example, the one that monitors cerebrospinal fluid within the ventricles of the brain: that fluid may require a specific sensory system that affects the way we sleep, circadian rhythms, or dreams."

It wouldn't be so strange either. In plants, for example, it has been documented that they have 14 sensory systems, he recalls. And other scientists, such as Nobel Prize winner in Medicine Ardem Patapoutian, also maintain that the idea of five senses is a bit "naive." This scientist proposes that proprioception—the ability to sense where your extremities are in space—is also a sense, and that there are others: "And what about the sensation of temperature? And the perception of the bladder? That's not touch, so what is it? It's another sense," he posed in an interview with EL PAÍS just over a month ago.