When it comes to gut health, it is almost always about bacteria. These millions-strong companions, some good, some bad, inhabit us and steer human digestion, influence the immune system, and perhaps even determine whether we feel upbeat or downcast.
Hardly any medical topic has attracted as much attention in recent years as the ‘gut microbiome,’ which besides bacteria also includes viruses and fungi. Yet something essential has slipped from view: the ‘gut brain,’ which is also an important player in the intestinal milieu.
For the gut possesses its own nervous system—the enteric nervous system, or ENS, which, evolutionarily, is much older than the network of nerves in the brain. The ENS runs through the entire digestive tract as a thin layer, like a finely branched network.
How many nerve cells the ENS houses is not precisely documented — but it is clear that it contains 200 to 600 million neurons, more than in the spinal cord. Like in the brain, glial cells are also present, supporting, nourishing and protecting the nervous tissue. The same neurotransmitters can be found in the gut, though they often act differently there than in the brain.
All-Inclusive Equipment in the Gut
With this all-inclusive equipment, the ENS controls the gut movements, is responsible for the secretion of digestive juices, measures pressure, stretch, and chemical stimuli in the gut. It operates autonomously, not dependent on commands from above. No other organ possesses such an in-house control center.
And studies in recent years show: the nervous system of the gut is not only responsible for digestion, but in concert with the gut bacteria for our health overall. Hannelore Daniel, emerita nutritionist at the Technical University of Munich, calls the ENS a “masterpiece of biological complexity.”
It is already known that diseases such as irritable bowel syndrome are linked to a disruption of the gut’s own nervous system. Irritable bowel syndrome manifests as pain, diarrhea and constipation, but also in the form of depressive moods or anxiety symptoms. In affected individuals there is increased nerve density and greater branching of synapses, leading to chronic activation of the immune system and to pain.
But allergies, inflammatory bowel diseases, diabetes, colon cancer or Parkinson’s could also depend on how well or poorly the ENS operates. For example, a recent study led by Charité and the University of Bern shows that the enteric nervous system actively governs the so-called intestinal barrier – at least in mice. This barrier separates the intestinal lumen from the rest of the body. It decides which substances from the gut may enter the body and which may not.
Nutrients such as glucose or vitamins may pass, while pathogens are repelled by an intact intestinal wall. Up to now, the microbiome was chiefly regarded as the guardian of this border. But nerves also participate: specialized intestinal neurons send signaling molecules that influence the development of cells of the intestinal mucosa from stem cells.
The Gut Brain Acts Like a Conductor
These signaling molecules also play a role in how strongly the immune system responds. When this control becomes imbalanced, it can promote inflammation. “The mechanism discovered could explain why some people react hypersensitively in the gut,” says Christoph Klose of Charité. “Crucially, the gut does not simply become ‘permeable’ or ‘leaky.’ Rather, finely tuned processes become scrambled. The gut brain acts here like a conductor, dictating which cells become active when—and when not.”
Klose and his team were able to show in the study that allergic reactions depend on the ENS. If the control of the intestinal neurons does not work, it leads to immune reactions in the gut that are typical of allergic asthma. The gut acts here as a control center for the immune system of the whole body.
This finding fits a growing field of research: the gut-brain axis. While it has long been known that the gut and brain communicate intensively, for example via the vagus nerve or via signaling substances such as serotonin, dopamine, or inflammatory substances in the blood, thereby modulating immune processes.
What is new, however, is the insight that the enteric nervous system itself actively initiates or slows immune programs. In a 2024 study, German researchers showed, for instance, that under chronic stress more glucocorticoids are released, triggering inflammatory reactions in the gut—mediated by the ENS. This helps explain why chronic stress worsens inflammatory bowel diseases.
Consistency Makes a Difference
Perhaps nutrition could also influence the gut brain. For a long time, research focused on what food does to the gut bacteria. New studies, such as the work of Christoph Klose, now show: even the texture of food—whether liquid or solid—can directly influence the gut brain.
Mechanical stimuli in the gut are translated by nerve cells into biological signals that in turn regulate the gut barrier and immune reactions. “The texture of the food has a direct impact on the barrier function of the gut and the immune response,” says Klose. “These effects occur here independently of the microbiome.”
Whether specific nutritional components are directly detected by the enteric nervous system is still open. “This is an interesting hypothesis we are actively pursuing,” says Klose. From other studies there are already indications that fibers, fatty acids, secondary plant compounds or hormone-like substances in the gut not only influence bacteria but also nerves.
Dietary fiber, for example, acts through its breakdown products, short-chain fatty acids, to stabilize gut nerves and the intestinal barrier. Omega-3 fatty acids from the diet dampen inflammatory processes and trigger neuronal signaling pathways. Amino acids such as tryptophan are precursors of important signaling molecules, such as the “happiness hormone” serotonin.
So-called polyphenols from fruits, vegetables, tea or cocoa can also exert protective effects on the nerve network in the gut and dampen inflammation. Also the so-called probiotics from fermented foods could help calibrate the nerve network.
Knowledge Is Growing Rapidly
Indeed, this is the who’s who of a healthy diet—these substances are found in vegetables, fruits, whole grains, fatty fish, and protein-rich foods. Those who adhere to such a dietary pattern not only reduce their risk of diabetes or heart disease, but possibly also the risk of disorders arising from a dysbalance in the ENS.
Parallel to this, knowledge about the ENS is growing rapidly. Studies show how diverse the nerve cells in the gut are and how closely they work with immune cells. Researchers are discovering new types of neurons, new signaling pathways, and even hints that the gut brain can adapt and regenerate over the course of life.
These insights are also fundamentally changing the picture of the gut. It is not a passive digestive tube and not merely a playground for microbes. It is a highly active sensory and control organ that decides how the body reacts to food, environmental stimuli, and pathogens.
“If we better understand the interaction of nerves, cells, and immune reactions in the gut, we can develop medications more precisely and personally—for allergies, irritable bowel syndrome, or inflammatory bowel diseases,” says Klose.
