Mapping the “brain in the gut” may provide clues to gastrointestinal disorders
Researchers at Karolinska Institutet have identified three types of nerve cells connected to the intestinal villi, suggesting that previously unknown neural networks regulate fluid balance in the gut. The findings, published in the journal Nature Neuroscience, could lead to a better understanding of diseases such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).
In Sweden, more than 30 percent of the population is estimated to suffer from chronic gastrointestinal issues such as IBS and IBD. In most cases, the causes of these problems are unknown. The gut has its own nervous system, known as the enteric nervous system, sometimes called the “brain in the gut.”
In this new study, researchers looked at a previously understudied part of this system, the so-called submucosal nerve layer. The results show that this layer contains three different types of nerve cells, at least one of which has a special ability to sense the contents of the intestine.
“We have identified the types of nerve cells embedded in the innermost part of the intestine, closest to the villi, in the so-called submucosal nerve layer. Contrary to previous studies, we found that this layer contains three types of nerve cells, one of which is a sensory nerve cell type—capable of receiving information about the intestinal contents and influencing other nerve cells to coordinate a response that optimizes nutrient absorption and fluid balance”, says Ulrika Marklund, associate professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
The researchers used single-cell RNA sequencing to map the nerve cells. This technique reveals which genes are active in individual cells. Using genetically modified mice, they were also able to visualize how the nerve cells communicate with each other and with the intestinal epithelial cells.
Understanding key neural networks in the gut
“The study provides a unique insight into the appearance, gene expression, and communication of submucosal nerve cells with surrounding cells in the innermost part of the intestine. We found that all three nerve cell types are connected to each other as well as to the intestinal villi. This opens up the possibility of previously unknown neural networks that could regulate fluid balance and blood flow, which may be highly relevant for conditions like constipation and diarrhea, and thus also associated diseases such as IBS and IBD,” says Ulrika Marklund.
The study also shows that the three nerve cell types are formed through a stepwise maturation process during fetal development. This process resembles that of the outer nerve layer of the gut, which controls intestinal movements—the myenteric layer—but differs from how nerve cells in the brain develop.
“We studied how the three nerve cell types form during development and found that they follow the same mechanisms we previously described in the myenteric layer of gut nerve cells, which differs from how nerve cell types in the central nervous system are generated. This suggests that all parts of the enteric nervous system develop through a stepwise maturation process, where even the neurotransmitters released by individual nerve cells gradually change”, explains Ulrika Marklund.
In the future, this knowledge could contribute to new treatments for diseases affecting gut function, for example, by targeting specific nerve cells with drugs. It may also be valuable in regenerative medicine, where the goal is to recreate nerve cell types in diseases such as Hirschsprung’s disease, using stem cells.
The next step for the researchers is to investigate how the three nerve cell types respond to different signals, such as pressure from intestinal contents, and which molecules they use to communicate. The goal is to understand how the gut regulates fluid balance and blood flow, key functions in both diarrhea and constipation.
Funding
The study was supported by the divENSify ERC Consolidator Grant, NIH R01 (in collaboration with David Linden, Mayo Clinic, Rochester, USA), the Swedish Research Council Consolidator Award, the Brain Foundation, StratNeuro, and StratRegen.
Publication
“The transcriptomes, connections and development of submucosal neuron classes in the mouse small intestine”. Wei Li*, Khomgrit Morarach*, Ziwei Liu, Sanghita Banerjee, Yanan Chen, Ashley L. Harb, Joel M. Kosareff, Charles R. Hall, Fernando López-Redondo, Elham Jalalvand, Suad H. Mohamed, Anastassia Mikhailova, David R. Linden & Ulrika Marklund.
Nature Neuroscience. doi 10.1038/s41593-025-01962-x