Scientists discover region of mouse gut tightly regulated by immune system

The gut maintains a delicate balance in the body, absorbing nutrients and water while maintaining a healthy relationship with the gut microbiome, but this balance is disrupted in certain parts of the gut in conditions such as celiac disease, ulcerative colitis and Crohn’s disease. Scientists do not fully understand how different regions of the organ resist or adapt to changes in the environment and how this is disrupted in disease.

Now, researchers from the Broad Institute of MIT and Harvard and Massachusetts General Hospital analyzed the entire mouse intestine, mapping gene expression, states and locations of cells in the gut healthy and in response to disturbances such as inflammation. They identified tight regulation of cell types and states in different regions of the organ, as well as a unique segment of the colon controlled by immune signals.

The results, which appear in Naturereveal the surprising adaptability and resilience of the gut to disruption and highlight the importance of considering how cellular processes are regulated and vary in different parts of a tissue or organ.

“The gut and especially the colon have been studied for decades, but they have never been characterized in this way before, which forces us to re-evaluate many different studies and opens a window for future research,” said Toufic Mayassi, researcher in general medicine. co-first author of the study with Chenhao Li. Mayassi and Li are postdoctoral researchers in the lab of Ramnik Xavier, a senior fellow at the Broad Institute, a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital (MGH) and lead author of the study.

“This work illustrates that you really need to integrate the spatial relationships governing a given organ into your thinking, and we hope our study provides a platform and framework that helps put previous and future findings into context,” said Mayassi.

Xavier is director of the Immunology Program at Broad, as well as the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, director of the Center for Computational and Integrative Biology and member of the Department of Molecular Biology at MGH, and co-director of the MIT Center for Microbiome Informatics and Therapeutics.

“We’ve built a whole-gut blueprint, and it’s a remarkable achievement,” Xavier said. “We now have a way to study the entire organ, examine the effect of genetic variants and immune responses associated with diet, the microbiome and gastrointestinal disease, and design many other experiments .”

Intestinal mapping

Many previous studies of the gut have looked at cells or organ-like cell assemblages on a plate. Although such approaches provide a controlled environment to study the function of specific genetic variants involved in disease, they do not illustrate how cells from different parts of an intact organ interact to cause disease.

In 2021, Mayassi, who completed her Ph.D. studying immune responses in the gut, teamed up with Li, a computational biologist, to create a comprehensive map of gene expression throughout the mouse small intestine and colon using spatial transcriptomics and computational approaches.

To the researchers’ surprise, the spatial composition of the gut – the relative location of different cell types and the genes they express – remained relatively stable when certain factors changed. It remained the same in animals with and without gut microbiota and in tissues collected at night or during the day, suggesting that neither the microbiome nor circadian rhythms had an impact on the spatial landscape.

The gut also showed signs of resilience. When Mayassi treated the animals with a molecule known to induce inflammation, gene expression and cellular spatial distribution changed, but showed signs of returning to normal a month later and had almost fully recovered by after three months. The findings suggest that the gut’s ability to recover from changes caused by inflammation may be critical to gut health and function.

“As a computational biologist, it is exciting to participate in the generation and exploration of such a unique dataset,” said Li. “This opens the door to developing data analysis tools and informs the design of future studies of the small and large intestines.”

Immune control

Although the gut is stable in the face of many influences, unique niches within the organ have been affected by the gut microbiota and shown signs of adaptation. Mice with a normal microbiome expressed unique genes in a specific region of the colon compared to germ-free mice.

Using single-cell RNA sequencing, the authors found that the changes occurred in three structural cell types. In particular, goblet cells (cup-shaped cells that secrete mucus) only express these genes in the presence of ILC2, a type of immune cell.

Next, the researchers plan to apply their method to study how other factors, including gender, diet, food allergies and genetic risk factors for diseases such as inflammatory bowel disease, impact on the spatial landscape of the intestine. They also hope to elucidate to what extent the results obtained in mice correlate with spatial control in the human gut.