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 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 that is altered in diseases.
Now, researchers at MIT’s Broad Institute and Harvard and Massachusetts General Hospital have analyzed the entire mouse intestine, mapping gene expression and the states and location of cells in the healthy intestine and in response to perturbations 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 that is controlled by immune signals. The findings, which appear in Naturereveal the surprising adaptability and resistance of the intestine to perturbations and highlight the importance of considering how cellular processes are regulated and vary in different parts of a tissue or organ.
“The intestine and in particular the colon have been studied for decades, but they have not been characterized in this way before, and that forces us to reevaluate many different studies and opens a window for future research,” said Toufic Mayassi, a co-first author of the study together with Chenhao Li. Mayassi and Li are postdoctoral researchers in the laboratory of Ramnik Xavier, a core member of the Broad Institute, a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital (MGH), and senior author of the study.
“This work illustrates that you really have to integrate the spatial relationships that govern a given organ into your thinking, and we hope that our study provides a platform and framework to help put previous and future discoveries into context,” Mayassi said.
Xavier is the director of the Broad Immunology Program, 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 have created a model of the entire intestine and that is a remarkable achievement,” Xavier said. “We now have a way to study the entire organ, examining the effect of genetic variants and immune responses associated with diet, the microbiome and gastrointestinal diseases, and designing many other experiments.”
Gut mapping
Many previous studies of the intestine looked at organ-like cells or collections of cells in a dish. While these approaches provide a controlled environment to study the function of specific genetic variants implicated in disease, they do not illustrate how cells from different parts of an intact organ interact to cause disease.
In 2021, Mayassi, who dedicated his PhD to studying immune responses in the gut, teamed up with Li, a computational biologist, to build 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 intestine (the relative location of various 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 tissue collected at night or during the day, suggesting that neither the microbiome nor circadian rhythms impacted 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 they showed signs of returning to normal a month later and had almost completely recovered by three months. The findings suggest that the gut’s ability to recover from changes caused by inflammation could be critical for gut health and function.
“As a computational biologist, it is exciting to be involved in the generation and exploration of such a unique data set,” Li said. “It opens the door to the development of tools to analyze spatial data and informs the design of future studies on the small and large intestine.”
immune control
Although the gut remained stable under many influences, unique niches within the organ were affected by the gut microbiota and showed signs of adaptation. Mice that had 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. Notably, goblet cells (cup-shaped cells that secrete mucus) expressed those genes only in the presence of ILC2, a type of immune cell.
Next, the researchers plan to apply their method to study how other factors, such as sex, diet, food allergies, and genetic risk factors for conditions such as inflammatory bowel disease, affect the spatial landscape of the gut. They also hope to elucidate the extent to which the findings in mice correlate with spatial control in the human gut.