Researchers have conducted a thorough examination of the entire mouse intestine, mapping the expression of genes, as well as the states and locations of cells not only in a healthy gut but also when faced with disturbances like inflammation. They discovered strict regulation of various cell types and their states in different sections of the organ, including a unique part of the colon influenced by immune signals. These results demonstrate the intestine’s remarkable ability to adapt and recover from disturbances, emphasizing the need to understand how cell processes are regulated and how they can differ across various areas of a tissue or organ.
The intestine plays a crucial role in the body by absorbing nutrients and water while maintaining a healthy relationship with the gut microbiome. However, this balance can be disrupted in conditions like celiac disease, ulcerative colitis, or Crohn’s disease. Scientists have yet to fully grasp how various parts of the intestine resist or adapt to environmental changes and the mechanisms behind these disruptions in disease.
Now, a team working at the Broad Institute of MIT and Harvard, along with Massachusetts General Hospital, has mapped the entire mouse intestine, detailing gene expression and the types and locations of cells in both healthy tissues and those affected by disturbances such as inflammation. Their analysis revealed a tightly regulated environment among cell types in different areas of the organ, and they pinpointed a specific colon segment governed by immune signals. Their findings, published in Nature, uncover the astonishing capacity of the intestine to adapt and recover from disturbances and stress the importance of understanding how cellular processes are regulated and vary across different regions of a tissue or organ.
“While the intestine, especially the colon, has been studied for many years, it has never been characterized in this manner, which prompts a reevaluation of many previous studies and opens avenues for future research,” stated Toufic Mayassi, one of the co-first authors on the paper alongside Chenhao Li. Both are postdoctoral researchers in Ramnik Xavier’s lab, a core member at the Broad Institute and part of the Center for Computational and Integrative Biology at Massachusetts General Hospital (MGH), who serves as the study’s senior author.
“This research underscores the need to consider the spatial dynamics that govern an organ, and we hope our study lays the foundation for contextualizing both earlier and future discoveries,” Mayassi added.
Xavier directs Broad’s Immunology Program and holds multiple prominent positions, including the Kurt J. Isselbacher Professorship of Medicine at Harvard Medical School, director of the Center for Computational and Integrative Biology, and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.
“We’ve created a comprehensive blueprint of the entire gut, a significant milestone,” Xavier remarked. “This allows us to investigate the entire organ, analyze the effects of genetic variations and immune responses related to diet, the microbiome, and gastrointestinal diseases, and to design various new experiments.”
Mapping the intestine
Many earlier gut studies focused on individual cells or cell clusters grown in laboratory settings. Although these methods provide a controlled environment to examine the functions of specific genetic changes related to diseases, they don’t reveal how cells from various regions of an intact organ interact in the context of disease.
In 2021, Mayassi, who did his PhD on immune responses in the intestine, collaborated with Li, a computational biologist, to create a detailed map of gene expression across the entire mouse small intestine and colon utilizing spatial transcriptomics and computational techniques.
To their surprise, the spatial arrangement of the intestine—the locations of various cell types and the genes they express—remained mostly stable even when certain factors changed. This stability was observed in mice with and without gut microbiota and in tissues collected during different times of day, indicating that neither the microbiome nor circadian rhythms significantly altered the spatial structure.
The intestine also displayed resilience. After treating the animals with a substance known to induce inflammation, researchers noted changes in gene expression and the spatial layout of cells, but they observed a return to normality after a month, with almost complete recovery by the three-month mark. These observations suggest that the gut’s ability to recover from inflammatory changes could be vital for its health and function.
“As a computational biologist, it’s thrilling to contribute to the generation and exploration of such a unique dataset,” Li expressed. “This research opens up opportunities for developing tools to analyze spatial data and influences the design of future investigations into the small and large intestines.”
Immune control
While the intestine remained stable under many influences, certain unique niches within the organ were impacted by the gut microbiota and exhibited signs of adaptation. Mice with a typical microbiome expressed specific genes in a certain area of the colon compared to germ-free mice. Through single-cell RNA sequencing, the researchers discovered that these changes occurred within three structural cell types, particularly in goblet cells—mucus-secreting cells that only expressed those genes in the presence of ILC2s, a type of immune cell.
Next, the research team plans to utilize their methods to investigate how various factors, including sex, diet, food allergies, and genetic predispositions for conditions like inflammatory bowel disease, affect the spatial structure of the intestine. They also aim to clarify how the findings from mice relate to spatial regulation within the human gut.
