Spatial and Single-Cell Data Combined to Create Comprehensive Cell Map of the Human Gut

Researchers from the Wellcome Sanger Institute and collaborators say they have combined spatial and single-cell data from 1.6 million cells to create the most comprehensive cell map of the human gut to date. Mapping these cells can provide further insights into what happens in conditions such as bowel cancer and inflammatory bowel disease (IBD). Using this atlas, the team uncovered a new role of a specific gut cell, highlighting its contributions to a cycle of inflammation in some individuals, possibly causing pain and distress.

The study “Single-cell integration reveals metaplasia in inflammatory gut diseases,” published in Nature, details how the scientists harmonized over 25 single-cell datasets of the human gastrointestinal (GI) tract to create the world’s largest freely-available resource of the human gut—the Gut Cell Atlas. This includes samples from those with health conditions as well as those without.

By having a more complete picture of the human gut in health and disease, researchers can identify any key changes or differences that could be involved in the onset of conditions such as ulcerative colitis and Crohn’s disease, and lead to new possible targets for drug development.

“Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states,” write the investigators.

“We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis, and Crohn’s disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner’s glands. Although previously linked to mucosal healing, we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils.

“Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases.”

New tool to harmonize data

In this study, the team developed a new tool to harmonize the data, creating a standardized resource of gut cells that is available to researchers worldwide. This tool could also be applied to other organs and help facilitate further studies.

The scientists merged 25 datasets, resulting in an atlas of 1.6 million cells containing both single-cell and spatial data, allowing researchers to see what cells were present, where they were located, and how they communicated with the environment around them. The atlas was created with data from tissue samples from those without GI issues, as well as those with gastric and colorectal cancers, celiac disease, ulcerative colitis, and Crohn’s disease.

The team also identified a type of gut cell that may have a role in inflammation. The cells, known as gut metaplastic cells, are known to be involved in healing the stomach lining. However, the team discovered that these cells contained genetic similarities to other GI cells involved in inflammation. They suggest that inflammation in IBD leads to changes in these metaplastic cells, which actively contributes to further inflammatory responses.

By understanding more about this cycle of inflammation, it might be possible to find new ways to prevent or treat this in IBD and possibly apply this knowledge to other tissues and conditions.

“Spatial and single-cell data provide unique information about how gut cells interact, that can be used to continue piecing together an in-depth understanding of how the human body works,” explained Amanda Oliver, PhD, first author from Wellcome Sanger. “Combining existing single-cell datasets allows us to create a more complete picture of the human gut and ensures that researchers can work together to continue to benefit human health.”