Researchers produce the first draft cell atlas of the small intestine
(Courtesy of the Broad Institute)

By surveying gene expression in over 53,000 cells from the small intestine, researchers have created a rich reference for understanding the biology of inflammatory bowel disease and food allergies, among other conditions.

The lining or epithelium of the gut is one of the body's most diverse and dynamic tissues, an ecosystem of cells that acts as one of the body's main interfaces with the outside world. To better understand this complex tissues and its functions — and the diseases that affect it — a multicenter team led by researchers at the Broad Institute of MIT and Harvard and Massachusetts General Hospital has released a census of the cells that make up the lining of the small intestine, using gene expression profiles of more than 53,000 individual cells from the mouse gut or gut organoid models.

This census, published in Nature, comprises a first-draft atlas of the small intestine's cellular composition, providing a reference for studying the biology of a host of conditions affecting or involving the gut, such as inflammatory bowel disease, cancers of the small intestine, celiac disease, and food allergies. The study also enhances our understanding of the hormones and other signals gut cells produce and sheds new light on how the gut responds to different pathogenic invasions.

The gut has to perform many functions, including absorbing nutrients, generating many of the body's hormones, and denying entry to noxious substances and pathogens. To do so, it relies on many specialized cells and their specific activities and interactions. Some of these cells are well known, but some have thus far remained unfamiliar.

To carry out their census, the study team relied heavily on single-cell RNA sequencing (scRNA-seq), a suite of genomic techniques capable of identifying specific gene expression profiles within individual cells.

"Every new technology is an opportunity for studying cells and tissues in greater detail," said Broad core institute member Aviv Regev, a co-corresponding author on the paper, director of the Klarman Cell Observatory (KCO) at the Broad and the institute's Cell Circuits Program, and — along with Broad institute member and Infectious Disease and Microbiome Program co-director Ramnik Xavier — a co-corresponding author on the paper. "They allow us to ask new biological questions or take a fresh look at old ones.

"We wanted to utilize single-cell RNA sequencing to understand what normal intestinal tissue looks like at a deeper level," she continued. "With that baseline we can start looking at disease."

"The gut epithelium is in contact with both the immune system and the gut microbiome, and as such the gut is a major hub of cellular connections and therefore it is very important for us to understand gut physiology in health and disease," said Moshe Biton, a postdoctoral researcher in the KCO and co-first author — with postdoctoral associate Adam Haber and research associate Noga Rogel — and co-corresponding author on the Nature paper. "It's also a tissue that we know a great deal about already. So we decided to revisit it and see whether we can find new things using scRNA-seq."

Leveraging these technologies, the team generated expression profiles for a total of 53,193 small intestinal epithelial cells. Within the data, the team pinpointed expression signatures specific to known cell types (e.g., enterocytes, goblet cells, Paneth cells, tuft cells), specific cell subtypes or populations (e.g., enterocytes at different stages of maturation), and rare cell types (e.g., M cells).

"An exciting outcome of this study was the allocation of known and novel specific sensory molecules associated with each epithelial cell type," said Rogel. "We hope this will have positive implications in designing drugs targeting metabolic disorders."

The data also revealed the existence of previously unrecognized cell subtypes and provided support for reclassifying known ones. For instance, the team uncovered a new type of chemical-sensing tuft cell (which helps alert the immune system to infection or other forms of injury) that displayed markers previously thought to be exclusive to immune cells and which may help sound the alarm about allergens and invading parasites.

"We were surprised to see that expression of the gene TSLP — which encodes a cytokine long known to be involved in epithelial-induced inflammation — was exclusive to a particular subset of tuft cells," Haber noted. "This suggests an even more significant 'lookout' role for these recently characterized cells than previously thought."

In addition, the data showed that the gut's hormone-producing enteroendocrine cells (EECs) — long divided into subsets based on the idea that each only expressed a single hormone — can actually express multiple hormones at once. The team has therefore proposed a new taxonomy for EECs based on their expression profile data, with many new subsets of hormone-producing cells.

The team also mapped their data to different locations along the length of the small intestinal tract. For example, they found that EECs that produce ghrelin (which triggers hunger) tend to group near the beginning of the small intestine (the duodenum, adjacent to the stomach). Those producing peptide YY (which prompts the feeling of being sated), on the other hand, aggregate near the far end (the ileum).

Oral bacteria in the gut associated with inflammatory bowel disease

Bacteria living in the mouth are ingested with saliva, but normally do not persist in healthy intestine. In several disease states—inflammatory bowel disease (IBD), HIV infection, liver cirrhosis, colon cancer—orally-derived bacteria are found living in patients’ guts, leading researchers to hypothesize that oral bacteria colonizing the gut contribute to disease.

Collaborating with researchers in Japan, Dr. Ramnik Xavier and his laboratory at MGH recently published a study in Science demonstrating that certain strains of antibiotic-resistant oral bacteria colonize the gut and drive inflammation in genetically susceptible hosts. These bacteria were significantly more abundant in the guts of IBD and Crohn’s disease patients than of healthy individuals.

These findings highlight the disease potential of bacterial strains in susceptible hosts and the need to better understand the relationships between human hosts, their genomes, and resident bacterial communities.

Read the study

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