Organization of the human intestine at single-cell resolution

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health(1). The intesting has a length of over nine metres, along which there are differences in structure and function(2). The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.

Automated summary

The intestine is a complex organ with various functions including digestion, immune surveillance, and maintaining symbiotic relationships with microbiota. It has differences in structure and function along its over nine-meter length. Through multiplexed imaging and single-cell assays, this study reveals substantial differences in cell compositions across different regions of the intestine, highlighting distinct immunological niches. The findings also suggest a regulatory differentiation cascade and associate specific cell types with intestinal disease heritability. This research provides an important reference map for understanding human biology and disease.