Organization of the human intestine at single-cell resolution

Abstract

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. 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.

Tethering of soluble immune effectors to mucin and chitin reflects a convergent and dynamic role in gut immunity

“…Dense polymicrobial biofilm communities, in specific regions of the gut, can form due to the glycan structure of mucins and other biophysical factors, with microbial nutrition preferences serving as a primary driver of settlement along with niche preference distributions of strain variants. A parallel distribution of unique immune recognition responses and secreted effectors influence these communities [16,[99][100][101], and remains a guiding principle of the restaurant hypothesis for microbial settlement in the gut. Variation in the local distribution of antibody responses in vertebrates [5,59], and by inference, the VCBPs in protochordates [18,102], could strongly impact the dynamics of microbial settlement.…”

“…a complex repertoire of specificity can be maintained. Secreted effectors, such as antibodies, can have a distinctive impact on downstream immune responses within the mucosal environment, depending on how their Ig domain(s), such as the Fc region, interact with and transmit signals to other types of membrane-bound effector molecules [101,[104][105][106]. This combination of microbes, antibodies and mucins plays a crucial role in enabling interactions with innate immune receptors and regulating inflammation.…”

Tuft cells act as regenerative stem cells in the human intestine

“…4g-h). Combining two published datasets spanning 14 healthy donors 19,26 , we estimated that 3.9% of intestinal tuft cells are cycling in steady state (Extended Data Fig. 4i).…”

Quantitative Analysis of NKX2-3 Expression in Human Colon: An Immunohistochemical Study

“…[13][14][15] In the human intestines, altogether over 100 different types of cellular components have been identified from various anatomical locations along the gut using high-throughput single-cell RNA sequencing (scRNAseq). [16][17][18] Several transcription factors regulating gut development belong to the homeodomain-containing transcription factor families. 19,20 In a complex lineage-, cell-type, and context-dependent fashion, these transcription factors act in a temporal and spatial pattern.…”

“…13 –15 In the human intestines, altogether over 100 different types of cellular components have been identified from various anatomical locations along the gut using high-throughput single-cell RNA sequencing (scRNAseq). 16 –18…”