The enteric nervous system (ENS) consists of enteric neurons and enteric glial cells located within the gut wall. It is crucial not only for gut homeostasis but also can shape extraintestinal organs. Despite major advances regarding the role of the ENS in gut function, the way in which it interacts with dietary components and the gut microbiota is largely unknown, mainly due to the limitations of available methodologies for studying the system.

A recent study provides new insights into the transcriptomic landscape of the ENS and its constituent cells by profiling 5,068 mouse and 1,445 human enteric neurons and diverse gut cell types at the single-cell level.

In order to characterize enteric neurons and enteric glial cells from the mouse and human intestine, Drokhlyansky and colleagues used a new approach. Their technique consisted of isolating and profiling the nuclei and associated ribosomes of ENS populations at single-cell resolution using ribosome and intact single nucleus sequencing, without requiring specific labelling of cell populations. In contrast, previous methodologies used to characterize the transcriptomic properties of the ENS were limited to the mouse embryonic and postnatal gut.

As such, the authors identified populations of ENS cells that vary according to species and location along the gastrointestinal tract and other tissues (i.e., heart and lung) and which have unique roles in gut function. Specifically, the researchers found neuronal subtypes expressing transcripts that are regulated by circadian rhythm and age, although the role of ENS in age and circadian rhythm-related diseases remains to be seen.

Interestingly, some human ENS subsets share transcripts with mouse subsets, while expression differences in the melanocortin, leptin and serotonin pathways can indicate adaptations to feeding behavior in the human and mouse gut.

By mapping ligand-receptor interactions, the authors also unraveled interactions occurring between enteric neurons and surrounding cells such as enteroendocrine, lymphatic, adipose and immune cells.

In addition, a group of genes associated with a higher risk of intestinal diseases (e.g., inflammatory bowel disease and Hirschsprung’s disease) and extraintestinal disorders involving gut dysmotility (e.g. DSCAM and SCN3A in Parkinson’s disease and autism spectrum disorder) have been found to be enriched in ENS cells from the human colon mucosa and muscularis propria. Those findings offer new clues into the potential role of harnessing enteric neurons and surrounding epithelial and immune cells in disease pathogenesis.

This is the first study to provide a detailed characterization of enteric neuron and enteric glial cell subtypes coupled with their interactions with surrounding cells. The new findings show that integrative approaches focusing on the whole gastrointestinal landscape can be of value in the field of neurogastroenterology, not only for gut-related diseases but also for systemic diseases that present with gastrointestinal issues.

Furthermore, a Nature Reviews Gastroenterology & Hepatology’s news & views article acknowledges that integrating the study’s findings can aid in our current knowledge on the physiology of ENS. Yet, it was also suggested that translation into the current networks involved in regulating intestinal physiology is not straightforward because sequencing of nuclear envelope containing ribosomes excludes cytosolic mRNA that may also be relevant for neurons.



Drokhlyansky E, Smillie CS, Van Wittenberghe N, et al. The human and mouse enteric nervous system at single-cell resolution. Cell. 2020;182(6):1606-1622.e23. doi: 10.1016/j.cell.2020.08.003.

Bon-Frauches AC, Boesmans W. The enteric nervous system: the hub in a star network. Nat Rev Gastroenterol Hepatol. 2020. doi: 10.1038/s41575-020-00377-2.