Enteric Nervous System Mechanisms in Gastrointestinal Disorders

The enteric nervous system (ENS) comprises an extensive network of neurons and glia embedded within the gut wall, regulating motility, secretion and blood flow. It operates semi-autonomously yet communicates bidirectionally with the central nervous system and the immune and endocrine networks. ENS dysfunction underlies a spectrum of disorders from congenital neuropathies such as Hirschsprung disease to acquired conditions including inflammatory bowel disease and functional motility disorders. Key mechanisms involve failure of neural crest-derived progenitors to colonise the bowel, altered neuron–glia interactions, neuroinflammation and impaired enteric neurogenesis. Disruption of neurotransmitter balance, aberrant glial activation and changes in circuit wiring lead to symptoms such as dysmotility, pain and malabsorption. Recent advances have shed light on the plasticity of enteric glia, the role of microbiota in glial homeostasis and the potential for cell-based regenerative therapies. A deeper understanding of ENS cellular diversity and communication pathways has opened avenues for targeted interventions to restore intestinal function and alleviate global disease burden.

Research from Nature Portfolio

Recent studies have elucidated the latent neurogenic capacity of enteric glial cells, revealing that mature glia retain open chromatin at key neurogenic loci. Single-cell transcriptomics and in vivo gut injury models demonstrate that glial populations can be driven back toward a neuronal lineage by reactivating developmental transcriptional programmes, suggesting new avenues for endogenous repair of neural deficits. In addition, inflammation models of colitis have shown that specific glial and progenitor markers (Sox2 and PLP1) identify cells that rapidly differentiate into functional excitatory neurons in adult gut, increasing neuronal density without cell division. These findings highlight dynamic enteric neurogenesis in response to injury and inflammation. Foundational methodological advances have further enabled large-scale isolation of pure myenteric plexus tissue from human and mouse gut, facilitating high-resolution proteomic and functional analyses of ENS networks under physiological and pathological conditions.

Enteric Nervous System Mechanisms in Gastrointestinal Disorders publication trend

The graph below shows the total number of articles in enteric nervous system mechanisms in gastrointestinal disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Enteric Nervous System (ENS): The intrinsic network of neurons and glia within the gastrointestinal tract that controls gut function.

Enteric glia: Supportive glial cells in the ENS that maintain neuronal health, modulate inflammation and can serve as progenitors.

Myenteric plexus: A major ENS network situated between muscle layers, primarily regulating gut motility.

Aganglionosis: Absence of enteric ganglion cells in segments of the bowel, leading to impaired peristalsis.

Neurogenesis: The process of generating new neurons from progenitor or glial cells.

Neuroinflammation: Immune-mediated inflammatory responses within the ENS that can alter neuronal excitability and circuit function.

References

1. Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue. Gut (2024).
2. A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia. Nature Communications (2023).
3. Microbiota Controls the Homeostasis of Glial Cells in the Gut Lamina Propria. Neuron (2015).
4. Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia (2014).
5. Isolation of high-purity myenteric plexus from adult human and mouse gastrointestinal tract. Scientific Reports (2015).
6. Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells. Scientific Reports (2017).
7. Functional circuits and signal processing in the enteric nervous system. Cellular and Molecular Life Sciences (2020).