Summary: Long-held assumptions that the enteric nervous system (ENS) finishes its development before birth are being overturned. New research shows that ENS development continues after birth in both mice and human tissues, and reveals a significant population of enteric neurons that arise from the mesoderm. This discovery reshapes our understanding of gut maturation, aging, and disease.
The enteric nervous system, an extensive network of neurons and glial cells lining the gastrointestinal tract, governs digestion, immune interactions, and bidirectional communication between the gut and the brain. While traditionally thought to arise solely from the neural crest during prenatal development, recent findings identify a previously unrecognized mesodermal source of enteric neurons that emerges and expands after birth.
Key Facts:
- The ENS contains millions of neurons and glial cells, produces many of the same neurotransmitters as the brain, and is essential for digestion, immune regulation, and gut–brain signaling.
- Researchers at Beth Israel Deaconess Medical Center (BIDMC) documented the postnatal appearance and progressive expansion of a distinct population of enteric neurons derived from the mesoderm—the embryonic layer that also produces muscle and heart cells.
- This mesoderm-derived neuronal lineage grows with age and presents new molecular markers and pharmacological targets that could be used to treat age-related gastrointestinal dysfunction.
Source: BIDMC
Following your gut. Losing your appetite. A gutsy move.
Common expressions reflect the many roles the gut plays beyond digestion. The ENS, sometimes called the “second brain,” predates the central nervous system in evolutionary terms and produces many of the same signaling molecules found in the brain. It also controls intestinal motility, secretion, and local immune responses, and plays a central part in gut–brain communication that affects mood and behavior.
For decades, the dominant model held that enteric neurons derive from neural crest progenitors during embryogenesis and that the ENS is essentially fixed after birth. In a new paper published in eLife, investigators at BIDMC challenge that dogma by demonstrating ongoing ENS development after birth in mice and identifying the same novel neuronal lineage in human gut tissue.
Using transgenic mouse models, high-resolution microscopy, single-cell RNA sequencing, and genetic lineage tracing, the team tracked how ENS composition changes with age. Early postnatal enteric neurons largely matched the expected neural crest lineage, but as animals matured a different pattern emerged: a growing fraction of enteric neurons originated from mesodermal progenitors.
This mesoderm-derived population increases steadily over the lifespan. In the study’s mice, mesodermal neurons accounted for about one-third of enteric neurons in adolescence, roughly half in adulthood, and became the majority in aged animals. The authors identified distinctive molecular markers that distinguish these mesoderm-derived neurons from neural crest–derived neurons and used those markers to detect the same cell type in human gut samples.
Crucially, the balance between the two neuronal lineages depends on specific trophic signaling pathways: GDNF-RET supports neural crest–derived neurons, while HGF-MET supports mesoderm-derived neurons. Manipulating these pathways in mice altered the relative proportions of each lineage. Restoring GDNF signaling in aged mice improved intestinal motility, demonstrating that lineage composition has direct functional consequences and suggesting therapeutic strategies for age-related dysmotility.
“These findings show that the mesoderm contributes substantially to the ENS after birth and that this shift in lineage composition is linked to maturation and aging,” said Subhash Kulkarni, PhD, a staff scientist at BIDMC and assistant professor in the Division of Medical Sciences at Harvard Medical School. “Because these lineages may differ in disease susceptibility, identifying them opens new opportunities for targeted therapies.”
The study also analyzed human intestinal transcriptomes and found patterns consistent with the mouse data: patients with intestinal dysmotility displayed reduced GDNF-RET signaling, a decline in neural crest neuronal markers, and an increased transcriptional signature matching mesoderm-derived neurons. These observations suggest that an imbalance between ENS lineages may contribute to human gastrointestinal disorders.
The research team included collaborators from Johns Hopkins University School of Medicine, Stanford University School of Medicine, the National Cancer Institute, and the Mayo Clinic. Advanced imaging work was performed at the Ross Imaging Core at the Johns Hopkins Conte Digestive Disease Center, and single-cell RNA processing and sequencing were carried out at Johns Hopkins core facilities.
Funding: This work was supported by grants from the Ludwig Foundation; the National Institute on Aging (R01AG066768); Hopkins Digestive Diseases Center grants and pilot awards (P30DK089502); Diacomp initiative pilot funding; a Johns Hopkins Catalyst Award; the Maryland Genetics, Epidemiology, and Medicine training program; NIDDK (R01DK080920); the Maryland Stem Cell Research Foundation; and philanthropic support from the AMOS family.
About this neuroscience research news
Author: Chloe Meck
Source: BIDMC
Contact: Chloe Meck – BIDMC
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease” by Subhash Kulkarni et al. eLife
Abstract
Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease
The enteric nervous system (ENS) is a complex network of neural cells embedded in the gut wall and is essential for gastrointestinal and systemic health. The prevailing view held that the ENS is established prenatally from neural crest progenitors and remains largely unchanged thereafter. Our work demonstrates that the lineage composition of the maturing ENS shifts over time: canonical neural crest–derived neurons decline while a newly identified mesoderm-derived neuronal population expands.
Single-cell transcriptomics and immunochemical profiling reveal a distinct molecular signature for mesoderm-derived neurons. The relative proportions of neurons from each lineage depend on trophic signals—GDNF-RET favors neural crest neurons, while HGF-MET supports mesoderm-derived neurons. With age, mesoderm-derived neurons become the dominant lineage, a change that correlates with altered intestinal motility but can be reversed by GDNF treatment.
Transcriptomic analysis of human gut tissue shows reduced GDNF-RET signaling in patients with intestinal dysmotility, associated with lower expression of neural crest neuronal markers and higher expression of mesoderm-specific transcriptional programs. These results suggest that healthy adult gut function requires a balanced composition of the two distinct ENS lineages and that shifting this balance may underlie or exacerbate gastrointestinal disease.