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Inflammation Rewires the Enteric Nervous System Through Neurogenic Monocyte Recruitment

ABSTRACT: The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2+ monocytes into the neural myenteric plexus of the intestinal muscle followed by the expansion of monocyte-derived macrophages, their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes promotes disproportionate ENS remodeling and PI-GID. Expansion of immune cells in the tissue also promotes tissue hypoxia. We find that enteric neurons are hypoxic upon colitis; hypoxia-induced signaling via HIF1alpha induces an adaptation program in enteric neurons to suppress CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1alpha signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and mitigating ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention.

ORGANISM(S): Mus musculus

PROVIDER: GSE263945 | GEO | 2026/01/08

REPOSITORIES: GEO

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Inflammation Rewires the Enteric Nervous System Through Neurogenic Monocyte Recruitment

Project description:The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2+ monocytes into the neural myenteric plexus of the intestinal muscle followed by the expansion of monocyte-derived macrophages, their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes promotes disproportionate ENS remodeling and PI-GID. Expansion of immune cells in the tissue also promotes tissue hypoxia. We find that enteric neurons are hypoxic upon colitis; hypoxia-induced signaling via HIF1alpha induces an adaptation program in enteric neurons to suppress CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1alpha signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and mitigating ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention.

2026-01-08 | GSE266254 | GEO

Gpr37 contributes to inflammation-induced GI dysmotility by regulating enteric reactive gliosis.

Project description:The enteric nervous system (ENS) is contained within two layers of the gut wall and is made up of neurons, immune cells, and enteric glia cells (EGCs) that regulate gastrointestinal (GI) function. EGCs in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) change in response to inflammation, referred to as reactive gliosis. Whether EGCs restricted to a specific layer or region within the GI tract alone can influence intestinal immune response is unknown. Using bulk RNA-sequencing and in situ hybridization, we identify G-protein coupled receptor, Gpr37, as a gene expressed only in EGCs of the myenteric plexus, one of the two layers of the ENS. We show that Gpr37 contributes to key components of LPS-induced reactive gliosis including activation of NF-kB and IFN-y signaling and response genes, lymphocyte recruitment, and inflammation-induced GI dysmotility. Targeting Gpr37 in EGCs presents a potential avenue for modifying inflammatory processes in the ENS.

2025-06-24 | GSE262418 | GEO

Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2

Project description:The N-Myc Downstream-Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4-/-) CRC models and an in-direct co-culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that absence of Ndrg4 does not trigger any functional or morphological GI-abnormalities. However, combining in vivo, in vitro and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4-/- ENS cell secretome, which is enriched for Nidogen-1 (Nid1) and Fibulin-2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance tumorigenic capacities of CRC cells and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS-derived Nidogen-1 and Fibulin-2 enhance colorectal carcinogenesis.

2021-04-23 | PXD024502 | Pride

Engineered human pluripotent stem cell-derived intestinal tissues with a functional enteric nervous system

Project description:The enteric nervous system (ENS) of the gastrointestinal (GI) tract controls many diverse functions including motility and epithelial permeability. Perturbations in ENS development or function are common, yet a human model to study ENS-intestinal biology is lacking. We have used a tissue engineering approach with pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining PSC-derived neural crest cells (NCCs) with developing human intestinal organoids (HIOs). When cultured alone, NCCs had full differentiation potential in vitro, however when recombined with HIOs they differentiated into neurons and glial cells. NCC-derived ENS neurons self-assembled within the developing intestinal mesenchyme and exhibited neuronal activity as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, formed interstitial cells of Cajal, and had an electro-mechanical coupling that regulated waves of propagating contraction. This is the first demonstration of a human PSC-derived intestinal tissue with a functional ENS.

2016-11-23 | GSE84666 | GEO

Maturing an Enteric Nervous System in Human Intestinal Organoid-derived Tissue-Engineered Small Intestine

Project description:Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIO). However, HIO-TESI fails to develop an ENS. In a previous report of combined HIO with additional human enteric neural crest cells (ENCC), an ENS was established but lacked maturity. The purpose of our study is to establish a mature ENS derived exclusively from hPSC in HIO-TESI. hPSC-derived ENCC supplementation of HIO-TESI generates ENCC-HIO-TESI with mature submucosal and myenteric ganglia, repopulates excitatory, inhibitory, and sensory neurons, and restores the neuroepithelial circuit and neuron-dependent contractility and relaxation. Our findings validate a novel approach to restoring a functional hPSC-derived ENS in ENCC-HIO-TESI and implicate their potential for the treatment of enteric neuropathies.

2017-10-20 | GSE99317 | GEO

Single Cell RNA-sequencing analyasis of mouse glutamatergic myenteric neurons

Project description:The study aimed to uncover the molecular profile of mouse Vglut2-possitive enteric neurons (VGLUT2-ENs) by single-cell mRNA sequencing (scRNA-seq). Method: We performed scRNA-seq of VGLUT2-ENs from distal intestine extracted from 6-8 weeks mice. We removed the non-neuronal cells, performed Principal Component Analysis (PCA) on the gene expression level of 15 well accepted and curated myenteric neuron markers, and analyzed the expression of the mechanosensitive ion channels. Results: clustering analysis results from PCA on the 15 gene markers indicates a dominant cluster of VGLUT2-ENs; By comparing the expression levels of the mechanosensitive ion channels Piezo1 and Piezo2 in the non-VGLUT2- ENs and VGLUT2-ENs, we find significantly less expression level of piezo1 and piezo2 genes in the VGLUT2-EN population as compared with myenteric neurons negative for VGLUT2. Conclusion: Molecular profiling of VGLUT2-ENs through single-cell mRNA sequencing unveiled a unique expression profile, distinguishing them from typical interneurons. Additionally, VGLUT2-ENs displayed minimal expression of mechanosensitive ion channels (Piezo1 and Piezo2), setting them apart from mechanosensitive interneurons.

2023-12-17 | GSE250388 | GEO

Single Cell RNA-sequencing analysis of the juvenile and embryonic mouse enteric nervous system (ENS) of the small intestine

Project description:The study aimed to make a molecular definition of myenteric neuron classes in the mouse small intestine and describe their differentiation from enteric stem cells during embryogenesis. Method: We performed single cell RNA-sequencing of enteric neurons from small intestine at the juvenile stage (postnatal day (P)21) and ENS cells from the small intestine at embryonic day (E)15.5 and E18.5. We confirmed novel marker genes for all classes using immunohistochemistry and characterised the morphology/axons of three of newly discovered ENS neuron types. Results: 12 unique enteric neuron classes (ENC1-12) were identified and confirmed in native tissue by histochemical methods. The communication machinery (ligand, receptors, adhesion molecules), axonal patterns and morphologies were presented to infer functional roles of the ENCs. Analysis of embryonic transcriptomes revealed that enteric stem cells differentiate into two neuronal branches, that successively diversify into ENC1-7 and ENC8-12, respectively. Conclusion: Utilizing single cell RNA-sequencing we conclude that murine small intestine consists of 12 major myenteric classes that emerge through a step-wise fashion during embryonic development. Reference: Morarach, Mikhailova et al., 2020. BioRxiv 2020.03.02.955757

2020-09-18 | GSE149524 | GEO

scRNA-sequencing reveals new enteric nervous system roles for GDNF, NRTN, and TBX3

Project description:Bowel function requires coordinated activity of many enteric neuron subtypes. Clear definition of subtype-specific gene expression may facilitate molecular diagnoses for bowel motility disorders. Using adult mouse colon RNAseq data from 635 myenteric neurons and 707 E17.5 neurons, we defined seven adult myenteric neuron subtypes, eight E17.5 neuron subtypes and hundreds of differentially-expressed genes. Manually dissected human colon myenteric plexus yielded data from 48 neurons, 3798 glia, 5568 smooth muscle, 377 interstitial cells, and 2153 macrophages. Immunohistochemistry demonstrated differential protein abundance for BNC2, PBX3, RBFOX1, TBX2, and TBX3 in enteric neuron subtypes. Conditional Tbx3 loss reduced NOS1-expressing myenteric neurons. Differential Gfra1 and Gfra2 expression coupled with calcium imaging revealed that GDNF and neurturin acutely and differentially regulate activity of ~50% of myenteric neurons with distinct effects on smooth muscle contractions. This insight into enteric nervous system biology provides a foundation for future studies of bowel motility disorders.

2021-01-01 | GSE156905 | GEO

Ret loss-of-function decreases neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

Project description:The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

2021-12-30 | GSE192676 | GEO

Expression analysis of adult zebrafish enteric nervous system

Project description:The enteric nervous system (ENS) encompasses the intrinsic neuroglia networks of the gastrointestinal (GI) tract that are essential for digestive function and gut homeostasis. To investigate the ENS of zebrafish, we carried out bulk RNA sequencing on nuclei purified by FACS (fluorescent-activated cell sorting) representing both the Cherry+ (ENS) and Cherry- (non-ENS) muscularis externa cell populations of Tg(sox10:Cre;Cherry) zebrafish gut.

2020-09-14 | GSE145885 | GEO

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