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The enteric nervous system relays psychological stress to intestinal inflammation [ScRNASeqCD45seq]

ABSTRACT: Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), where psychological stress is associated with disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated colitis via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGFβ2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in two cohorts of human IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

ORGANISM(S): Mus musculus

PROVIDER: GSE229321 | GEO | 2023/05/25

REPOSITORIES: GEO

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The enteric nervous system relays psychological stress to intestinal inflammation [SnRNASeq_ENS]

Project description:Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), where psychological stress is associated with disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated colitis via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGFβ2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in two cohorts of human IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

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The enteric nervous system relays psychological stress to intestinal inflammation [ColonBulkseq]

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Enteric nervous system injury and intestinal dysmotility after West Nile virus infection is mediated by perforin and Fas-ligand dependent T cell effector functions

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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.

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Project description:The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss and dysmotility during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via b2-adrenergic receptors (b2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and -13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease- or tissue tolerance that preserves ENS number and functionality.

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2021-04-23 | PXD024502 | Pride

The epigenetic regulator BAP1 is required before birth for differentiation and maintenance of the postnatal enteric nervous system in mice.

Project description:Epigenetic regulatory mechanisms are underappreciated but critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage causes severe postnatal bowel dysfunction and early death in Tyrosinase-Cre; Bap1fl/fl mice. Bap1-depleted ENS appears normal in neonates, however, by postnatal day 15 (P15), Bap1-deficient enteric neurons are largely absent from the small and large intestine of Tyrosinase-Cre; Bap1fl/fl mice. Bowel motility becomes markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 shows that fetal Bap1 loss inTyrosinase-Cre; Bap1fl/fl mice markedly alters the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for enteric neuron survival.

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Gene expression profile at single cell level of splenocytes from wild-type and S100a9 knock-out mice ± repeated social defeat stress

Project description:Psychological trauma increases inflammation. In a mouse model of psychological trauma (repeated social defeat stress), we used single cell RNA sequencing to assess the gene expression in splenocytes ± psychological trauma as well as without S100a9 (gene of interest)

2023-01-01 | GSE209553 | GEO

Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system

Project description:To identify the gene expression profile of enteric glia and assess the transcriptional similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oli- godendrocytes, although there is no evidence of myelination in the murine ENS. Total RNA expression profiles of PLP1 expressing enteric glial cells (GFP+) and non-glial cells (GFP-negative) were obtained from the ileum and colon of juvenile PLP1-eGFP transgenic mice.

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