Deletion of
            <i>choline acetyltransferase</i>
            in enteric neurons results in postnatal intestinal dysmotility and dysbiosis

Johnson, Carl D.; Barlow‐Anacker, Amanda J.; Pierre, Joseph F.; Touw, Ketrija; Erickson, Christopher S.; Furness, John B.; Epstein, Miles L.; Gosain, Ankush

doi:10.1096/fj.201701474rr

Cited by 27 publications

(19 citation statements)

References 33 publications

(45 reference statements)

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“…Lacking intestinal MΦ or ENS affects the composition of intestinal microbiome 66–69 . In a chemically induced colitis model in mice, CX3CR1 + MΦ were crucial to maintain the intestinal barrier function to prevent bacterial translocation 47, 70 .…”

Section: Resultsmentioning

confidence: 99%

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Keck

Galati-Fournier

Kym

et al. 2020

Preprint

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Background & AimsHirschsprung’s disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric nervous cells (ganglia). The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates extramural innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.MethodsWe enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal cholinergic innervation using immunohistochemistry. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using quantitative reverse-transcribed real-time polymerase chain reaction (qRT-PCR) of whole colonic tissue and fluorescence-activated cell sorting (FACS) analysis of isolated colonic immune cells. Fiber-associated immune cells were identified using confocal immunofluorescence microscopy and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic patient tissue using 16S rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.ResultsWe provided evidence that extrinsic mucosal innervation correlated with reduced interleukin (IL)-17 cytokine levels and T-helper-17 (Th17) cell frequencies. Bipolar CD14high macrophages colocalized with neurons and expressed significantly less interleukin-23, a Th17-promoting cytokine. HSCR patients lacking mucosal cholinergic nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.ConclusionThe mucosal fiber phenotype might serve as a new prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new future therapeutic options. (www.clinicaltrials.gov accessing number NCT03617640)

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Section: Resultsmentioning

confidence: 99%

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Keck

Galati-Fournier

Kym

et al. 2020

Preprint

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“…Studies have revealed that a significant population of GALpositive cells showed significant co-localization with choline acetyltransferase (ChAT)-IR neurons (76). Since acetylcholine is necessary to maintain intestinal motility, a similar role of GAL in this part of the intestine can be assumed (85). In studies carried out on mouse and rat preparations, GAL-positive nerve fibers were found in the caecum, particularly well visualized in the enteric plexuses (6).…”

Section: Large Intestinementioning

confidence: 99%

Review: Occurrence and Distribution of Galanin in the Physiological and Inflammatory States in the Mammalian Gastrointestinal Tract

Brzozowska

Całka

2021

Front. Immunol.

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Galanin (GAL) is a broad-spectrum peptide that was first identified 37 years ago. GAL, which acts through three specific receptor subtypes, is one of the most important molecules on an ever-growing list of neurotransmitters. Recent studies indicate that this peptide is commonly present in the gastrointestinal (GI) tract and GAL distribution can be seen in the enteric nervous system (ENS). The function of the GAL in the gastrointestinal tract is, inter alia, to regulate motility and secretion. It should be noted that the distribution of neuropeptides is largely dependent on the research model, as well as the part of the gastrointestinal tract under study. During the development of digestive disorders, fluctuations in GAL levels were observed. The occurrence of GAL largely depends on the stage of the disease, e.g., in porcine experimental colitis GAL secretion is caused by infection with Brachyspira hyodysenteriae. Many authors have suggested that increased GAL presence is related to the involvement of GAL in organ renewal. Additionally, it is tempting to speculate that GAL may be used in the treatment of gastroenteritis. This review aims to present the function of GAL in the mammalian gastrointestinal tract under physiological conditions. In addition, since GAL is undoubtedly involved in the regulation of inflammatory processes, and the aim of this publication is to provide up-to-date knowledge of the distribution of GAL in experimental models of gastrointestinal inflammation, which may help to accurately determine the role of this peptide in inflammatory diseases and its potential future use in the treatment of gastrointestinal disorders.

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“…NO is the main inhibitory neurotransmitter, with nNOS being the rate controlling enzyme in its production within ENS. Acetylcholine is the primary transmitter of excitatory muscle motor neurons in the ENS, and ChAT is responsible for ACh synthesis [31][32][33]. Recent studies have shown that one of the most common gastric cellular defects in gastroparesis is the loss of nNOS [1].…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture at ST36 Improve the Gastric Motility by Affecting Neurotransmitters in the Enteric Nervous System in Type 2 Diabetic Rats

Han

Chen

Wang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Electroacupuncture (EA) can effectively relieve hyperglycemia and gastric emptying disorders in diabetic gastroparesis (DGP). However, the effect of EA on type 2 diabetes mellitus (T2DM) gastroparesis and its mechanism in the enteric nervous system (ENS) are rarely studied. We investigated the therapeutic effect of EA at ST36 and its effect on the main inhibitory and excitatory neurotransmitters in the ENS in DGP rats. Male Sprague-Dawley (SD) rats were fed a high-fat diet for 2 weeks and injected with streptozotocin (STZ) at 35 mg/kg to induce T2DM. T2DM rats were divided into the diabetic mellitus (DM) group and the EA group. The control (CON) group comprised normal rats without any intervention. EA treatment was started 6 weeks after the induction of DM and continued for 5 weeks. The body weight and food intake of the rats were recorded every week. Blood glucose, insulin, glucose tolerance, gastric emptying, and antral motility were measured after treatment. The expression of protein gene product 9.5 (PGP9.5), neuronal nitric oxide synthase (nNOS), and choline acetyltransferase (ChAT) in gastric antrum were quantified by western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The T2DM gastroparesis model was successfully established. EA treatment reduced the body weight, food intake, and blood glucose; improved glucose intolerance and insulin resistance; increased the gastric emptying rate, the mean antral pressure, and the amplitude of antral motility; and decreased the frequency of antral motility compared with those in the DM group. EA treatment increased the expression level of nNOS, ChAT, and PGP9.5 proteins, and nNOS and ChAT mRNA. The results suggested that EA at ST36 could ameliorate DGP, partly restore the damage to general neurons, and increase nNOS and ChAT in the gastric antrum. EA improved DGP partly via reducing the loss of inhibitory and excitatory neurotransmitters in the ENS.

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Deletion of choline acetyltransferase in enteric neurons results in postnatal intestinal dysmotility and dysbiosis

Cited by 27 publications

References 33 publications

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

Review: Occurrence and Distribution of Galanin in the Physiological and Inflammatory States in the Mammalian Gastrointestinal Tract

Electroacupuncture at ST36 Improve the Gastric Motility by Affecting Neurotransmitters in the Enteric Nervous System in Type 2 Diabetic Rats

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