The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in <scp>U</scp>lcerative colitis and <scp>C</scp>rohn's disease

Fontgalland, Dayan de; Brookes, Simon Jonathan; Gibbins, Ian L.; Sia, Tiong Cheng; Wattchow, David

doi:10.1111/nmo.12327

Cited by 37 publications

(24 citation statements)

References 60 publications

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“…Global sympathectomy can ameliorate and exacerbate colitis, depending on the model used (see summary in 31 ). Presently, we found a decrease in sympathetic nerve density (Figure 3), which is consistent with modestly decreased TH axons in gut submucosal arteries in 2,4,6-Trinitrobenzenesulfonic acid (TNBS) colitis 32 but in contrast to unchanged TH nerves in human submucosal arteries 33 and increased TH nerves in human MAs 34 with IBD. Sensory denervation exacerbates colitis in female oxazolone-induced 35 , TRPV1 -/-Dextran Sulfate Sodium (DSS)induced 36 mouse models and some TNBS-induced rat models 37, 38 but improves colitis in a different TNBS rat model 39 and DSS and TNBS mouse models 40 .…”

Section: Discussionsupporting

confidence: 80%

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Norton

Grunz-Borgmann

Hart

et al. 2020

Preprint

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Objective: Inflammatory Bowel Disease (IBD) is associated with cardiovascular disease risk and impaired intestinal blood flow, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine is unknown in IBD. Because perivascular sensory nerves and their transmitters calcitonin gene-related peptide (CGRP) and substance P (SP) are important mediators of both vasodilation and inflammatory responses, our objective was to identify IBD-related deficits in perivascular sensory nerve function and vascular neurotransmitter signaling.Approach and Results: In MAs from an IL-10 -/mouse model, we found that IBD significantly impairs EFS-mediated sensory vasodilation and sensory inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are slightly decreased with IBD, but IBD has different effects on each transmitter. CGRP nerve density, receptor expression, hyperpolarization and vasodilation are preserved with IBD. In contrast, SP nerve density and receptor expression are increased, and SP hyperpolarization and vasodilation are impaired with IBD. A critical finding is that blocking neurokinin 1 (SP) receptors restored EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice.Conclusions: An aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. With IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD.

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Section: Discussionsupporting

confidence: 80%

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Norton

Grunz-Borgmann

Hart

et al. 2020

Preprint

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“…It should be pointed out that in contrast to the stomach and small intestine, knowledge about the distribution of CGRP in the descending colon is rather scanty [ 20 ]. Nevertheless, previous studies have shown some similarities between humans [ 13 , 41 ] and pigs [ 20 , 31 ]. Therefore, it is relatively well known that there is a resemblance between these species with regards to physiological, neuronal and biochemical organization in the ENS [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Inflammation and Nerve Damage on the Neurochemical Characterization of Calcitonin Gene-Related Peptide—Like Immunoreactive (CGRP-LI) Neurons in the Enteric Nervous System of the Porcine Descending Colon

Makowska

Gonkowski

2018

IJMS

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The enteric nervous system (ENS), localized in the wall of the gastrointestinal tract, regulates the functions of the intestine using a wide range of neuronally-active substances. One of them is the calcitonin gene-related peptide (CGRP), whose participation in pathological states in the large intestine remains unclear. Therefore, the aim of this study was to investigate the influence of inflammation and nerve damage using a double immunofluorescence technique to neurochemically characterize CGRP-positive enteric nervous structures in the porcine descending colon. Both pathological factors caused an increase in the percentage of CGRP-positive enteric neurons, and these changes were the most visible in the myenteric plexus after nerve damage. Moreover, both pathological states change the degree of co-localization of CGRP with other neurochemical factors, including substance P, the neuronal isoform of nitric oxide synthase, galanin, cocaine- and amphetamine-regulated transcript peptide and vesicular acetylcholine transporter. The character and severity of these changes depended on the pathological factor and the type of enteric plexus. The obtained results show that CGRP-positive enteric neurons are varied in terms of neurochemical characterization and take part in adaptive processes in the descending colon during inflammation and after nerve damage.

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“…In addition, patients with CD have an increased perivascular nerve density around the mesenteric artery, suggesting that neurogenic inflammation may be involved in increased vasodilation and edema observed in chronic inflammatory diseases, such as CD. 209 Meanwhile, changes in blood flow and angiogenesis may result in dysfunction of adipocytes and accumulation of visceral fat mass. Lymphatic vessels mediate lipid absorption and transportation, share an intimate spatial association with adipose tissue, and regulate the traffic of immune cells, 210,211 whereas neuropeptides, such as substance-P (SP), have substantial effects on lymphatic functions, creating lymphatic function and inflammation.…”

Section: Cross Talk Between Mesenteric Tissuesmentioning

confidence: 99%

The Role of the Mesentery in Crohnʼs Disease

Zhu

Zuo

et al. 2016

Inflammatory Bowel Diseases

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Crohn's disease (CD) is a complex gastrointestinal disorder involving multiple levels of cross talk between the immunological, neural, vascular, and endocrine systems. The current dominant theory in CD is based on the unidirectional axis of dysbiosis-innate immunity-adaptive immunity-mesentery-body system. Emerging clinical evidence strongly suggests that the axis be bidirectional. The morphologic and/or functional abnormalities in the mesenteric structures likely contribute to the disease progression of CD, to a less extent the disease initiation. In addition to adipocytes, mesentery contains nerves, blood vessels, lymphatics, stromal cells, and fibroblasts. By the secretion of adipokines that have endocrine functions, the mesenteric fat tissue exerts its activity in immunomodulation mainly through response to afferent signals, neuropeptides, and functional cytokines. Mesenteric nerves are involved in the pathogenesis and prognosis of CD mainly through neuropeptides. In addition to angiogenesis observed in CD, lymphatic obstruction, remodeling, and impaired contraction maybe a cause and consequence of CD. Lymphangiogenesis and angiogenesis play a concomitant role in the progress of chronic intestinal inflammation. Finally, the interaction between neuropeptides, adipokines, and vascular and lymphatic endothelia leads to adipose tissue remodeling, which makes the mesentery an active participator, not a bystander, in the disease initiation and precipitation CD. The identification of the role of mesentery, including the structure and function of mesenteric nerves, vessels, lymphatics, and fat, in the intestinal inflammation in CD has important implications in understanding its pathogenesis and clinical management.

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The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in Ulcerative colitis and Crohn's disease

Abstract: There is an increase in SP and TRPv1, and a reduction in SOM immunoreactive nerve fibres in IBD. Changes in the perivascular functional nerve subclasses may underlie the hyperaemia, and ulceration, characteristic of IBD. Furthermore, pain may relate to underlying neural changes.

Cited by 37 publications

References 60 publications

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

The Influence of Inflammation and Nerve Damage on the Neurochemical Characterization of Calcitonin Gene-Related Peptide—Like Immunoreactive (CGRP-LI) Neurons in the Enteric Nervous System of the Porcine Descending Colon

The Role of the Mesentery in Crohnʼs Disease

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