Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel

Yu, Yang; Daly, Donna; Adam, I. J.; Kitsanta, Panagiota; Hill, Chris; Wild, Jonathan; Shorthouse, A. J.; Grundy, David; Jiang, Weiwei

doi:10.1111/nmo.12842

Cited by 42 publications

(37 citation statements)

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“…Firstly, whilst every effort was made to match the relative age range and sex of the NMR and mice used in this study, we acknowledge that age may have an impact on afferent sensitivity. For example, reduced responses of afferent firing to some stimuli are observed in tissues from older mice [44] and humans [45,46]. We accept that this may have introduced variability into our study, but given the relatively comparable spread in age of the individuals used from both species, we do not believe that this is responsible for the dramatic differences observed between species.…”

Section: Discussionmentioning

confidence: 88%

Acid and inflammatory sensitisation of naked mole-rat colonic afferent nerves

Hockley

Barker

Taylor

et al. 2019

Preprint

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23Acid sensing in the gastrointestinal tract is required for gut homeostasis and the 24 detection of tissue acidosis caused by ischaemia, inflammation and infection. In the 25 colorectum, activation of colonic afferents by low pH contributes to visceral 26 hypersensitivity and abdominal pain in human disease including during inflammatory 27 bowel disease. The naked mole-rat (Heterocephalus glaber; NMR) shows no pain-28 related behaviour to subcutaneous acid injection and cutaneous afferents are 29 insensitive to acid, an adaptation thought to be a consequence of the subterranean, 30 likely hypercapnic, environment in which it lives. As such we sought to investigate 31 whether NMR interoception within the gastrointestinal tract differed from other rodents, 32 specifically the mouse. Here we show the presence of calcitonin gene regulated 33 peptide (CGRP) expressing extrinsic nerve fibres innervating both mesenteric blood 34 vessels and the myenteric plexi of the smooth muscle layers of the NMR colorectum. 35Using ex vivo colonic-nerve electrophysiological recordings we show differential 36 sensitivity of NMR, compared to mouse, colonic afferents to acid and the prototypic 37 inflammatory mediator bradykinin, but not direct mechanical stimuli. In NMR, but not 38 mouse, we observed mechanical hypersensitivity to acid, whilst both species 39 sensitised to bradykinin. Collectively, these findings suggest that NMR colonic 40 afferents are capable of detecting acidic stimuli however their intracellular coupling to 41 downstream molecular effectors of neuronal excitability and mechanotransduction 42 likely differs between species. 43 44 Keywords 45 Acid, bradykinin, mechanosensation, sensitisation, visceral pain 46 Introduction 47 The gastrointestinal tract coordinates the digestion of food, absorption of nutrients and 48 evacuation of waste with acidification of the stomach contents a critical component of 49 this process. Through compartmentalisation, sensory surveillance and specialised 50 mucosal defence mechanisms, not only is the breakdown of food and elimination of 51 ingested pathogens achieved through acidification in the foregut, but also the delicate 52 gut microbiota-host symbiosis of the hindgut maintained. It is clear that when gastric 53 acid regulation is lost then significant pathogenesis can occur, including acid-related 54 diseases such as gastro-eosophageal reflux disease, gastroduodenal ulceration, 55 dyspepsia and gastritis [1]. Recent associations between gut microbiota and a diverse 56 range of human disease, from depression, autism, schizophrenia, Alzheimer's disease 57 and Parkinson's disease, to diabetes and obesity [2], also highlight the significant 58 impact that alterations in the gut luminal environment, including pH on which this 59 microbiota rely, can have on human behaviour, mood and physiology. 60 61 Sensory neurones innervating the gastrointestinal tract are central to the feedback 62 regulation of gastric acid secretion and can additionally detect tissue acidosis caused 63 by inflam...

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Section: Discussionmentioning

confidence: 88%

Acid and inflammatory sensitisation of naked mole-rat colonic afferent nerves

Hockley

Barker

Taylor

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…For example, reduced responses of afferent firing to some stimuli are observed in tissues from older mice 44 and humans. 45,46 We accept that this may have introduced variability into our study, but given the relatively comparable spread in age of the individuals used from both species, we do not believe that this is responsible for the dramatic differences observed between species. Secondly, all NMR used in this study were subordinates and therefore their sexual maturity will have been suppressed.…”

Section: Discussionmentioning

confidence: 92%

Acid and inflammatory sensitisation of naked mole-rat colonic afferent nerves

et al. 2020

View full text Add to dashboard Cite

Acid sensing in the gastrointestinal tract is required for gut homeostasis and the detection of tissue acidosis caused by ischaemia, inflammation and infection. In the colorectum, activation of colonic afferents by low pH contributes to visceral hypersensitivity and abdominal pain in human disease including during inflammatory bowel disease. The naked mole-rat (Heterocephalus glaber) shows no pain-related behaviour to subcutaneous acid injection and cutaneous afferents are insensitive to acid, an adaptation thought to be a consequence of the subterranean, likely hypercapnic, environment in which it lives. As such we sought to investigate naked mole-rat interoception within the gastrointestinal tract and how this differed from the mouse (Mus Musculus). Here, we show the presence of calcitonin gene-related peptide expressing extrinsic nerve fibres innervating both mesenteric blood vessels and the myenteric plexi of the smooth muscle layers of the naked mole-rat colorectum. Using ex vivo colonic-nerve electrophysiological recordings, we show differential sensitivity of naked mole-rat, compared to mouse, colonic afferents to acid and the prototypic inflammatory mediator bradykinin, but not direct mechanical stimuli. In naked mole-rat, but not mouse, we observed mechanical hypersensitivity to acid, whilst both species sensitised to bradykinin. Collectively, these findings suggest that naked mole-rat colonic afferents are capable of detecting acidic stimuli; however, their intracellular coupling to downstream molecular effectors of neuronal excitability and mechanotransduction likely differs between species.

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“…Several animal studies have indicated that the mechanical stimulus threshold can be decreased upon chemical activation with mustard oil. These findings have recently been confirmed in an ex vivo study using human colonic tissue . Moreover, TRPA1 can be sensitized via PAR 2 activation.…”

Section: Trpa1mentioning

confidence: 86%