Microbial Modulation of Vagal Afferent Neurons in Inflammatory Bowel Disease and Obesity

Loading...
Thumbnail Image

Authors

Tashtush, Ayssar

Date

Type

thesis

Language

eng

Keyword

Nodose ganglia , Inflammatory bowel disease , Obesity

Research Projects

Organizational Units

Journal Issue

Alternative Title

Abstract

Background: The gut-microbiota-brain axis has received increasing attention recently due to evidence that colonic microbes can affect brain function and behavior. Vagal afferent neurons are an important conduit between the gut microbiota and the brain, as they can detect mediators released from the gut microbiota. However, much remains unknown regarding the innervation of the colon by vagal afferent neurons and how gut microbiota dysbiosis during inflammatory bowel disease (IBD) and obesity impacts the function of these neurons. Aims: i) Assess the extent of vagal afferent colonic innervation using the retrograde labeling technique. ii) Examine the excitability of nodose ganglion (NG) neurons exposed to fecal supernatants (FS) from 5 Crohn’s disease and 7 ulcerative colitis patients, and 5 healthy volunteers (HV) and the mechanism underlying that. iii) Study the effect of FS from obese and control mice, 12 obese patients (7 females/ 5 males), and 7 HV on NG neuronal excitability and the mechanism underlying that. iv) Examine whether depletion of microbiota by antibiotics alone or followed by fecal microbiota transplantation (FMT) could alter eating behavior and NG neuronal excitability in mice. Methods: Current and voltage-clamp recordings were used to assess changes in neuronal excitability and ion channel function. Results: i) 25 % of NG neurons innervate the colon, and 8 % innervate the distal colon. Single NG neurons innervate both the proximal and distal colon. ii) FS from active CD and UC patients, but not HV increased NG neuronal excitability and significantly reduced voltage-gated K+ current density. Cysteine proteases mediate the effect of FS from IBD patients on NG neurons by activating the protease-activated receptor 2. iii) FS from obese mice and patients decreased NG neuronal excitability and significantly increased voltage-gated K+ current density. This inhibitory effect was blocked by orexin-receptor antagonists. iv) Bacterial depletion decreased food intake by one-third in obese mice but increased it by twofold in control mice, suggesting that the microbiota of obese mice contributes to excessive caloric intake during obesity. v) FMT from obese or control mice into antibiotic-depleted mice was sufficient to induce eating behavior alterations similar to the donors. Collectively, these findings suggest that remodeling of gut microbiota during IBD and obesity increases the secretion of microbial mediators that change the excitability of NG neurons.

Description

Citation

Publisher

License

Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.

Journal

Volume

Issue

PubMed ID

External DOI

ISSN

EISSN