Acetylcholinesterase Inhibitor Pyridostigmine Bromide Attenuates Gut Pathology and Bacterial Dysbiosis in a Murine Model of Ulcerative Colitis

Dig Dis Sci. 2020 Jan;65(1):141-149. doi: 10.1007/s10620-019-05838-6. Epub 2019 Oct 23.

Abstract

Background: Ulcerative colitis (UC) is a Th2 inflammatory bowel disease characterized by increased IL-5 and IL-13 expression, eosinophilic/neutrophilic infiltration, decreased mucus production, impaired epithelial barrier, and bacterial dysbiosis of the colon. Acetylcholine and nicotine stimulate mucus production and suppress Th2 inflammation through nicotinic receptors in lungs but UC is rarely observed in smokers and the mechanism of the protection is unclear.

Methods: In order to evaluate whether acetylcholine can ameliorate UC-associated pathologies, we employed a mouse model of dextran sodium sulfate (DSS)-induced UC-like conditions, and a group of mice were treated with Pyridostigmine bromide (PB) to increase acetylcholine availability. The effects on colonic tissue morphology, Th2 inflammatory factors, MUC2 mucin, and gut microbiota were analyzed.

Results: DSS challenge damaged the murine colonic architecture, reduced the MUC2 mucin and the tight-junction protein ZO-1. The PB treatment significantly attenuated these DSS-induced responses along with the eosinophilic infiltration and the pro-Th2 inflammatory factors. Moreover, PB inhibited the DSS-induced loss of commensal Clostridia and Flavobacteria, and the gain of pathogenic Erysipelotrichia and Fusobacteria.

Conclusions: Together, these data suggest that in colons of a murine model, PB promotes MUC2 synthesis, suppresses Th2 inflammation and attenuates bacterial dysbiosis therefore, PB has a therapeutic potential in UC.

Keywords: Acetylcholine; Bacterial dysbiosis; Dextran sodium sulfate; Pyridostigmine bromide; Ulcerative colitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cholinesterase Inhibitors / pharmacology*
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / enzymology
  • Colitis, Ulcerative / microbiology
  • Colitis, Ulcerative / pathology
  • Colon / drug effects*
  • Colon / enzymology
  • Colon / microbiology
  • Colon / pathology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dysbiosis*
  • GPI-Linked Proteins / metabolism
  • Gastrointestinal Microbiome*
  • Inflammation Mediators / metabolism
  • Mucin-2 / metabolism
  • Pyridostigmine Bromide / pharmacology*
  • Th2 Cells / drug effects
  • Th2 Cells / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cholinesterase Inhibitors
  • Cytokines
  • GPI-Linked Proteins
  • Inflammation Mediators
  • Muc2 protein, mouse
  • Mucin-2
  • Acetylcholinesterase
  • Ache protein, mouse
  • Pyridostigmine Bromide