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

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.

Acetylcholine ameliorates colitis by promoting IL-10 secretion of monocytic myeloid-derived suppressor cells through the nAChR/ERK pathway

“…Evidence that the ACh-related cholinergic pathway could remarkably impact the pathogenesis of IBDs comes from the effect of smoking in UC patients (38,39). In addition, administration of α7 nAChR agonists or acetylcholinesterase inhibitors, including clinically approved galantamine, results in mitigation of colitis in mice (40)(41)(42)(43). Their antiinflammatory effects are mainly attributed to the vagus nerve-based splenic pathway, in which situation these cholinergic reagents need be administrated systemically.…”

Cholinergic immunomodulation in inflammatory bowel diseases

“…However, further investigation is needed to demonstrate tropisetron's potential as a therapy for IBD, prior to evaluating this molecule's effect in clinical studies. Moreover, pyridostigmine bromide, an acetylcholinesterase inhibitor, attenuated DSS-induced colitis, by increasing Ach tissue levels, reducing colon eosinophilic infiltration and Th2 pro-inflammatory factors and promoting MUC2 synthesis, a mucin that plays a critical role in gut homeostasis ( Singh et al., 2020 ). Nevertheless, the study did not evaluate whether said increase in ACh tissue levels was followed by a decrease in macrophage activation and subsequent decreased secretion of TNF-α.…”

Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity

“…It has a pro-eosinophilic effect through downregulation of IL-5, IL-13, and eotaxin in DSSinduced colitis. It also attenuates DSS-induced microbiota dysbiosis and improves epithelial integrity (91). Cholinergic modulation with PY induces greater recruitment of M2 macrophages and circulatory Treg cells soon after myocardial infarction in rats (92).…”