Allergic inflammation disrupts epithelial electrogenic electrolyte transport through cholinergic regulation in the mouse colon.

Intestinal transport of electrolytes is regulated by the enteric nervous system. Acetylcholine (ACh) is considered the most important neurotransmitter for electrolyte transport in the colon. However, electrolyte transport regulated by ACh is not fully understood in the colon. We investigated the regulation of electrogenic electrolyte transport by cholinergic agonists in the mouse colon by measuring the short-circuit current (Isc) using an Ussing chamber system. Muscarinic stimulation induced transient electrogenic Cl- secretion, and nicotinic stimulation induced electrogenic K+ secretion to the apical side in the normal mouse colon, and these effects were reduced in the colon of mice with food allergy (FA). Administration of prednisolone to mice with FA suppressed mild inflammation in the colon and allergic symptoms and thereby ameliorated the disruption of electrogenic electrolyte transport induced not only by cholinergic pathway activation but also by electrical field stimulation and intracellular cAMP signaling pathway activation in the colon. These results suggest that the electrogenic electrolyte transport function in the colon is impaired by FA-induced colonic inflammation and that the suppression of inflammation ameliorates the dysfunction of electrogenic electrolyte transport in the colon of mice with FA.

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Diagnostic Features of Perianal Fistula in Patients With Crohn's Disease: Analysis of a Japanese Claims Database.

Background: Perianal fistula (PAF) is a disabling complication of Crohn's disease (CD) which greatly impacts the quality of life. To address a scarcity of data in Asian populations, we determined the prevalence of CD-associated PAF in Japan, the order of diagnosis, and medical history of patients. Methods: A retrospective, longitudinal, observational cohort study was conducted, using an employer-based health insurance claims database. The study included patients diagnosed with CD and/or PAF from October 2013 to September 2019. Results: The age- and gender-adjusted prevalence rates of CD-associated PAF increased from 10.33 per 100 000 in 2014, to 13.68 per 100 000 in 2019. Among patients with CD-associated PAF, 15.7% were diagnosed with PAF after diagnosis of CD, 68.6% were diagnosed with PAF before diagnosis with CD, and 15.7% were diagnosed with CD and PAF within the same month. Of the patients diagnosed with CD after PAF, approximately 30% were diagnosed with PAF by the age of 20 years, whereas less than 10% of PAF patients without CD were diagnosed with PAF by the age of 20 years. Conclusions: The study reveals the prevalence of CD-associated PAF in Japan and that most individuals were diagnosed with CD after the diagnosis of PAF. Crohn's disease may be underdiagnosed in patients with PAF; patients diagnosed with PAF at a young age should be monitored to allow timely diagnosis of CD.