CDP-choline modulates cholinergic signaling and gut microbiota to alleviate DSS-induced inflammatory bowel disease

Biochem Pharmacol. 2023 Nov:217:115845. doi: 10.1016/j.bcp.2023.115845. Epub 2023 Oct 10.

Abstract

Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous research has revealed that IBD patients often have a deficiency of choline and its metabolites, including acetylcholine (ACh) and phosphatidylcholine (PC), within the colon. However, a comprehensive study linking these three substances and their mechanistic implications in IBD remains lacking. This study aimed to investigate the efficacy and underlying mechanism of cytidine diphosphate (CDP)-choline (citicoline), an intermediate product of choline metabolism, in a mouse model of IBD induced by dextran sulfate sodium salt (DSS). The results demonstrated that CDP-choline effectively alleviated colonic inflammation and deficiencies in choline, ACh, and PC by increasing the raw material. Further detection showed that CDP-choline also increased the ACh content by altering the expression of high-affinity choline transporter (ChT1) and acetylcholinesterase (AChE) in DSS-induced mice colon. Moreover, CDP-choline increased the expression of alpha7 nicotinic acetylcholine receptor (α7 nAChR) and activated the cholinergic anti-inflammatory pathway (CAP), leading to reduced colon macrophage activation and proinflammatory M1 polarization in IBD mice, thus reducing the levels of TNF-α and IL-6. In addition, CDP-choline reduced intestinal ecological imbalance and increased the content of hexanoic acid in short-chain fatty acids (SCFAs) in mice. In conclusion, this study elucidates the ability of CDP-choline to mitigate DSS-induced colon inflammation by addressing choline and its metabolites deficiencies, activating the CAP, and regulating the composition of the intestinal microbiome and SCFAs content, providing a potential prophylactic and therapeutic approach for IBD.

Keywords: CDP-choline; Cholinergic anti-inflammatory pathway; Inflammatory bowel diseases; Intestinal microbiome; Short-chain fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Acetylcholinesterase
  • Animals
  • Choline / pharmacology
  • Colitis* / chemically induced
  • Colon / metabolism
  • Cytidine Diphosphate Choline / pharmacology
  • Cytidine Diphosphate Choline / therapeutic use
  • Dextran Sulfate / toxicity
  • Disease Models, Animal
  • Gastrointestinal Microbiome*
  • Humans
  • Inflammation
  • Inflammatory Bowel Diseases* / chemically induced
  • Inflammatory Bowel Diseases* / drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Nicotinic Antagonists / pharmacology

Substances

  • Cytidine Diphosphate Choline
  • Acetylcholinesterase
  • Choline
  • Acetylcholine
  • Nicotinic Antagonists
  • Dextran Sulfate