Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis

Area of Science:

• Pharmacology
• Gastroenterology
• Oncology

Background:

• The Farnesoid X Receptor (FXR) is a nuclear receptor activated by bile acids.
• FXR activation is known to inhibit intestinal inflammation and tumor development.
• Nelumal A is a novel FXR agonist derived from Ligularia nelumbifolia.

Purpose of the Study:

• To investigate the potential of nelumal A in preventing colitis and inflammation-related colorectal carcinogenesis.
• To evaluate the effects of nelumal A on intestinal integrity, oxidative stress, and bile acid metabolism.

Main Methods:

• Mouse models of dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis were used.
• Mice were fed diets containing nelumal A.
• Gene expression of tight junctions, antioxidant enzymes, and FXR target genes in the intestine, as well as bile acid synthesis in the liver, were analyzed.

Main Results:

• Nelumal A significantly reduced colonic mucosal ulcers and inflammation in the colitis model.
• Nelumal A decreased the incidence of colonic ulcers and adenocarcinomas in the carcinogenesis model.
• Administration of nelumal A enhanced tight junctions and antioxidant enzymes, upregulated intestinal FXR target genes, and decreased hepatic bile acid synthesis.

Conclusions:

• Nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis in mice.
• The therapeutic effects are likely mediated by reduced bile acid synthesis and oxidative damage.
• Nelumal A holds potential for treating inflammatory bowel diseases and for colorectal cancer chemoprevention.