Targeting cystathionine-β-synthase (CBS)-mediated cell stemness and gut microbiome homeostasis: mechanism and clinical study of combined resveratrol-curcumin treatment for ulcerative colitis.

Abstract

Background: Durable mucosal healing is the primary therapeutic goal in ulcerative colitis (UC). Intestinal epithelial stemness and microbiota homeostasis drive this healing process. Cystathionine-β-synthase (CBS) is a key enzyme in endogenous sulfur metabolism. Sulfur metabolism is essential for mitochondrial energy production and mucosal integrity. However, the precise role of CBS in UC pathogenesis remains unclear. Single plant-derived polyphenols, such as resveratrol or curcumin, show limited clinical efficacy due to low bioavailability. The combined effect of these botanical agents on CBS-mediated gut homeostasis requires further investigation.

Purpose: This study aimed to define the molecular function of CBS in colitis and to evaluate the therapeutic mechanism and clinical translational potential of a combined plant-derived resveratrol-curcumin treatment for UC.

Study design: A comprehensive bench-to-bedside translational approach was employed. The study integrated human clinical sample analysis, in vivo animal experiments using transgenic models, in silico molecular docking, and a pilot clinical trial.

Methods: CBS expression was quantified in colonic biopsies from UC patients and healthy controls. Dextran sulfate sodium (DSS) was used to induce colitis in wild-type (WT) and CBS knockout (Cbs^-/-) mice. Clinical phenotypes, mucosal protein expression, microbiota composition, and short-chain fatty acid (SCFA) profiles were systematically assessed. Molecular docking evaluated the binding affinity between the CBS protein and the resveratrol-curcumin combination. The in vivo efficacy of this combination was tested in both WT and Cbs^-/- mice. Finally, a pilot clinical trial assessed the combination therapy alongside mesalamine in UC patients.

Results: Colonic CBS expression was downregulated in both UC patients and colitis mice. CBS deficiency worsened DSS-induced clinical damage. It disrupted intestinal barrier homeostasis and severely impaired SCFA production. Molecular docking demonstrated strong binding affinity between the resveratrol-curcumin combination and the CBS protein. In vivo, this combined treatment effectively alleviated colitis symptoms. It reduced pro-inflammatory cytokines, upregulated mucosal proteins via CBS activation, and restored microbiota structure. Notably, these mucosal protective effects were completely abolished in Cbs^-/- mice, confirming CBS as the essential target for this combined protective effect. In the pilot trial, the addition of resveratrol and curcumin to mesalamine improved clinical outcomes in UC patients.

Conclusion: CBS acts as a crucial endogenous protector in the colon. It maintains epithelial stemness and microbiota metabolic homeostasis. The plant-derived resveratrol-curcumin combination specifically targets and restores CBS expression, promoting epithelial regeneration and microbiota remodeling. These findings highlight host-microbiome interactions in UC pathogenesis and offer a novel, targeted polyphenol strategy to achieve mucosal healing.