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

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.