Anthraquinone-containing compound in rhubarb prevents indole production via functional changes in gut microbiota

Indole is produced from dietary tryptophan by tryptophanase in intestinal bacteria, such as Escherichia coli. In the liver, indole is converted into indoxyl sulfate, a uremic toxin and risk factor for chronic kidney disease (CKD). Probiotics and prebiotics are currently used for suppressing CKD, but there are no drugs that directly suppress indole production. In this study, we developed an optimized HPLC method for analyzing indole production and evaluated the effect of diets and rhubarb on indole production via the changes of gut microbiota. In high-carbohydrate and high-fat diet-fed mice, the indole production was significantly higher than in high-fiber diet-fed mice. We further used the high-carbohydrate diet-fed mice as a model for examining the effect of rhubarb on indole production. The 20% methanol-eluted fraction of aqueous rhubarb extract significantly suppressed indole production, and the eluate constituent rhein 8-O-β-D-glucopyranoside (RG) contributed to this effect in a concentration-dependent manner. The effect of RG depended on the anthraquinone core substructure, i.e., the aglycone moiety (rhein) of RG, which appeared to inhibit the tryptophanase function in gut microbiota. Thus, in addition to earlier reports that rhubarb is an effective CKD treatment, our study demonstrated that the anthraquinone moiety in rhubarb prevents uremic toxin production via functional changes in gut microbiota, which suppresses CKD progression.