Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol

Abstract

Kaempferol is a natural flavonol that possesses various pharmacological activities, including anti-arthritis effects, yet the underlying mechanisms remain controversial. To evaluate the anti-arthritis efficacy and the underlying mechanisms of kaempferol, collagen-induced arthritis (CIA) mice were treated with kaempferol intragastrically (200 mg · kg −1 · d −1 ) and intraperitoneally (20 mg · kg −1 · d −1 ). Pharmacodynamic and pharmacokinetic studies showed that the oral administration of kaempferol produced distinct anti-arthritis effects in model mice with arthritis in terms of the spleen index, arthritis index, paw thickness, and inflammatory factors; the bioavailability (1.5%, relative to that of the intraperitoneal injection) and circulatory exposure of kaempferol ( C max = 0.23 ± 0.06 ng/mL) and its primary metabolite kaempferol-3- O -glucuronide ( C max = 233.29 ± 89.64 ng/mL) were rather low. In contrast, the intraperitoneal injection of kaempferol caused marginal anti-arthritis effects, although it achieved a much higher in vivo exposure. The much higher kaempferol content in the gut implicated a potential mechanism involved in the gut. Analysis of 16S ribosomal RNA revealed that CIA caused imbalance of 14 types of bacteria at the family level, whereas kaempferol largely rebalanced the intestinal microbiota in CIA mice. A metabolomics study showed that kaempferol treatment significantly reversed the perturbation of metabolites involved in energy production and the tryptophan, fatty acid and secondary bile acid metabolisms in the gut contents of the CIA mice. In conclusion, we demonstrate for the first time that the high level of kaempferol in the gut regulates the intestinal flora and microbiotic metabolism, which are potentially responsible for the anti-arthritis activities of kaempferol.

Role of tryptophan-metabolizing microbiota in mice diarrhea caused by Folium sennae extracts

“…Moreover, there's research that CYP 450 transgenic mice were used to prove that regulation of intestinal and hepatic drug-processing enzymes by the intestinal microbiota via tryptophan and its metabolites [36]. Kaempferol, as one of the active ingredients in Folium sennae filtered in network pharmacology in this study, increased small bowel transit in mice through cholinergic pathways [37] and regulated the metabolites involved in tryptophan [38]. So we come to the conclusion that Folium sennae targeted CYP 3A4 to altered intestinal microbiota microecology and intervened the tryptophan metabolism of intestinal microbiota, which may be one of the pharmacological mechanisms of laxative action of Folium sennae.…”

Role of Tryptophan-Metabolizing Microbiota On Diarrhea Mice Caused by Folium sennae Extracts

“…Moreover, there's research that CYP 450 transgenic mice were used to prove that regulation of intestinal and hepatic drugprocessing enzymes by the intestinal microbiota via tryptophan and its metabolites [36]. Kaempferol, as one of the active ingredients in Folium sennae filtered in network pharmacology in this study , increased small bowel transit in mice through cholinergic pathways [37] and regulated the metabolites involved in tryptophan [38]. So we come to the conclusion that Folium sennae targeted CYP 3A4 to altered intestinal microbiota microecology and intervened the tryptophan metabolism of intestinal microbiota, which may be one of the pharmacological mechanisms of laxative action of Folium sennae.…”

Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs

“…In this respect, a dietary approach could be taken. A natural flavanol Kaempferol demonstrated significant activity against collagen-induced arthritis in mice when administered orally but not intraperitoneally, and Kaempferol was retained in the gut and diversified the microbiota; these data support the contribution of microbiome diversity towards the therapeutic effect (Aa et al, 2020). Kaempferol mimics with potent microbial re-shaping ability could be designed for the treatment of arthritis (Aa et al, 2020).…”