Article

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

Authors: Li-xiang Aa1, Fei Fei1, Qi Qi1, Run-bin Sun1, Sheng-hua Gu2, Zi-zhen Di3, Ji-ye Aa1, Guang-ji Wang1, Chang-xiao Liu4
1 Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
2 Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3 Liaoning Provincial Academy of Traditional Chinese Medicine, Shenyang 110034, China
4 State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
Correspondence to: Ji-ye Aa: jiyea@cpu.edu.cn, Chang-xiao Liu: liuchangxiao@163.com,
DOI: 10.1038/s41401-019-0279-8
Received: 19 March 2019
Accepted: 23 June 2019
Advance online: 19 August 2019

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 (Cmax = 0.23 ± 0.06 ng/mL) and its primary metabolite kaempferol-3-O-glucuronide (Cmax = 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.
Keywords: kaempferol; collagen-induced arthritis; anti-arthritis effects; pharmacokinetics; intestinal microbiota; metabolomics

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