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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 (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.

SUBMITTER: Aa LX

PROVIDER: S-EPMC7468310 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Aa Li-Xiang LX Fei Fei F Qi Qi Q Sun Run-Bin RB Gu Sheng-Hua SH Di Zi-Zhen ZZ Aa Ji-Ye JY Wang Guang-Ji GJ Liu Chang-Xiao CX

Acta pharmacologica Sinica 20190819 1

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 ...[more]

PMID: 31427695

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Project description:1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.

Project description:INTRODUCTION:High-fat diet (HFD)-induced obesity is accompanied by compromised nitric oxide (NO) signaling and gut microbiome dysregulation. Inorganic dietary nitrate, which acts as a NO donor, exerts beneficial effects on metabolic disorders. Here, we evaluated the effects of dietary nitrate on HFD-induced obesity and provided insights into the underlying mechanism. RESEARCH DESIGN AND METHODS:To investigate the preventive effect of dietary nitrate on HFD-induced obesity, C57BL/6 mice were randomly assigned into four groups (n=10/group), including normal control diet group (normal water and chow diet), HFD group (normal water and HFD), HFD+NaNO3 group (water containing 2 mM NaNO3 and HFD), and HFD+NaCl group (water containing 2 mM NaCl and HFD). During the experiment, body weight was monitored and glucolipid metabolism was evaluated. The mechanism underlying the effects of nitrate on HFD-induced obesity was investigated by the following: the NO3 --NO2 --NO pathway; endothelial NO synthase (eNOS) and cyclic guanosine monophosphate (cGMP) levels; gut microbiota via 16SRNA analysis. RESULTS:Dietary nitrate reduced the body weight gain and lipid accumulation in adipose and liver tissues in HFD-fed mice. Hyperlipidemia and insulin resistance caused by HFD were improved in mice supplemented with nitrate. The level of eNOS was upregulated by nitrate in the serum, liver, and inguinal adipose tissue. Nitrate, nitrite, and cGMP levels were decreased in mice fed on HFD but reversed in the HFD+NaNO3 group. Nitrate also rebalanced the colon microbiota and promoted a normal gut microbiome profile by partially attenuating the impacts of HFD. Bacteroidales S24-7, Alistipes, Lactobacillus, and Ruminococcaceae abundances were altered, and Bacteroidales S24-7 and Alistipes abundances were higher in the HFD+NaNO3 group than that in the HFD group. CONCLUSIONS:Inorganic dietary nitrate alleviated HFD-induced obesity and ameliorated disrupted glucolipid metabolism via NO3 --NO2 --NO pathway activation and gut microbiome modulation.

Project description:BackgroundAtherosclerosis has been widely accepted as an inflammatory disease of vascular, adhesion molecules play an important role in the early progression of it. The aim of the present study was to evaluate the effect of kaempferol on the inflammatory molecules such as E-selectin (E-sel), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesionmolecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in high cholesterol induced atherosclerosis rabbit models.MethodsThirty male New Zealand white (NZW) rabbits were randomly divided into five groups, control group, model group, fenofibrate (12 mg/kg) group and kaempferol groups (150 mg/kg and 30 mg/kg). The rabbits were fed with a normal diet or a high cholesterol diet for 10 weeks. Levels of blood lipids, serum tumour-necrosis factor-alpha (TNF-α) and serum interleukin-1beta (IL-1β) were detected at the end of the sixth and tenth week. Malonaldehyde (MDA) level and superoxide dismutase (SOD) activity in serum were also determined. Lesion areas of the aorta were measured with morphometry analysis after ten weeks. Gene expression of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas was determined by RT-PCR (reverse transcription-polymerase chain reaction). Immunohistochemical staining was employed to measure protein expression of E-sel, ICAM-1, VCAM-1 and MCP-1.ResultsModel rabbits fed with ten weeks of high-cholesterol diet developed significant progression of atherosclerosis. Compared with the control, levels of blood lipids, TNF-α, IL-1β and MDA increased markedly in serum of model rabbits, while SOD levels decreased. Gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas increased remarkably in model group. However, comparing to the model rabbits, levels of TNF-α, IL-1β and MDA decreased significantly and serum SOD activity increased, gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas decreased significantly with the treatment of kaempferol.ConclusionKaempferol shows anti-atherosclerotic effect by modulating the gene and protein expression of inflammatory molecules.

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

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

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