Kaempferol Alleviates Murine Experimental Colitis by Restoring Gut Microbiota and Inhibiting the LPS-TLR4-NF-κB Axis

Abstract

Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)–dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration via increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of IL-1β, IL-6, and TNF-α and downregulated transcription of an array of inflammatory signaling molecules, while it increased IL-10 mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the Firmicutes to Bacteroidetes ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as Prevotellaceae and Ruminococcaceae; and reducing the richness of Proteobacteria in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.

Effect of Extracellular Vesicles Derived From Lactobacillus plantarum Q7 on Gut Microbiota and Ulcerative Colitis in Mice

“…It was reported that EVs could play a role in host-microbe r e s p o n s e s a n d r e g u l a t e t h e g u t m i c r o fl o r a ( 4 3 ) . Proteobacteria was reported to be the main phylum of pathogenic bacteria, which promoted the production of excessive pro-inflammatory cytokines and related to IBD pathogenesis (24,42). Akkermansia was a confirmed probiotic with anti-inflammatory effect by improving neutrophil infiltration and alleviating intestinal inflammation (44)(45)(46).…”

“…The results showed that oral Q7-EVs down-regulated TLR4 and MyD88 gene expression compared with DSS-induced colitis mice ( Figure S4 ) . After binding to the ligand, MyD88-dependent signal transduction could lead to phosphorylation of NF-κB, thereby regulating the levels of transcription factors of IL-1β, IL-6, and TNF-α ( 24 ). It was speculated that Q7-EVs improved colitis by regulating the TLR4-MyD88-NF-κB pathway.…”

“…Mice were housed in an animal care facility and provided with sufficient food (Beijing Keao Xieli Feed Co., Ltd., Beijing, China) and water. Colitis was induced by 3.5% dextran sulfate sodium (DSS, Yeasen Biotech, Shanghai, CN) administration in the drinking water ( 23 ) and the mice were treated Q7-EVs by gavage ( 23 , 24 ). The mice were acclimated for a week and randomly divided into four groups: control group (PBS, daily), DSS+PBS group (PBS, daily), DSS+10 μg Q7-EVs group (0.5 mg/kg body weight Q7-EVs, daily), DSS+20 μg Q7-EVs group (1 mg/kg body weight Q7-EVs, daily).…”

Research on the Mechanism of Kaempferol for Treating Senile Osteoporosis by Network Pharmacology and Molecular Docking

“…There is growing evidence for the role of kaempferol in attenuating inflammatory response mediated by NF- к B, indicating its protective effects on bone loss in postmenopausal osteoporosis by blocking TNF- α -induced nuclear translocation of the NF- к B subunit p65 from the cytoplasm to the nucleus [ 52 ]. And KP could suppress age-related NF- к B activation by inhibition of NF- к B subunit p65 translocation so as to restrain inflammatory response [ 53 ]. Some evidence showed that there was a negative correlation between dietary intake level of KP and serum CRP level, suggesting the key role of KP in reducing the risk of inflammation [ 54 ].…”

Using Network Pharmacology and Molecular Docking Technology to Explore the Mechanism of Modified Pulsatilla Decoction in the Treatment of Ulcerative Colitis

“…32 It is confirmed that kaempferol plays a protective role in colitis mice by regulating intestinal microbiota and toll-like receptor-related signaling pathways. 33 Stigmasterol has been shown to be an immunomodulator with great therapeutic potential. 34 Stigmasterol plays an important anti-inflammatory role and can reduce oxidative stress in a variety of diseases.…”