Chebulagic acid ameliorates DSS-induced colitis in mice by improving oxidative stress, inflammation and the gut microbiota

Objectives: Chebulagic acid (CA), isolated from the fruits of Terminalia chebula Retz, has a number of pharmacological activities, but its effect on ulcerative colitis (UC) has not been reported. Here, we explored the protective effect of CA against dextran sulfate sodium (DSS)-induced acute colitis and elucidated the potential mechanisms. Methods: The mouse model of DSS-induced acute colitis was employed to evaluate the effect of CA on UC. The expression of pro-inflammatory cytokines and tight junction proteins were evaluated by quantitative real-time PCR (qRT-PCR). Western blotting was used to explore the potential signal pathway. The gut microbiota was analyzed by 16S rDNA amplicon sequencing. Results: The data showed that CA significantly mitigated colitis severity, as manifested by the suppression of weight loss, shortening of colon, disease activity index (DAI) and histopathological score. CA increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity and reduced malondialdehyde (MDA) content in the colon of colitis mice through inhibiting the mitogen-activated protein kinase (MAPK) pathway and the activating nuclear respiratoty factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway. Meanwhile, myeloperoxidase (MPO) activity and proinflammatory cytokines levels of the CA group were markedly decreased due to suppression of the nuclear factor kappa-B (NF-kappa B) signaling pathway. Moreover, CA could upregulate the expression of tight junction proteins and reduced apoptosis. Furthermore, CA remodeled the gut microbiota through suppressing the growth of harmful bacteria (Clostridium_sensu_stricto_1, Streptococcus and Escherichia_Shigella) and promoting the growth of beneficial bacteria (Faecalibacterium, Dubosiella and Muribaculaceae). Conclusions: This study revealed that CA treatment could ameliorate DSS-induced acute colitis mainly via reducing oxidative stress and inflammation, maintaining the integrity of the intestinal barrier and modulating diversity and abundance of gut microbiota; thus, CA may become a promising novel drug candidate for initial and maintenance therapy of UC.