The improvement of nonalcoholic steatohepatitis by Poria cocos polysaccharides associated with gut microbiota and NF-κB/CCL3/CCR1 axis

Nonalcoholic steatohepatitis (NASH) has been linked to inflammation induced by intestinal microbiota. Poria cocos polysaccharides (PCP) possesses anti-inflammation and immunomodulation functions; however, its preventive effects against NASH and potential mechanisms need to be explored.The composition of PCP was determined using ion chromatography. C57BL/6 mice were administered the methionine and choline deficient (MCD) diet for 4 weeks to establish the NASH model or methionine-choline-sufficient (MCS) diet to serve as the control. Mice were assigned to the MCS group, MCD group, low-dose PCP (LP) group, and high-dose PCP (HP) group, and were administered the corresponding medications via gavage. Serum biochemical index analysis and liver histopathology examination were performed to verify the successful establishment of NASH model and to evaluate the efficacy of PCP. The composition of intestinal bacteria was profiled through 16S rRNA gene sequencing. Hepatic RNA sequencing (RNA-Seq) was performed to explore the potential mechanisms, which were further confirmed using qPCR, western blot, and immunohistochemistry.PCP consists of glucose, galactose, mannose, D-glucosamine hydrochloride, xylose, arabinose, and fucose. PCP could significantly alleviate symptoms of NASH, including histological liver damage, impaired hepatic function, and increased oxidative stress. Meanwhile, HP could reshape the composition of intestinal bacteria by significantly increasing the relative abundance of Faecalibaculum and decreasing the level of endotoxin load derived from gut bacteria. PCP could also downregulate the expression of pathways associated with immunity and inflammation, including the chemokine signaling pathway, Toll-like receptor signaling pathway, and NF-kappa B signaling pathway. The expression levels of CCL3 and CCR1 (involved in the chemokine signaling pathway), Tlr4, Cd11b, and NF-κb (involved in the NF-kappa B signaling pathway), and Tnf-α (involved in the TNF signaling pathway) were significantly reduced in the HP group compared to the MCD group.PCP could prevent the development of NASH, which may be associated with the modulation of intestinal microbiota and the downregulation of the NF-κB/CCL3/CCR1 axis.