Intervention of Shugan Xiaozhi Decoction on Nonalcoholic Fatty Liver Disease via Mediating Gut-Liver Axis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with an increasing incidence rate but few therapies. Shugan Xiaozhi decoction (SX) has demonstrated beneficial effects in treating NAFLD with an unclear mechanism. This study was aimed at investigating the therapeutic mechanism of SX on high-fat diet-induced NAFLD rats via the gut-liver axis. Hepatic steatosis and integrity of intestinal mucosa in NAFLD rats were assessed by histopathological staining. The level of lipid and inflammation were estimated by enzyme-linked immunosorbent assay. Western Blotting was used to detect apolipoprotein (apo) B48 expression. 16S rRNA analysis was used to measure the changes of gut microbial composition after SX treatment. The expressions of zona occludens 1 protein (ZO-1), occludin, and secretory immunoglobulin A (sIgA) in the colon were detected by immunostaining to investigate the intestinal barrier function. Our study found that SX reduced hepatic steatosis, the levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, and triglyceride and apoB48 expression but increased peroxisome proliferator activated receptor α (PPARα) level. Moreover, SX altered the diversity of gut microbiota, upregulating the relative abundance of f_Prevotellaceae, while downregulating f_Bacteroidales_ S24-7, f_Lachnospiraceae, f_Ruminococcaceae, f_Erysipelotrichaceae, and f_Desulfovibrionaceae. By increasing the expression of ZO-1 and occludin and decreasing the level of proinflammatory factors, including sIgA, lipopolysaccharide, tumor necrosis factor-α, interleukin-1β, monocyte chemotactic protein-1, and transforming growth factor-β1, SX improved intestinal mucosal integrity and barrier function. Our study illustrated that the gut-liver axis was a potential way for SX to ameliorate NAFLD, that is, by regulating the expression of PPARα, apoB48, and modulating gut microbiota to protect the intestinal barrier function, and thus alleviate lipid deposition and inflammatory response in the liver.

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites

“…These inconsistent results might be due to different subjects observed in the studies. An animal study revealed that the relative abundance of Ruminococcaceae was elevated in high fat diet-induced NAFLD rats, and a TCM formula called Shugan Xiaozhi decoction exerted beneficial effects in treating NAFLD with decreased abundance of Ruminococcaceae and other gut microbiota ( Yang et al., 2022 ). Interestingly, we also noticed similar results in the present study.…”

Repairing gut barrier by traditional Chinese medicine: roles of gut microbiota

“…Besides, Shugan Xiaozhi Decoction, a formula that can attenuate NAFLD in high-fat diet-induced rats, can also inhibit the translocation of LPS to avoid inflammation damage and increase ZO-1, occludin to fortify the gut barrier. This effect may be correlated with the lifting levels of f_Prevotellaceae and declining those of f_Desulfovibrionaceae and f_Erysi-Pelotrichaceae ( Yang et al., 2022a ). Mulberry leaf polysaccharide (MLP) can enhance the gene expression of occludin 1, ZO-1 and claudin 5 and relive intestinal villus damages.…”

Experimental model and novel therapeutic targets for non-alcoholic fatty liver disease development

“…First, PPARα activation can prevent HFD-induced NAFLD steatosis in models by activating the AMPK activation-mediated PPARγ coactivator-1α (PGC-1α) signaling pathway [ 59 ]. In addition, treatment with the Shugan Xiaozhi decoction, a component of artemisiae scopariae herb, significantly suppressed the gut-liver axis in NAFLD models by activating PPAR-mediated lipid metabolism [ 60 ]. Previous studies have indicated that PPARβ/δ shows high metabolic activity, lipid metabolism, glucose homeostasis, and inflammation in hepatocytes, Kupffer cells, and hepatic stellate cells through AMPK activation-mediated suppression of the inflammatory signaling pathway [ 58 ].…”