Epigallocatechin Gallate Protects Mice against Methionine–Choline-Deficient-Diet-Induced Nonalcoholic Steatohepatitis by Improving Gut Microbiota To Attenuate Hepatic Injury and Regulate Metabolism

Abstract

Epigallocatechin gallate (EGCG) has been regarded as a protective bioactive polyphenol in green tea against nonalcoholic steatohepatitis (NASH), but the mechanism remains poorly deciphered. Herein, we assessed the role and mechanism of EGCG on gut microbiota and the metabolism in NASH development. Forty-eight male C57BL/6J mice were fed with either a methionine–choline-sufficient diet or a methionine–choline-deficient (MCD) diet with or without EGCG administration for 4 weeks. Liver injury, inflammation, lipid accumulation, and iron overload were examined. 16S ribosomal RNA sequencing was used to detect the fecal microbiome. In our research, we observed that EGCG notably improved MCD-diet-derived gut microbiota dysbiosis, as proved by a distinctively clustered separation from that of the MCD group and by the decrease of the Oxalobacter , Oscillibacter , Coprococcus_1, and Desulfovibrio genera and enrichment of norank_f__Bacteroidales_S24_7_group , Alloprevotella , and Bacteroides . Spearman-correlation heatmap analysis indicated that Bacteroides and Alloprevotella induced by EGCG were strongly negatively correlated with lipid accumulation. Functional enzymes of the gut microbiome were predicted by PICRUSt based on the operation classification unit. The results revealed that 1468 enzymes were involved in various metabolic pathways, and 371 enzymes showed distinct changes between untreated and EGCG-treated mice. Long-chain-fatty-acid-CoA ligase ACSBG played a distinct role in fatty acid metabolism and ferroptosis and was significantly negatively correlated with Bacteroides . Altogether, the salutary effect of EGCG on NASH might be via shifting gut flora and certain enzymes from genera. Our study thus takes a step toward NASH prevention and therapy.

Salubrious Effects of Green Tea Catechins on Fatty Liver Disease: A Systematic Review

“…It is important to consider the effects of EGCG on carbohydrate metabolism, as carbohydrate accumulation has detrimental effects on obesity and liver disease. Interestingly, all studies addressing the impact of EGCG on carbohydrate metabolism reported significant decreases in glucose and insulin levels, as well as insulin resistance (IR), with EGCG treatment [ 11 , 12 , 14 , 15 , 16 , 17 , 23 , 24 , 25 , 26 , 27 , 33 , 34 , 35 , 36 , 37 ] ( Table 1 ). Gan et al showed in their study that intraperitoneal administration of EGCG dose-dependently alleviates hyperinsulinemia, hyperglycemia, and IR [ 23 ].…”

“…EGCG treatment also improves liver damage biomarkers [ 10 , 11 , 12 , 14 , 16 , 17 , 19 , 24 , 27 , 28 , 29 , 30 , 32 , 34 , 35 , 36 , 37 , 38 ]. As shown in Table 1 , EGCG decreases levels of enzymes associated with liver damage, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).…”

Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity

“…Ferroptosis, a newly identified type of “programmed necrosis” characterized by lipid peroxidation in an iron-dependent manner ( Dixon et al, 2012 ; Chen et al, 2020 ), has been confirmed to be involved in the pathological processes of various diseases ( Fang et al, 2019 ; Martin-Sanchez et al, 2020 ; Mahoney-Sanchez et al, 2021 ). Recently, ferroptosis was proven to affect the progression of NASH by modulating lipid peroxidation in a methionine/choline-deficient diet-induced NASH mouse model ( Ning et al, 2020 ). Previous studies have reported that Que has the ability to alleviate pancreatic β cell injury in type 2 diabetes and acute kidney injury by inhibiting ferroptosis ( Li D. et al, 2020 ; Wang et al, 2021 ), but whether Que can inhibit ferroptosis to improve NAFLD has not been studied.…”

Green Tea and Its Relation to Human Gut Microbiome

“…However, they noticed that each treatment had a different effect on the gut microbiota, suggesting that the benefits observed in the liver were not, at least entirely, dependent on the gut microbiota [ 69 ]. Conversely, Ning et al [ 70 ] suggested that shifts caused in gut microbiome by EGCG could be related to benefits against nonalcoholic steatohepatitis. They fed C57BL/6J mice with EGCG, observing a change in the microbial community similar to those described before and characterized by a decrease in Firmicutes and an increase in Bacteroidetes .…”

“…They fed C57BL/6J mice with EGCG, observing a change in the microbial community similar to those described before and characterized by a decrease in Firmicutes and an increase in Bacteroidetes . Additionally, they found that several enzymes implicated in lipid accumulation were expressed in lower abundance when mice were fed with EGCG [ 70 ]. These authors therefore suggested a potential benefit against liver disease, though they acknowledged that more research was needed since results were not definitive.…”