Thyme (Thymus quinquecostatus Celak) Polyphenol-Rich Extract (TPE) Alleviates HFD-Induced Liver Injury in Mice by Inactivating the TLR4/NF-κB Signaling Pathway through the Gut–Liver Axis

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents a significant and urgent global health concern. Thyme (Thymus quinquecostatus Celak) is a plant commonly used in cuisine and traditional medicine in Asian countries and possesses potential liver-protective properties. This study aimed to assess the hepatoprotective effects of thyme polyphenol-rich extract (TPE) on high-fat diet (HFD)-induced NAFLD and further explore possible mechanisms based on the gut–liver axis. HFD-induced liver injury in C57 mice is markedly ameliorated by TPE supplementation in a dose-dependent manner. TPE also regulates the expression of liver lipid metabolic genes (i.e., Hmgcr, Srebp-1, Fasn, and Cyp7a1), enhancing the production of SCFAs and regulating serum metabolites by modulating gut microbial dysbiosis. Furthermore, TPE enhances the intestinal barrier function and alleviates intestinal inflammation by upregulating tight junction protein expression (i.e., ZO-1 and occluding) and inactivating the intestinal TLR4/NF-κB pathway in HFD-fed mice. Consequently, gut-derived LPS translocation to the circulation was blocked, the liver TLR4/NF-κB signaling pathway was repressed, and subsequent pro-inflammatory cytokine production was restrained. Conclusively, TPE might exert anti-NAFLD effects through the gut–liver axis and has the potential to be used as a dietary supplement for the management of NAFLD.

Mitigation of high-fat diet-induced hepatic steatosis by thyme (Thymus quinquecostatus Celak) polyphenol-rich extract (TPE): insights into gut microbiota modulation and bile acid metabolism

“…These beneficial outcomes can be partially attributed to histopathological examination and inactivation of the TLR4/NF-κB signaling pathway in both the liver and colon. 25 Nevertheless, BAs and the gut microbiota, whose interactions in the enterohepatic circulation are highly associated with metabolic diseases ( e.g. NAFLD, obesity, and cancer), 8,27,28 have been inadequately studied as potential therapeutic targets in TPE's anti-NAFLD mechanism.…”

“…TPE was prepared according to our previous research (refer to the ESI†). 25 Experimental diets were purchased from Jiangsu Xietong Pharmaceutical Bio-Engineering Co. Ltd (Nanjing, China). The compositions of the experimental diets are listed in Table S1 †.…”

“…As the primary pathway for eliminating excessive cholesterol from the liver, activation of hepatic BA synthesis could potentially account for the observed reduction in total cholesterol in our previous study. 25 The levels of non-12-OH BAs (UDCA, α/β-MCA and LCA) were also elevated in HFD-fed mice supplemented with TPE, exerting a positive influence on metabolic disease progression. 33 We further examined the mRNA expression of genes involved in BA metabolism.…”

Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways

“…Several studies have demonstrated that certain tea extracts such as Liupao tea extract [ 54 ]; epigallocatechin gallate [ 55 ]; pentoxifylline [ 56 ]; Camellia oleifera seed extract [ 57 ]; flavonoid compounds such as didymin [ 58 ], chrysin [ 59 ], luteolin [ 60 ] and Tremella fuciformis crude polysaccharides [ 61 ]; black ginseng [ 62 ], Rhodomyrtus tomentosa (Ait.) husk fruit phenolic rich extract [ 63 ]; and thyme polyphenol-rich extract [ 64 ] could reduce IR, improve intestinal microecology, and mitigate MAFLD progression by downregulating TLR4/MyD88/NF-κB signaling pathway transduction and reducing TNF-α, IL-6, and TGF-β levels. It is worth noting that pentoxifylline and chlorogenic acid [ 65 ] also have the ability to improve MAFLD by attenuating macrophage M1 polarization.…”