Phillygenin Attenuates Carbon Tetrachloride-Induced Liver Fibrosis via Modulating Inflammation and Gut Microbiota

Abstract

Liver fibrosis is a chronic pathological process that various pathogenic factors lead to abnormal hyperplasia of hepatic connective tissue, and its main feature is the excessive deposition of extracellular matrix. However, there are currently no drugs approved for the treatment of liver fibrosis. Phillygenin (PHI), a lignan isolated from Forsythiae Fructus, showed potential anti-inflammatory and anti-fibrosis effects but the mechanisms remain unknown. In view of the vital role of gut microbiota in the development of liver fibrosis, this study aimed to explore whether PHI could protect intestinal epithelial barrier and attenuate liver fibrosis by maintaining the homeostasis of intestinal microbiota. Therefore, the liver fibrosis model was induced by intraperitoneal injection of olive oil containing 10% carbon tetrachloride (CCl4) for 4 weeks in C57BL/6J mice. Histological analysis including Hematoxylin-Eosin, Masson, Sirius red, and immunohistochemistry staining were carried out to detect the histopathology and collagen deposition of mice liver tissues. The biochemical indexes related to liver function (ALT, AST, AKP, γ-GT), fibrosis (HYP, HAase, LN, PC III, IV-C) and inflammation (TNF-α, MIP-1, LPS) were determined by specific commercial assay kits. In vivo experimental results showed that PHI could improve liver histopathological injury, abnormal liver function, collagen deposition, inflammation and fibrosis caused by CCl4. Moreover, PHI restored the intestinal epithelial barrier by promoting the expression of intestinal barrier markers, including ZO-1, Occludin and Claudin-1. More importantly, the corrective effect of PHI on the imbalance of gut microbiota was confirmed by sequencing of the 16 S rRNA gene. In particular, PHI treatment enriches the relative abundance of Lactobacillus, which is reported to alleviate inflammation and fibrosis of damaged liver. Collectively, PHI attenuates CCl4-induced liver fibrosis partly via modulating inflammation and gut microbiota.

Phillygenin Protects the Intestinal Barrier from Dysfunction via let-7b Signaling Pathway and Regulation of Intestinal Microbiota

“…let-7b significantly ameliorated the mice colitis and reduced the secretion of inflammatory cytokines through TLR4. Another study showed that phillygenin could improve inflammation and fibrosis caused by CCl 4 [ 4 ]. Furthermore, it restored the intestinal barrier by promoting ZO-1, occludin, and claudin-1.…”

“…Furthermore, it restored the intestinal barrier by promoting ZO-1, occludin, and claudin-1. Phillygenin enriches the relative abundance of Lactobacillus and regulated the intestinal microbiota, which are reported to effectively alleviate the intestinal barrier injury [ 4 ]. Recent study also found that phillygenin also inhibited LPS-induced inflammation through TLR4/MyD88 signaling and suppress the adaptive immune response and inflammatory activities.…”

“…However, effective drugs and the treatment methods still need to be further investigated [ 3 ]. It is reported that phillygenin is an important active ingredient of lignans with a fingerprint component in Forsythiae Fructus [ 4 ]. Furthermore, it is reported as a wide-used protector with various functions, such as antiviral, antioxidant, anti-inflammatory, anticancer, and antifibrosis effects [ 4 – 8 ].…”

“…It is reported that phillygenin is an important active ingredient of lignans with a fingerprint component in Forsythiae Fructus [ 4 ]. Furthermore, it is reported as a wide-used protector with various functions, such as antiviral, antioxidant, anti-inflammatory, anticancer, and antifibrosis effects [ 4 – 8 ]. MicroRNAs (miRs) are mainly negative regulators of their target genes through binding to 3'untranslated regions (3'UTRs) [ 9 – 12 ].…”

Phillygenin Inhibits Helicobacter pylori by Preventing Biofilm Formation and Inducing ATP Leakage

“…In this study, phillygenin, which is an effective antibacterial component of F. suspensa belonging to the lignans, was screened out (Liu et al, 2018 ). Studies have reported that phillygenin had the effects of regulating the intestinal microbiota, reducing fibrosis herein (Sun et al, 2021 ), inhibiting the release of inflammatory cytokines (Wang et al, 2021 ), inhibiting adhesion and migration, etc. (Quan et al, 2021 ), while, less has been studied about its antibacterial effects.…”