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Flaxseed Powder Attenuates Non-Alcoholic Steatohepatitis via Modulation of Gut Microbiota and Bile Acid Metabolism through Gut-Liver Axis.

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is gradually becoming one of the most common and health-endangering diseases; therefore, it is very important to prevent the occurrence of NASH and prevent simple non-alcoholic fatty liver (NAFL) from further developing into NASH. We fed mice a high-fat diet (HFD, 60% fat) for 14 weeks to induce NAFL and then fed different doses of flaxseed powder (low (10%), middle (20%), and high (30%)) to the mice for 28 weeks. After the animal experiment, we analyzed fecal bile acid (BA) profiles of the HFD mice, flaxseed-fed (FLA-fed) mice, and control mice with a normal diet (10% fat) using a targeted metabolomics approach, and we analyzed the gut microbiota at the same time. We also investigated the mechanistic role of BAs in NASH and identified whether the altered BAs strongly bind to colonic FXR or TGR5. In the present study, we found that 28-week FLA treatment notably alleviated NASH development in NAFL model mice fed with an HFD, and the beneficial effects may be attributed to the regulation of and improvement in the gut flora- and microbiota-related BAs, which then activate the intestinal FXR-FGF15 and TGR5-NF-κB pathways. Our data indicate that FLA might be a promising functional food for preventing NASH through regulating microbiomes and BAs.

SUBMITTER: Yang C

PROVIDER: S-EPMC8509295 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundYinChen WuLing Powder (YCWLP) has been recommended by consensus for the treatment of non-alcoholic steatohepatitis (NASH); nevertheless, its specific pharmacological mechanisms remain to be elucidated. This study aims to dissect the mechanisms underlying the therapeutic effects of YCWLP on NASH using a hybrid approach that encompasses network pharmacology, molecular docking, and in vitro experimental validation.MethodsWe compiled the chemical constituents of YCWLP from the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform (TCMSP), while potential targets were predicted using the SwissTargetPrediction database. To identify NASH-related candidate targets, comprehensive retrieval was carried out using five authoritative databases. Protein-Protein Interaction (PPI) networks of direct targets of YCWLP in NASH treatment were then constructed using the String database, and functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, were conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Core targets were discerned using the Molecular Complex Detection (MCODE) and cytoHubba algorithms. Subsequently, molecular docking of key compounds to core targets was conducted using AutoDock software. Moreover, we established a free fatty acid-induced HepG2 cell model to simulate NASH in vitro, with YCWLP medicated serum intervention employed to corroborate the network pharmacology-derived hypotheses. Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), and Western blotting analyses was employed to investigate the lipid, hepatic enzyme, SHP2/PI3K/NLRP3 signaling pathway and associated cytokine levels.ResultsThe network pharmacology analysis furnished a list of 54 compounds from YCWLP and 167 intersecting targets associated with NASH. Through analytic integration with multiple algorithms, PTPN11 (also known as SHP2) emerged as a core target of YCWLP in mitigating NASH. The in vitro experiments validated that 10% YCWLP medicated serum could remarkably attenuate levels of total cholesterol (TC, 1.25 vs. 3.32) and triglyceride (TG, 0.23 vs. 0.57) while ameliorating alanine aminotransferase (ALT, 7.79 vs. 14.78) and aspartate aminotransferase (AST, 4.64 vs. 8.68) leakage in NASH-afflicted cells. In addition, YCWLP significantly enhanced the phosphorylation of SHP2 (0.55 vs. 0.20) and downregulated the expression of molecules within the SHP2/PI3K/NLRP3 signaling axis, including p-PI3K (0.42 vs. 1.02), NLRP3 (0.47 vs. 0.93), along with downstream effectors-cleaved Caspase-1 (0.21 vs. 0.49), GSDMD-NT (0.24 vs. 0.71), mature interleukin-1β (IL-1β, 0.17 vs. 0.48), pro-IL-1β (0.49 vs. 0.89), mature interleukin-18 (IL-18, 0.15 vs. 0.36), and pro-IL-18 (0.48 vs. 0.95).ConclusionOur research reveals that YCWLP exerts therapeutic effects against NASH by inhibiting lipid accumulation and inflammation, which involves the attenuation of pyroptosis via the SHP2/PI3K/NLRP3 pathway.

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Flaxseed Powder Attenuates Non-Alcoholic Steatohepatitis via Modulation of Gut Microbiota and Bile Acid Metabolism through Gut-Liver Axis.

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