The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD. EXPERIMENTAL APPROACHThe NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing. KEY RESULTSTUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONSTUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition. Abbreviations ACOX1, peroxisomal acyl-CoA oxidase 1; ANOSIM, analysis of similarities; C3GNT, core 3β1,3-N-acetyl glucosaminyltransferase; CYP7a, cholesterol 7α-hydroxylase; ER, endoplasmic reticulum; FABP, fatty acid-binding protein; FATP4, fatty acid transport protein 4; FAR3, fatty acid receptor 3; H&E, haematoxylin and eosin; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of the insulin resistance index; Iap, intestinal alkaline phosphatase; ICAM1, intercellular cell adhesion molecule-1; IPGTT, i.p. glucose tolerance test; IPITT, i.p. insulin tolerance test; Irak4, IL-1 receptor-associated kinase 4; JAM, junctional adhesion molecule; Lcad, long-chain acyl-CoA dehydrogenase; NAFLD, non-alcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis; NCD, normal chow diet; OTU, operational taxonomic unit; PCoA, principal coordinates analysis; Tab1, TGF-β activated kinase 1 mitogen-activated protein kinase kinase kinase 7-binding protein 1; TC, total cholesterol; TEERs, transepithelial electrical resistances; TGs, triglycerides; TLR, toll-like receptor; Tram, toll or IL-1 receptor domain-containing adaptor inducing IFN-β-related adaptor molecule; TUDCA, tauroursodeoxycholic acid; UDCA...

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6−/− mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.

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