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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Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in-depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A-stimulated genes (CREG), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of CREG in hepatic I/R remains largely unknown. A genetic engineering technique was employed to explore the function of CREG in hepatic I/R injury. Hepatocyte-specific Creg knockout (Creg ) and transgenic (HTG) mice were generated and subjected to hepatic I/R injury, as were the controls. CREG in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from Creg that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo. Moreover, further molecular experiments showed that CREG suppressed MAPK signaling by inhibiting TAK1 phosphorylation. Inhibiting TAK1 by 5Z-7-ox or mutating the TAK1-binding domain of CREG abolished the protective role of CREG, indicating that CREG binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion These data demonstrated that CREG prevents hepatocytes from liver I/R injury. The CREG-TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury. This article is protected by copyright. All rights reserved.

Proton pump inhibitor or long-term antibiotics intake, which have been linked to intestinal dysbiosis, are associated with increased risk of acute liver failure in the 500,000 participants of the UK BioBank population-based cohort. In mice, APAP intoxication prompts intestinal dysbiosis, barrier impairment, and bacterial translocation. Dysbiotic microbiota of Nlrp6-/mice induces a Ly6C hi phenotype of hepatic monocyte-derived macrophages and amplifies acute liver injury, a phenotype that is transferable to WT mice by fecal microbiota transfer. BACKGROUND & AIMS: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. METHODS: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK Bio-Bank population-based cohort. For functional studies, male Nlrp6-/mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. RESULTS: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/mice displayed exacerbated APAP-and LPS

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC.

Transforming growth factor beta (TGFβ) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGFβ signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGFβ receptor II-deficient (Tgfbr2 ΔHEP ) and Tgfbr2 flox/flox mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL-316,243 (a β3-adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 flox/flox mice, Tgfbr2 ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2 ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and whiteto-beige fat conversion. A further mechanistic study revealed that exosomal let-7b-5p derived from hepatocytes was robustly elevated after stimulation with palmitic acid and TGFβ. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2 ΔHEP mice. Moreover, 3T3-L1 cells internalized hepatocyte-derived exosomes. An in vitro experiment demonstrated that let-7b-5p overexpression increased hepatocyte fatty acid transport and inhibited adipocyte-like cell thermogenesis, whereas let-7b-5p inhibitor exerted the opposite effects. Conclusion: Hepatocyte TGFβ-let-7b-5p signaling promotes HFD-induced steatosis and obesity by reducing mitochondrial oxidative phosphorylation and suppressing white-to-beige fat conversion. This effect of hepatocyte TGFβ signaling in metabolism is partially associated with exosomal let-7b-5p. (Hepatology Communications 2022;6:1301-1321).N onalcoholic fatty liver disease (NAFLD) and obesity are associated with the prevalence and incidence of type 2 diabetes, cardiovascular disease, carcinogenesis, and other metabolic diseases. (1,2) Due to a rapid increase in prevalence, obesity, and NAFLD have become leading public health problems worldwide. (3,4) Thus, it is necessary to identify therapeutic targets for this critical problem.The liver and adipose tissue are crucial for the whole-body homeostasis of energy metabolism. Specifically, the liver is not only critical for controlling glucose, fatty acid, and amino acid metabolism but also acts as a hub of communication with extrahepatic tissues, including cardiac and adipose tissue. (5) In addition, the pathogenic cross-talk between the liver and the adipose tissue is thought to be the key factor that links NAFLD and its related complications. (6) Recently, a major breakthrough revealed that liver could regulate adipose tissue inflammation, lipid storage, and white adipose tissue (WAT) browning by

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