Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment

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. Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.Peer reviewe

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β 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 TGF-β receptor II-deficient (Tgfbr2ΔHEP ) and Tgfbr2flox/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, Tgfbr2ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and white-to-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 TGF-β. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2ΔHEP 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 TGF-β-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 TGF-β signaling in metabolism is partially associated with exosomal let-7b-5p

Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis

Abstract 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

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.

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 BioBank 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

Alcohol-related liver disease is rarely detected at early stages compared with liver diseases of other etiologies worldwide

© 2019 by the AGA InstituteBackground & aims: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies. Methods: We performed a cross-sectional study of 3453 consecutive patients with either early or advanced liver disease (1699 patients with early and 1754 with advanced liver disease) seen at 17 tertiary care liver or gastrointestinal units worldwide, from August 2015 through March 2017. We collected anthropometric, etiology, and clinical information, as well as and model for end-stage liver disease scores. We used unconditional logistic regression to estimate the odds ratios for evaluation at late stages of the disease progression. Results: Of the patients analyzed, 81% had 1 etiology of liver disease and 17% had 2 etiologies of liver disease. Of patients seen at early stages for a single etiology, 31% had HCV infection, 21% had hepatitis B virus infection, and 17% had nonalcoholic fatty liver disease, whereas only 3.8% had ALD. In contrast, 29% of patients seen for advanced disease had ALD. Patients with ALD were more likely to be seen at specialized centers, with advanced-stage disease, compared with patients with HCV-associated liver disease (odds ratio, 14.1; 95% CI, 10.5-18.9; P < .001). Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. These patients had significantly more visits to health care providers, with more advanced disease, compared with patients without excess alcohol use. The mean model for end-stage liver disease score for patients with advanced ALD (score, 16) was higher than for patients with advanced liver disease not associated with excess alcohol use (score, 13) (P < .01). Conclusions: In a cross-sectional analysis of patients with liver disease worldwide, we found that patients with ALD are seen with more advanced-stage disease than patients with HCV-associated liver disease. Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. Early detection and referral programs are needed for patients with ALD worldwide.This study was funded by the National Institute of Alcohol Abuse and Alcoholism grants U01AA021908 and U01AA020821, a scholarship grant from the Spanish Association for the Study of the Liver (M.V.-C.), and a grants NSFC 81570530 and 81370550 from the National Natural Science Foundation of China (L.Y.).info:eu-repo/semantics/publishedVersio