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

Evaluation of the long-term results of vascular anastomosis using polyurethane adhesive and shape-memory stent in the rat carotid artery model

INTRODUCTION: In free flaps, 5%-10% of complications are related to failure of sutured vascular anastomoses. Adhesive-based microvascular anastomoses are potential alternatives but are associated with failure rates of 70% in research studies. VIVO is a new adhesive with slow biodegradation within 6 months that has shown a 100% patency rate in research studies over 2 h observation time but long-term patency has not been evaluated. The authors hypothesize that VIVO will enable a reliable microvascular procedure comparable to sutured anastomoses over a 28-day period. MATERIALS AND METHODS: The right common carotid artery of 60 male Sprague Dawley rats, ~450 g, were used for microvascular end-to-end anastomosis. VIVO was applied with reduced sutures with a temporary catheter in one group and in the other with a custom-shaped memory stent. Anastomoses with eight interrupted sutures served as control. All groups were n = 20. Anastomosis time and bleeding were recorded for each procedure. Doppler flowmetry was performed 20 min, 1, 10, and 28 days postoperatively. Postmortem toluidine staining was used for semi-quantitative analysis of stenosis, thrombosis, necrosis, and aneurysm formation by histologic evaluation. RESULTS: No occlusion was detected 20 min and 1 day postoperative, and after 28 days of observation in all anastomoses. The anastomosis time of the VIVO with catheter group was about 32% significantly faster than the VIVO with stent group. In the VIVO group with stent, the bleeding time was ~80% shorter than in the control group with 2.1 ± 0.3 and VIVO with catheter 2.0 ± 0.5 (p ≤ .001 each). Minor and nonsignificant stent-associated thrombus formation and stent-typical intraluminal stenosis were detected exclusively in the VIVO with stent group. CONCLUSION: Within the limitations of a rat study, the use of VIVO in anastomosis showed promising results. VIVO with catheter was found to be advantageous

Intestinal Microbiota Protects against MCD Diet-Induced Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can ameliorate high-fat diet or western-diet induced experimental Non-alcoholic steatohepatitis (NASH). However, its functional implications in the methionine-choline dietary model, remain incompletely understood. Here, we investigated the physiological relevance of gut microbiota in methionine-choline deficient (MCD) diet induced NASH. Experimental liver disease was induced by 8 weeks of MCD feeding in wild-type (WT) mice, either with or without commensal microbiota depletion, by continuous broad-spectrum antibiotic (AB) treatment. MCD diet induced steatohepatitis was accompanied by a reduced gut microbiota diversity, indicating intestinal dysbiosis. MCD treatment prompted macroscopic shortening of the intestine, as well as intestinal villi in histology. However, gut microbiota composition of MCD-treated mice, neither resembled human NASH, nor did it augment the intestinal barrier integrity or intestinal inflammation. In the MCD model, AB treatment resulted in increased steatohepatitis activity, compared to microbiota proficient control mice. This phenotype was driven by pronounced neutrophil infiltration, while AB treatment only slightly increased monocyte-derived macrophages (MoMF) abundance. Our data demonstrated the differential role of gut microbiota, during steatohepatitis development. In the context of MCD induced steatohepatitis, commensal microbiota was found to be hepatoprotective

Intestinal Microbiota Protects against MCD Diet-Induced Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can ameliorate high-fat diet or western-diet induced experimental Non-alcoholic steatohepatitis (NASH). However, its functional implications in the methionine-choline dietary model, remain incompletely understood. Here, we investigated the physiological relevance of gut microbiota in methionine-choline deficient (MCD) diet induced NASH. Experimental liver disease was induced by 8 weeks of MCD feeding in wild-type (WT) mice, either with or without commensal microbiota depletion, by continuous broad-spectrum antibiotic (AB) treatment. MCD diet induced steatohepatitis was accompanied by a reduced gut microbiota diversity, indicating intestinal dysbiosis. MCD treatment prompted macroscopic shortening of the intestine, as well as intestinal villi in histology. However, gut microbiota composition of MCD-treated mice, neither resembled human NASH, nor did it augment the intestinal barrier integrity or intestinal inflammation. In the MCD model, AB treatment resulted in increased steatohepatitis activity, compared to microbiota proficient control mice. This phenotype was driven by pronounced neutrophil infiltration, while AB treatment only slightly increased monocyte-derived macrophages (MoMF) abundance. Our data demonstrated the differential role of gut microbiota, during steatohepatitis development. In the context of MCD induced steatohepatitis, commensal microbiota was found to be hepatoprotective