Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.

BACKGROUND & AIMS Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH

Induction de réponses T cytotoxiques dirigées contre des antigens exogènes par les cellules dendritiques plasmacytoïdes

La présentation croisée est un mécanisme crucial dans l immunité tumorale et virale car elle permet la présentation des Ag exogènes en association avec les molécules de CMH I induisant des réponses T CD8+. Notre étude a permis de montrer que les cellules dendritiques plasmacytoïdes (pDC) internalisent différentes formulations antigéniques in vitro et in vivo. Cependant, à l état initial, elles sont incapables d apprêter ces Ag dans la voir de CMH de classe I. Après activation par des TLR ligands synthétiques ou par des virus, les pDC acquièrent la capacité de réaliser la présentation croisée aboutissant à l induction d une réponse CTL fonctionnelle in vivo. De manière intéressante, les pDC dégradent très fortement les Ag à l état initial. Or, il a été montré qu une dégradation antigénique trop extensive détruit les épitopes, rendant la présentation inefficace. Après activation les pDC réduisent drastiquement leur potentiel de dégradation, expliquant leur capacité de présentation croisée. Une oxydase sensible à l inhibition par le DPI (diphenyleneiodonium), et que nous n avons pas encore identifié, est impliquée dans cette régulation.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Biomimetic superabsorbent hydrogel acts as a gut protective dynamic exoskeleton improving metabolic parameters and expanding A. muciniphila

The rising prevalence of obesity and metabolic disorders worldwide highlights the urgent need to find new long-term and clinically meaningful weight-loss therapies. Here, we evaluate the therapeutic potential and the mechanism of action of a biomimetic cellulose-based oral superabsorbent hydrogel (OSH). Treatment with OSH exerts effects on intestinal tissue and gut microbiota composition, functioning like a protective dynamic exoskeleton. It protects from gut barrier permeability disruption and induces rapid and consistent changes in the gut microbiota composition, specifically fostering Akkermansia muciniphila expansion. The mechanobiological, physical, and chemical structures of the gel are required for A. muciniphila growth. OSH treatment induces weight loss and reduces fat accumulation, in both preventative and therapeutic settings. OSH usage also prevents liver steatosis, immune infiltration, and fibrosis, limiting the progression of non-alcoholic fatty liver disease. Our work shows the potential of using OSH as a non-systemic mechano-biological approach to treat metabolic syndrome and its comorbidities