Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis

Brandl, Katharina; Hartmann, Phillipp; Jih, Lily; Pizzo, Donald; Argemí, Josepmaria; Ventura-Cots, Meritxell; Coulter, Sally; Liddle, Christopher; Ling, Lei; Rossi, Stephen J.; DePaoli, Alex M.; Loomba, Rohit; Mehal, Wajahat Z.; Fouts, Derrick E.; Lucey, Michael R.; Bosques-Padilla, Francisco; Maury, Philippe; Louvet, Alexandre; García–Tsao, Guadalupe; Verna, Elizabeth C.; Abraldes, Juan G.; Brown, Robert S.; Vargas, Vı́ctor; Altamirano, José; Caballería, Juan; Shawcross, Debbie L.; Stärkel, Peter; Ho, Samuel B.; Bataller, Ramón; Schnabl, Bernd

doi:10.1016/j.jhep.2018.03.031

Cited by 167 publications

(179 citation statements)

References 30 publications

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“…Endotoxin is thought to be important in the pathogenesis of alcoholic hepatitis (AH) as well . Although this had been considered a disease that mostly reflects inflammatory damage to hepatocytes, evolving evidence suggests that cholestasis can also be an important component of AH, and, in fact, the presence of cholestasis may reflect more‐severe disease . The molecular basis for endotoxin‐induced cholestasis has been examined mostly in hepatocytes and has been attributed to decreased expression of several transporters that are important for canalicular bile formation .…”

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confidence: 99%

Effects of Endotoxin on Type 3 Inositol 1,4,5‐Trisphosphate Receptor in Human Cholangiocytes

et al. 2018

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Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis, often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor TLR4, which links to activation of NF-κB. Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5 and 1.0 kb deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. ChIP assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression, and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from patients with severe alcoholic hepatitis CONCLUSION: Stimulation of TLR4 via LPS activates NF-κB to downregulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or alcoholic hepatitis. This article is protected by copyright. All rights reserved.

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confidence: 99%

Effects of Endotoxin on Type 3 Inositol 1,4,5‐Trisphosphate Receptor in Human Cholangiocytes

et al. 2018

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“…Inclusion criteria for alcoholic hepatitis were (1) active alcohol abuse (>50 g/day for men and >40 g/day for women) in the last 3 months, (2) aspartate aminotransferase (AST) > alanine aminotransferase (ALT) and total bilirubin > 3 mg/dl in the past 3 months, and (3) liver biopsy and/or clinical picture consistent with alcoholic hepatitis. Exclusion criteria were (1) autoimmune liver disease (ANA > 1/320), (2) chronic viral hepatitis, (3) hepatocellular carcinoma, (4) complete portal vein thrombosis, (5) extrahepatic terminal disease, (6) pregnancy, and (7) lack of signed informed consent . In all patients, the clinical picture was consistent with alcoholic hepatitis and in patients who underwent liver biopsy, and the histology was in line with the diagnosis of alcoholic hepatitis.…”

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confidence: 99%

Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis

et al. 2019

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Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol‐related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal‐specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti–Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90‐day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11‐8.82; P = 0.031). Conclusion: Patients with alcohol‐associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

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“…Chronic alcohol consumption is associated with an impaired bile acids homeostasis . The level of plasma bile acids positively correlates with the histological severity of AH and is predictive of poor patient survival .…”

Section: Introductionmentioning

confidence: 99%