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Background and aims: Treatment of non‐alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH‐associated fibrosis in a mouse NASH model and human specimens. Methods: Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD‐HF/G) for 16 weeks; HFCD‐HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. Results: Along with NASH progression, fibrotic deposition was documented in HFCD‐HF/G‐fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase‐A (SDH‐A) in these mice; whereas, GPR‐91 receptor expression was much enhanced in histology compared to control mice, and co‐localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid‐overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up‐regulation of GPR‐91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR‐91 receptor expression abolished succinate stimulatory role in GPR‐91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR‐91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. Conclusion: Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR‐91 receptor signalling in NASH progression, and the cross‐talk between hepatocytes and HSC through GPR‐91 signalling is most likely to be the molecular basis of fibrogenesis in NASH. [ABSTRACT FROM AUTHOR]

Objective: Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. Methods: This multicenter, open‐label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp‐L) or no therapy as control (Gp‐NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose‐responders and non‐responders. Results: A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp‐NL group and 67 patients in the Gp‐L group. At day 60, the MHE reversal rate in Gp‐L (64.18%) was significantly higher than that in Gp‐NL (22.58%) (P =.0002) with a relative risk of 0.46 (95% confidence interval 0.32‐0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp‐L (4.62 ± 6.16) than in Gp‐NL (1.50 ± 5.34) (P =.0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non‐responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. Conclusions: Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR‐TRC‐12002342). [ABSTRACT FROM AUTHOR]

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Succinate-GPR-91 Receptor Signaling Is Responsible for Nonalcoholic Steatohepatitis-Associated Fibrosis: Effects of DHA Supplementation by Jian Wu, Ying Wang, Li Xie et al., https://doi.org/10.1111/liv.14370. GLO:Q18/01apr20:liv14442-toc-0001.jpg PHOTO (COLOR): . gl. [Extracted from the article]