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Targeting the gut microbiota is an emerging strategy to treat nonalcoholic fatty liver disease (NAFLD). Nonetheless, the causal relationship between specific gut microbiota and NAFLD remains unclear. We first obtained genome-wide association study statistics on gut microbiota and NAFLD from publicly available databases. We then performed the Mendelian randomization (MR) analysis to determine the potential causal relationship between the gut microbiota and NAFLD by 5 different methods, and conducted a series of sensitivity analyses to validate the robustness of the MR analysis results. Furthermore, we investigated the direction of causality by bidirectional MR analysis. For 211 gut microbiota, 2 MR methods confirmed that phylum Tenericutes, class Deltaproteobacteria and class Mollicutes were significantly associated with the risk of NAFLD. Heterogeneity (P > .05) and pleiotropy (P > .05) analyses validated the robustness of the MR results. There was no causal effect of NAFLD on these bacterial taxa in the reverse MR analysis. We identified specific gut microbiota with causal effects on NAFLD through gene prediction, which may provide useful guidance for targeting the gut microbiota to intervene and treat NAFLD.

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BACKGROUND: Nucleotide analogs treatment can reverse liver fibrosis in chronic hepatitis B (CHB). However, it has limited effect on fibrosis resolution in patients with CHB, particularly in preventing progression to hepatocellular carcinoma (HCC). Ruangan granule (RG), a Chinese herbal formula, has proven to produce a therapeutic effect against liver fibrosis in animal experiment. Thus, we aimed to evaluate the effect of our Chinese herbal formula (RG) combined with entecavir (ETV) to reverse advanced liver fibrosis/early cirrhosis from CHB. METHODS: A total of 240 CHB patients with histologically confirmed advanced liver fibrosis/early cirrhosis from 12 centers were randomly and blindly allocated to consume either ETV (0.5 mg/day) plus RG (2 times/day) or control (ETV) for 48 weeks (wk) treatment. Changes in histopathology, serology and imageology were observed. Liver fibrosis reversion, defined as a reduction in the Knodell HAI score by ≥ 2 points and Ishak score by ≥ 1 grade, was assessed. RESULTS: The rate of fibrosis regression and inflammation remission after 48 wk of treatment in histopathology was significantly higher in the ETV + RG group (38.73% vs. 23.94%, P = 0.031). The ultrasonic semiquantitative scores decreased by ≥ 2 points and were 41 (28.87%) and 15 (21.13%) in the ETV+RG and ETV groups, respectively (P = 0.026). The ETV+RG group had a significantly lower Fibrosis-4 score (FIB-4) index (P = 0.028). There was a significant difference between the ETV+RG and ETV groups in the liver function normalization rate (P < 0.01). Moreover, ETV plus RG combination treatment further reduced the risk of HCC in median 55-month follow-up (P < 0.01). CONCLUSIONS: This study illustrates that the Chinese herbal formula RG with ETV can improve advanced liver fibrosis/early cirrhosis regression in patients with CHB, further reducing the risk of HCC.

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BACKGROUND: Noninvasive diagnostic technologies that can dynamically monitor changes in liver inflammation are highly important for the management of chronic hepatitis B (CHB) patients and thus warrant further exploration. This study assessed the diagnostic efficacy of FibroScan for liver inflammation in CHB patients. METHODS: A total of 1185 patients were selected, and ultrasound-guided liver biopsy was performed within 1 month after the FibroScan test. The liver stiffness measurement (LSM), the reliability criteria (IQR/M) of LSM, the quality of liver biopsy (complete portal area, PA), and the liver inflammation grades were the main observation items of this study. With liver biopsy as the control, the diagnostic efficacy of FibroScan for liver inflammation in CHB patients was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The grade of liver inflammation was positively correlated with the stage of fibrosis (rho = 0.829, P < 0.001). Different grades of inflammation will have significant rise in LSM values within the same fibrosis stage, and LSM values were positively correlated with liver inflammation grade and fibrosis stage, and the rho is 0.579 and 0.593 respectively (P < 0.001). Significant differences in the LSM of FibroScan were observed among different grades of liver inflammation (P < 0.0001). Liver biopsy (PA > 10) served as the control, and the cutoff point and the area under ROC curves (AUCs) of the LSMs for different inflammation grades were as follows: G2, 8.6 kPa, 0.775; G3 9.8 kPa, 0.818; and G4, 11.0 kPa; 0.832. With LSM cutoff values of 8.6 kPa, 9.8 kPa and 11.0 kPa, FibroScan showed certain diagnostic value for CHB patients with G2, G3 and G4 liver inflammation, especially those with G4 inflammation. CONCLUSIONS: The grade of liver inflammation was positively correlated with the stage of fibrosis, different grades of inflammation will have significant rise in LSM values within the same fibrosis stage. In addition to liver fibrosis, FibroScan could evaluate liver inflammation in CHB patients in a noninvasive manner.

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BACKGROUND: No guideline recommends antiviral therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients with persistently normal alanine aminotransferase levels and a high hepatitis B virus (HBV) DNA viral load. AIM: To evaluate the feasibility and safety of a Chinese herbal formula as a therapeutic option for chronic HBV infection. METHODS: In total, 395 patients (30-65 years old) with confirmed HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase were randomized to receive either Chinese herbal formula or placebo for 96 wk. Endpoints to evaluate therapeutic efficacy included: (1) HBV DNA levels decreased to less than 4 log10 IU/mL at weeks 48 and 96; and (2) HBeAg clearance and seroconversion rates at weeks 48 and 96. RESULTS: HBV DNA levels ≤ 4 log10 IU/mL were 10.05% at week 48 and 18.59% at week 96 in the treatment group. The HBeAg clearance and conversion rates were 8.54% and 8.04% at week 48 and 16.08% and 14.57% at week 96, respectively. However, HBV DNA levels ≤ 4 log10 IU/mL were 2.55% and 2.55% at weeks 48 and 96, respectively, and the HBeAg clearance rates were 3.06% and 5.61% at weeks 48 and 96, respectively, in the control group. The quantitative hepatitis B surface antigen and HBeAg levels at baseline and changes during the treatment period as well as the alanine aminotransferase elevation at weeks 12 and 24 were strong predictors of HBeAg clearance. CONCLUSION: High rates of HBV DNA reduction, HBeAg clearance and seroconversion could be achieved with Chinese herbal formula treatments, and the treatments were relatively safe for HBeAg-positive chronic hepatitis B-infected patients with persistently normal alanine aminotransferase. The ability of the compound to modulate host immune function probably contributed to this effect.

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A20 is a powerful suppressor for inflammatory response. This study aims to determine A20 level in patients with chronic hepatitis B (CHB), and analyze its association with the disease severity. The role of A20 in inflammatory response was further investigated in vivo and in vitro. Our results showed significantly higher A20 in both serum and liver tissues in CHB patients than in health controls. Serum A20 level was positively correlated with ALT, AST and TNF-α. To induce hepatitis with inflammation and liver injury, mice were injected intraperitoneally with D-galactosamine (D-GalN), resulting in rapid increase of A20 in serum and liver tissues. Consistently, HepG2 and Huh-7 cells exposed to Lipopolysaccharide (LPS) or D-GalN were promoted to express A20. Moreover, overexpression or knockdown of A20 inhibited or increased TNF-α secretion separately. A20 significantly reduced pro-inflammatory cytokines expression and down-regulated phospho-IκBα and phospho-p65 in both cells. In conclusion, elevated A20 expression is involved in the severity of CHB, suggesting A20 to be a possible serological biomarker for the disease prognosis. Additionally, the inflammatory response is attenuated by A20 through inhibiting NF-κB activity, which partially contributes to the hepato-protective function of this molecule. Thus, up-regulating A20 might be a potential strategy for preventing the progress of CHB.

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Objective. To investigate the dendritic cells (DCs) maturity differences of HBeAg negative chronic hepatitis B (CHB) patients with different spleen deficiency (SD) syndromes and explore the role of syndrome differentiation in the therapeutic evaluation of Chinese medicine. Methods. 120 participants were recruited including three treatment groups in different SD syndrome categories as spleen deficiency with liver depression (SDLD), spleen deficiency with damp heat (SDDH), and spleen deficiency with kidney deficiency (SDKD) and one healthy control group; each group had 30 participants. Corresponding drugs were applied. The outcome measures included DC phenotype, liver function, IL-10, IL-12, and HBV-DNA levels. Results. The surface markers of mature DCs and cytokines levels were different in each group; the positive rate of CD80, CD1a, HLA-DR, and CD1a was the lowest in SDKD group. After 3-month intervention, the expression of CD80, CD86, CD1a, HLA-DR, and IL-12 significantly increased, while ALT, AST, and IL-10 significantly decreased (P < 0.05) in treatment groups. HBV-DNA level also significantly reduced in both SDKD and SDLD groups (P < 0.05). Conclusions. HBeAg negative patients had DCs dysmaturity, and there were differences between different SD syndromes. Chinese medicine intervention according to syndrome differentiation could advance the maturity and function of DCs and improve the therapeutic effect.

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UNLABELLED: Non-alcoholic steatohepatitis (NASH) is the most common cause of cryptogenic cirrhosis, is becoming more prevalent in China. However, there is as yet no clearly established therapy for reversing fatty liver. Our aim is to explore the effect of traditional Chinese herbs QuYuHuaTanTongLuo Decoction (QYHTTLD) on non-alcoholic steatohepatitis. Sixty-nine non-alcoholic steatohepatitis patients were randomly divided into two groups. One group of 35 patients were treated by QYHTTLD, another group of 34 patients were treated by Ursodeoxycholic acid (UDCA). The TNF-alpha, IL-8, MDA level, SOD activity and liver function, as well as B ultrasonic image were detected before and after being treated. The results showed: after 6 months treatment, MBI of the treatment group was obviously decreased (p<0.05). The levels of TC, TG and LDL-C were significantly decreased whereas the level of HDL-C increased (p<0.01, p<0.05, p<0.05, and p<0.05, respectively) in the treatment group, the levels of TC, TG, LDL-C and HDL-C had no significant difference in the control group (p>0.05). The levels of TNF-alpha, IL-8 and MDA were significantly decreased whereas SOD activity was significantly increased (p<0.01, p<0.05, p<0.01, and p<0.01, respectively) in the treatment group, the level of MDA was significantly decreased in the control group (p<0.05). B ultrasonic images were ameliorated in different degree (p<0.01 and p<0.01, respectively). Both QYHTTLD and UDCA had the effect in improving the scores of symptoms and signs of patients, however, the difference value of the scores in treatment group were significantly higher than that in control group after being treated for 6 months (p<0.05). CONCLUSION: QYHTTLD is effective for treating non-alcoholic steatohepatitis, and its effect seems to relate with the ways of QYHTTL down-regulating inflammation cytokine IL-8 level and relieving lipid peroxidation of liver.

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BACKGROUND: Seasonal variation in immunity has been found in healthy individuals and in association with some diseases. It is still unknown whether seasonal variation affects the clinical course of chronic hepatitis B. Our aim in this study was to explore the effect of seasonal variation on the clinical course of chronic hepatitis B. METHODS: The flare and remission time of chronic hepatitis B were observed in patients with hepatitis B virus (HBV) infection. All patients enrolled were followed up at least every 3 months for a mean follow-up time of 24.0 (range, 12-60) months. Seasonal decomposition was employed to analyze the relationship between seasonal variation and flares, remission, and hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients during follow-up. RESULTS: A total of 2238 patients were observed in our study. Flare and HBeAg seroconversion were seldom seen in 1076 patients (48.08%) with alanine aminotransferase (ALT) levels of less than 2.0 x upper limit of normal (ULN) during follow-up (mean, 36 months). The remaining 1162 patients (51.92%) (766, HBeAg positive; 387 anti-HBeAg positive; 9 negative for both HBeAg and anti-HBeAg) with ALT levels >or=2.0 x ULN were followed longitudinally for 12 months to judge flare, remission, and HBeAg seroconversion. Flare, remission, and HBeAg seroconversion in patients with ALT levels >or=2.0 x ULN showed clear seasonal patterns (P < 0.001), with high peaks during spring, summer, and summer, respectively. An autocorrelation correlogram showed that flares, remission, and HBeAg seroconversion occurred with distinct periodicity in winter, spring, summer, and autumn. CONCLUSIONS: Seasonal variation might affect the clinical course of chronic hepatitis B. The role of seasonal triggering factors should be further investigated.

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