Immune modulation of gut microbiota and its metabolites in chronic hepatitis B.

The gut microbiota is a diverse ecosystem consisting of 100 trillion microbiomes. The interaction between the host's gut and distal organs profoundly impacts various functions such as metabolism, immunity, neurology, and nutrition within the human body. The liver, as the primary immune organ, plays a crucial role in maintaining immune homeostasis by receiving a significant influx of gut-derived components and toxins. Perturbations in gut microbiota homeostasis have been linked to a range of liver diseases. The advancements in sequencing technologies, such as 16S rRNA and metagenomics, have opened up new avenues for comprehending the intricate physiological interplay between the liver and the intestine. Metabolites produced by the gut microbiota function as signaling molecules and substrates, influencing both pathological and physiological processes. Establishing a comprehensive host-bacterium-metabolism axis holds tremendous potential for investigating the mechanisms underlying liver diseases. In this review, we have provided a summary of the detrimental effects of the gut-liver axis in chronic liver diseases, primarily focusing on hepatitis B virus-related chronic liver diseases. Moreover, we have explored the potential mechanisms through which the gut microbiota and its derivatives interact with liver immunity, with implications for future clinical therapies.

Diagnostic role of transient elastography in patients with autoimmune liver diseases: A systematic review and meta-analysis.

BACKGROUND: Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy. However, previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease. The diagnostic value of transient elastography for autoimmune liver diseases (AILDs) is worth studying. AIM: To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD. METHODS: The PubMed, Cochrane Library and EMBASE databases were searched. Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs [autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)] were included. The summary area under the receiver operating characteristic curve (AUROC), diagnostic odds ratio, sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis. RESULTS: A total of 60 articles were included in this study, and the number of patients with AIH, PBC and PSC was 1594, 3126 and 501, respectively. The summary AUROC of transient elastography in the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in patients with AIH were 0.84, 0.88 and 0.90, respectively, while those in patients with PBC were 0.93, 0.93 and 0.91, respectively. The AUROC of cirrhosis for patients with PSC was 0.95. However, other noninvasive indices (aspartate aminotransferase to platelet ratio index, aspartate aminotransferase/alanine aminotransferase ratio, fibrosis-4 index) had corresponding AUROCs less than 0.80. CONCLUSION: Transient elastography exerts better diagnostic accuracy in AILD patients, especially in PBC patients. The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.

Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response.

Gut dysbiosis has been reported in chronic hepatitis B (CHB) infection, however its role in CHB progression and antiviral treatment remains to be clarified. Herein, the present study aimed to characterize gut microbiota (GM) in patients with chronic hepatitis B virus infection-associated liver diseases (HBV-CLD) by combining microbiome with metabolome analyses and to evaluate their effects on peripheral immunity. Fecal samples from HBV-CLD patients (n = 64) and healthy controls (n = 17) were collected for 16s rRNA sequencing. Fecal metabolomics was measured with untargeted liquid chromatography-mass spectrometry in subgroups of 58 subjects. Lineage changes of peripheral blood mononuclear cells (PBMCs) were determined upon exposure to bacterial extracts (BE) from HBV-CLD patients. Integrated analyses of microbiome with metabolome revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients, and disease progression and antiviral treatment were found to be two main contributing factors for the shift. Concordant decreases in Turicibacter with 4-hydroxyretinoic acid were detected to be inversely correlated with serum AST levels through host-microbiota-metabolite interaction analysis in cirrhotic patients. Moreover, depletion of E.hallii group with elevated choline was restored in patients with 5-year antiviral treatment. PBMC exposure to BE from non-cirrhotic patients enhanced expansion of T helper 17 cells; however, BE from cirrhotics attenuated T helper 1 cell count. CHB progression and antiviral treatment are two main factors contributing to the compositional shift in microbiome and metabolome of HBV-CLD patients. Peripheral immunity might be an intermediate link in gut microbe-host interplay underlying CHB pathogenesis.

Integrated analyses of microbiome with metabolomics revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients. Disease progression and entecavir treatment were found to be two main contributing factors for the shift. Novel host-microbiota-metabolite interplay was investigated (red, positive correlation; blue, negative correlation). Ex vivo results showed that exposure of PBMCs to BE from non-cirrhotic patients promoted expansion of T helper 17 cells whilst BE from cirrhotic patients attenuated T helper 1 cell count, suggesting peripheral immunity may be one of mechanisms by which overall bacterial products exert profibrotic effects and have an impact on prognosis of HBV-CLD patients. Our research confers new insights into the role of gut dysbiosis and metabolomics in the pathogenesis of HBV-CLD, and underscores that disrupted peripheral immunity homeostasis during the microbe-host interplay may contribute to fibrosis progression in HBV-CLD. CHB, chronic hepatitis B (treatment-naive); Crrh, cirrhosis; ETV, entecavir; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; MCFAs, medium chain fatty acids; NC, non-cirrhosis; Th1, T helper 1; Th17, T helper 17.Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ANOISM, analysis of similarities; AST, aspartate aminotransferase; BE, bacterial extracts; BMI, body mass index; CC, compensated cirrhosis; CHB, chronic hepatitis B; DB, direct bilirubin; DC, decompensated cirrhosis; DCA, deoxycholic acid; ETV, entecavir; FDR, false discovery rate; GGT, γ-glutamyl transpeptidase; GM, gut microbiota; HBV, hepatitis B virus; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; HCC, hepatocellular carcinoma; LC-MS, liquid chromatography-mass spectrometry; LRE, liver-related events; LS, liver stiffness; ImP, imidazole propionate; IQR, interquartile range; MCFAs, medium chain fatty acids; OCT, organic cation transporter; OPLS-DA, orthogonal partial least square discriminant analysis; PBMCs, peripheral blood mononuclear cells; PERMANOVA, permutational multivariate analysis of variance; PLS-DA, partial least square discriminant analysis; PCA, principal component analysis; PcoA, principal coordinates analysis; PT, prolonged prothrombin time; SDs, standard deviations; TB, total bilirubin; Tregs, regulatory T cells; Th1, T helper 1; Th17, T helper 17.

Phosphoinositide 3­kinase/protein kinase B regulates inflammation severity via signaling of Toll­like receptor 4 in severe acute pancreatitis.

Phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) has been indicated to serve an important role in the pathogenesis of inflammatory diseases. It was previously demonstrated that the PI3K/Akt inhibitor wortmannin alleviated the severity of inflammation and improved the survival rate in rats with induced severe acute pancreatitis (SAP), which indicates that PI3K/Akt may serve a role in the pathogenesis of acute pancreatitis. To date, the mechanism by which PI3K/Akt regulates inflammation has not been elucidated. In the present study, it was hypothesized that PI3K/Akt may be invovled in SAP inflammation via regulation of the Toll­like receptor 4 (TLR4) signaling pathway. Rats with SAP were treated with the PI3K/Akt agonist insulin­like growth factor (IGF)­1, which alleviated the severity of inflammation in a dose­dependent manner. Furthermore, to better understand the role of PI3K/Akt in inflammation, RAW264.7 murine macrophages were stimulated with IGF­1 and wortmannin alone or together before the induction of inflammation by treatment with lipopolysaccharide (LPS). The results indicated that LPS stimulated overexpression of TLR4, myeloid differentiation primary response gene 88 (MyD88), PI3K, Akt, p38MAPK and NF­κBp65 mRNA, and increased the levels of tumor necrosis factor (TNF)­α and interleukin (IL)­6 in RAW264.7 cells compared with the control group. The levels of all detected factors were increased by stimulation with IGF­1, whereas these levels were decreased following treatment with wortmannin alone, and the effect of IGF­1 was abolished by wortmannin in RAW264.7 cells. In vivo studies indicated that IGF­1 produced the same anti­inflammatory effect as wortmannin and that expression of TLR4, p38MAPK and NF­κBp65 decreased following treatment with IGF­1. These findings indicate that PI3K/Akt may take part in the progression of SAP by regulating the TLR4 signaling pathway and that IGF­1 can inhibit inflammation in SAP rats.

The role of Card9 overexpression in peripheral blood mononuclear cells from patients with aseptic acute pancreatitis.

Activated mononuclear cells are an early event in the course of severe acute pancreatitis (SAP). To date, the molecular mechanism triggering peripheral blood mononuclear cells (PBMCs) is poorly understood. The aim of this paper was to determine the potential role of Card9 in SAP. We collected data from 72 subjects between January 2013 and June 2014. Subsequently, PBMCs were isolated on day 1, 3 and 5 of pancreatitis. Immunofluorescence staining, quantitative real-time PCR, Western blotting, immunoprecipitation and ELISA were used to determine the role of Card9 in SAP. Microbial culture showed that SAP patients at the early period did not develop any bacteria and fungi infection. Card9 expression in SAP patients was higher than that in mild acute pancreatitis and volunteer healthy controls, up to the peak on day 1. The monocyte-derived cytokines interleukin (IL)-17, IL-1ß, IL-6 and tumour necrosis factor-α mediated by the induction of Card9 markedly increased in SAP patients compared with the control group. Furthermore, the inducible formation of Card9-Bcl10 complex was found in PBMCs, which may be involved in nuclear factor kappa B (NF-κB) and p38 activation in SAP. Receiver operating characteristic curve indicated that Card9 levels had a high sensitivity of 87.5% and specificity of 67.7%, showing the close correlation with SAP patients. Card9 overexpression was firstly found in aseptic SAP, which may be played an important role in NF-κB and p38 activation in PBMCs. It also provided the new insights into therapeutic interventions by targeting monocytes activation in SAP patients.