This study presents a comprehensive landscape of gut microbiota in PBC. Dysbiosis was found in the gut microbiome in PBC and partially relieved by UDCA. Our study suggests that gut microbiota is a potential therapeutic target and diagnostic biomarker for PBC.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

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Mucosal-associated invariant T (MAIT) cells, a novel population of innate-like lymphocytes, have been involved in various inflammatory and autoimmune diseases. However, their role in the development of nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated the alterations of phenotype and immunological function of MAIT cells in NAFLD. Analysis of PBMCs in 60 patients with NAFLD and 48 healthy controls (HC) revealed that circulating MAIT cell frequency decreased in NAFLD, especially in the patients with higher serum levels of γ-glutamyl transferase or total triglyceride. Functional alterations of circulating MAIT cells were also detected in NAFLD patients, such as the increased production of IL-4 whereas the decreased production of IFN-γ and TNF-α. Furthermore, elevated expression of CXCR6 was observed in circulating MAIT cells of patients. Meanwhile, we found an increased number of MAIT cells in the livers of NAFLD, and the number was even greater in patients with higher NAFLD activity score. Moreover, activated MAIT cells induced monocytes/macrophages differentiation into M2 phenotype in vitro. Additionally, MAIT cells were enriched and displayed Th2 type cytokines profile in livers of wild type mice fed with methionine and choline deficient diet (MCD). Notably, mice deficient of MAIT cells exhibited more severe hepatic steatosis and inflammation upon MCD, accompanied with more CD11c+ proinflammatory macrophages (M1) and less CD206+ anti-inflammatory macrophages (M2) in livers. Our results indicate that MAIT cells protect against inflammation in NAFLD through producing regulatory cytokines and inducing anti-inflammatory macrophage polarization, which may provide novel therapeutic strategies for NAFLD.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

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