Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress.

Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown.

Gut microbiome pattern impacts treatment response in primary biliary cholangitis.

Background: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC.

Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

Background & Aims: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC.

Methods: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts.

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis.

Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis.

Background: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.

Autoimmune Hepatitis: Pathophysiology.

Genome-wide association analyses suggest that HLA genes including HLA-DRB*0301, HLA-DRB*0401, and HLA-B*3501 as well as non-HLA genes including CD28/CTLA4/ICOS and SYNPR increased AIH susceptibility. The destruction of hepatocytes is the result of the imbalance between proinflammatory cells and immunosuppressive cells, especially the imbalance between Tregs and Th17 cells. The microbiome in patients with AIH is decreased in diversity with a specific decline in Bifidobacterium and enrichment in Veillonella and Faecalibacterium.

MGAT5/TMEM163 variant is associated with prognosis in ursodeoxycholic acid-treated patients with primary biliary cholangitis.

Background: Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.

A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

Background & Aims: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown.

Methods: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry.

Itaconate inhibits CD103 + T RM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.

Background And Aims: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM .

A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.

P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases.

Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases.

The immunological characteristics of TSPAN1 expressing B cells in autoimmune hepatitis.

Background And Aims: Tetraspanin proteins are closely related to the functional changes of B cells, including antigen presentation, production of cytokines, and transduction. We aim to explore the potential role of Tetraspanin 1 (TSPAN1) in the biological activities of B cells in AIH.

Methods And Results: Herein, this study found that numbers of cells expressing TSPAN1 were significantly increased in AIH patients compared to PBC, chronic hepatitis B, and healthy control (P < 0.

Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis.

Intestinal homeostasis in autoimmune liver diseases.

Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis.

Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function.

Tissue-resident memory (T) T cells are a unique subset of memory T cells that are critical for the first line of defense against pathogens or antigens in peripheral non-lymphoid tissues such as liver, gut, and skin. Generally, T cells are well adapted to the local environment in a tissue-specific manner and typically do not circulate but persist in tissues, distinguishing them from other memory T cell lineages. There is strong evidence that liver T cells provide a robust adaptive immune response to potential threats.

Intrahepatic activated leukocyte cell adhesion molecule induces CD6CD4 T cell infiltration in autoimmune hepatitis.

Background And Objectives: Autoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development.

NUDT1 promotes the accumulation and longevity of CD103 T cells in primary biliary cholangitis.

Background & Aims: Pyruvate dehydrogenase (PDC)-E2 specific CD8 T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8 T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8 T-cell subpopulations and investigate their immunobiology in PBC.

Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

Background And Aims: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease.