Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota-Bile Acid-Immunity Network.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Sequence of events leading to primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune disease, since liver injury is sustained by the presence of self-directed antimitochondrial antibodies targeting the bile duct cells. The prognosis may vary depending on an early diagnosis and response to therapy. However, nearly a third of patients can progress to liver cirrhosis, thus requiring a liver transplant. Traditional immunosuppressive therapies, commonly employed for other autoimmune diseases, have limited effects on PBC. In fact, dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury. In this minireview, after a background on the disease and possible predisposing factors, the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail. The rise and maintenance of the autoimmune process, as well as the response of the biliary epithelia during inflammatory injury, are key factors in the progression of the disease. The so-called "ductular reaction (DR)", intended as a reactive expansion of cells with biliary phenotype, is a process frequently observed in PBC and partially understood. However, recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis, cell senescence, and loss of biliary ducts. All these issues (onset of chronic inflammation, changes in secretive and proliferative biliary functions, DR, and its relationship with other pathological events) are discussed in this manuscript in an attempt to provide a snapshot, for clinicians and researchers, of the most relevant and sequential contributors to the progression of this human cholestatic disease. We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

Autoimmune liver diseases and SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry. Here we summarise the current knowledge about auto-immune liver diseases (AILDs) and SARS-CoV-2, focusing on: (1) The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs; (2) the role of SARS-CoV-2 in inducing liver damage and triggering AILDs; and (3) the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver. Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine. Although SARS-CoV-2 infection can lead to the development of several autoimmune diseases, few reports correlate it to the appearance of de novo manifestation of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or AIH/PBC overlap syndrome. Different case series of an AIH-like syndrome with a good prognosis after SARS-CoV-2 vaccination have been described. Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established, these reports suggest that this association could be more than coincidental.

The latest research trends in primary biliary cholangitis: a bibliometric analysis.

The bibliometric analysis uses the citation count of an article to measure its impact in the scientific community, but no study has been undertaken to determine the most influential papers in the field of primary biliary cholangitis (PBC). This study aimed to investigate the global research interest regarding PBC in dentistry using a bibliometric approach. We searched the Web of Science Core Collection database to find the top 100 most cited (T100) articles focusing on PBC. The information about each article including citations, authors, journals, countries, institutions, and keywords was recorded for bibliometric analysis. The T100 articles related to PBC were published from 1983 to 2019 and were originated from 26 countries. A total of 805 different authors were from 342 different institutions, and articles written by them were published in 35 journals. The five most frequently occurring keywords were "biochemical response," "ursodeoxycholic acid," "primary biliary cirrhosis," "antimitochondrial antibody," and "autoimmunity." The T100 articles were classified into different research focuses: pathogenesis (41%), treatment (20%), prognosis (12%), epidemiology (9%), diagnosis (8%), and others (10%). These 100 articles included 32 observational studies, 29 basic research articles, 15 reviews, eight meta-analyses, 12 clinical trials, and four clinical guidelines. The 100 top-cited articles are marked with the leading countries, institutions, journals, hotspots, and development trends in the PBC field that could provide the foundation for further investigations.

Practical management of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations. (AU)

Osteosarcopenia in autoimmune cholestatic liver diseases: Causes, management, and challenges.

Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.

[Guidelines on the diagnosis and management of primary biliary cholangitis (2021)].

In 2015, the Chinese Society of Hepatology and Chinese Society of Gastroenterology issued a consensus on the diagnosis and management of primary biliary cholangitis (PBC). In the past years, more clinical studies have been reported in the field of PBC. To provide guidance to the clinical diagnosis and management of patients with PBC, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulated the current guidelines which comprises 26 clinical recommendations.

Primary biliary cholangitis: advances in understanding and management.

Recent years have seen major advances in our understanding of primary biliary cholangitis, with the condition now renamed to reflect the majority of patients who do not have cirrhosis. Data from large multicentre studies have greatly increased our knowledge of the natural history of primary biliary cholangitis, making the identification of higher risk patients clearer and facilitating the development of new medications. Recent guidelines have emphasised the importance of risk stratification, targeted treatment of symptoms and early prioritisation for second line therapies. The review summarises recent major developments in our understanding of primary biliary cholangitis and its management.

Practical management of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations.

Guidelines on the diagnosis and management of primary biliary cholangitis (2021) / 中华肝脏病杂志

In 2015, the Chinese Society of Hepatology and Chinese Society of Gastroenterology issued a consensus on the diagnosis and management of primary biliary cholangitis (PBC). In the past years, more clinical studies have been reported in the field of PBC. To provide guidance to the clinical diagnosis and management of patients with PBC, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulated the current guidelines which comprises 26 clinical recommendations.

[Guidelines on the diagnosis and management of primary biliary cholangitis (2021)].

In 2015, the Chinese Society of Hepatology and Chinese Society of Gastroenterology issued the consensus on the diagnosis and management of primary biliary cholangitis (PBC). In the past years, more clinical studies have been reported in the field of PBC. To provide guidance to the clinical diagnosis and management of patients with PBC, the Chinese Society of Hepatology invited a panel of experts assessed the new clinical evidence and formulated the current guidelines which comprises 26 clincal recommendations.

Ileal mucosa-associated microbiota overgrowth associated with pathogenesis of primary biliary cholangitis.

The small intestinal mucosa-associated microbiota (MAM) can potentially impact the etiology of primary biliary cholangitis (PBC). Herein, we investigate the MAM profile to determine its association with liver pathology in patients with PBC. Thirty-four patients with PBC and 21 healthy controls who underwent colonoscopy at our hospital were enrolled in our study. We performed 16S ribosomal RNA gene sequencing of MAM samples obtained from the mucosa of the terminal ileum and examined the relationship between the abundance of ileal MAM and chronic nonsuppurative destructive cholangitis using liver specimens from patients with PBC. There was a significant reduction in microbial diversity within individuals with PBC (P = 0.039). Dysbiosis of ileal MAM was observed in patients with PBC, with a characteristic overgrowth of Sphingomonadaceae and Pseudomonas. Multivariate analysis showed that the overgrowth of Sphingomonadaceae and Pseudomonas is an independent association factor for PBC (P = 0.0429, P = 0.026). Moreover, the abundance of Sphingomonadaceae was associated with chronic nonsuppurative destructive cholangitis in PBC (P = 0.00981). The overgrowth of Sphingomonadaceae and Pseudomonas in ileal MAM was found in patients with PBC. Sphingomonadaceae may be associated with the pathological development of PBC.

Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation.

BACKGROUND: Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. METHODS: Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. RESULTS: Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. CONCLUSIONS: Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.

The impact of undiagnosed primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic autoimmune disease characterized by symptoms with a major impact on the quality of life. The aim of this study was to identify patients with undiagnosed PBC who are not under hepatology follow-up and to assess the clinical impact of lack of adequate treatment and surveillance. METHODS: Adult patients with a positive antimitochondrial antibodies (AMA) titer were identified from local biochemistry records. Patients with probable PBC who were not known by the hepatology services were invited to accurately stage their disease and optimize medical management. RESULTS: A total of 214 AMA-positive patients were identified, 148 of whom had diagnostic criteria for PBC. Twenty-three patients were not known by the hepatology services, most of them followed by specialties other than gastroenterology. These patients had significantly higher liver stiffness compared to those followed by the hepatology services (14.3 kPa vs. 6.2 kPa; P = 0.009). A large percentage of untreated individuals reported fatigue (72.7%) and pruritus (27.3%). CONCLUSIONS: A substantial number of patients with PBC are not known to have hepatology services with a significant long-term impact from a lack of follow-up and therapy. Strategies must be established to identify these patients and reduce the disease's progressive nature.

A consensus integrated care pathway for patients with primary biliary cholangitis: a guideline-based approach to clinical care of patients.

INTRODUCTION: Primary biliary cholangitis (PBC) is an infrequent, immune-mediated cholestatic liver disease, which can lead to liver fibrosis, cirrhosis and complications of end-stage liver disease. The established goals of treatment of PBC are prevention of end-stage liver disease and amelioration of associated symptoms. The European Association for the Study of the Liver (EASL) management guidelines provide extensive recommendations on the diagnosis and management of PBC. AREAS COVERED: This article describes the development by expert consensus of a 'PBC Integrated Patient Care Pathway' to simplify and standardize the management of PBC for clinicians based on current practice. EXPERT OPINION: Guideline adoption is potentially poor in practice since most patients with PBC in the community are seen by general gastroenterologists or hepatologists without a special interest in autoimmune liver disease. The PBC Integrated Patient Care Pathway is a best practice tool for clinicians designed to complement the EASL Clinical Practice Guidelines for the diagnosis and management of PBC patients. It gives clinicians a practical decision tree of the key steps in PBC management, thereby providing a simplified framework and an opportunity for more uniform practice that supports the safe and timely adoption of varied models of care provision to patients with PBC.