Biliary Cirrhosis Research Articles

S2711 Primary Biliary Cholangitis: A Peculiar Presentation

S2711 Primary Biliary Cholangitis: A Peculiar Presentation

S1988 Knowledge, Skills, and Confidence Gaps in Diagnosis of Primary Biliary Cholangitis Among Gastroenterologists and Advance Practice Providers Practicing in Gastroenterology or Hepatology

S1988 Knowledge, Skills, and Confidence Gaps in Diagnosis of Primary Biliary Cholangitis Among Gastroenterologists and Advance Practice Providers Practicing in Gastroenterology or Hepatology

S219 Evaluation of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis-4 Index Stabilization in the Phase 3 POISE Trial of Obeticholic Acid for the Treatment of Primary Biliary Cholangitis

S219 Evaluation of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis-4 Index Stabilization in the Phase 3 POISE Trial of Obeticholic Acid for the Treatment of Primary Biliary Cholangitis

S2593 Primary Biliary Cholangitis Unveiled by Positive Anti-centromere Antibodies

S2593 Primary Biliary Cholangitis Unveiled by Positive Anti-centromere Antibodies

S220 Stabilization of Enhanced Liver Fibrosis and Liver Stiffness Measures in the Open-Label Extension of the Phase 3 POISE Trial of Obeticholic Acid for the Treatment of Primary Biliary Cholangitis

S220 Stabilization of Enhanced Liver Fibrosis and Liver Stiffness Measures in the Open-Label Extension of the Phase 3 POISE Trial of Obeticholic Acid for the Treatment of Primary Biliary Cholangitis

Desmodium styracifolium (Osb.) Merr. Extracts alleviate cholestatic liver disease by FXR pathway

Ethnopharmacological relevanceCholestatic liver disease (CLD) is a disease characterized by cholestasis. Farnesoid X receptor (FXR) is a nuclear receptor that maintains homeostasis in bile acid metabolism. Studies have shown that gut microbiota interfered with the FXR pathway. Modulation of FXR to inhibit cholestasis has become a key measure in the treatment of CLD. In traditional folk medicine, Desmodium styracifolium (Osb.) Merr. was used as a primary treatment for gallstones, gonorrhea, jaundice, cholecystitis and other diseases. Modern pharmacological studies had also found that the herb has anti-calculus, anti-inflammatory, antioxidant, diuretic and liver damage. Therefore, we speculated that Desmodium styracifolium (Osb.) Merr. extracts (DME) could alleviate CLD through the FXR pathway and might be associated with the gut microbiota. However, studies of DME alleviating CLD through the FXR pathway have not been reported. Aim of studyTo study the effect and mechanism of DME in relieving CLD through in vivo and in vitro experiments. Materials and methodsFirst, mice were administrated with alpha-naphthyl isothiocyanate (ANIT) to establish a CLD model in vivo. Meanwhile, HepG2 cells were induced by lithocholic acid (LCA) to establish the CLD model in vitro. To evaluate the therapeutic effect of DME on CLD mice, hematoxylin-eosin (HE) staining, and biochemical indicators were performed. The prototype of the blood components in mice serum was detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). 16S rDNA sequencing was used to analyze the gut microbiota. Finally, the protein and mRNA expression of the FXR pathway in mice liver tissues or HepG2 cells were detected by Western blot, qRT-PCR, or immunofluorescence. ResultsPathological testing and biochemical indexes showed that DME significantly reduced serum ALT, AST, ALP, TBIL, DBIL, TBA and liver TBA levels, and attenuated liver tissue injury, necrosis and jaundice in CLD mice. In addition, MetagenomeSeq analysis of gut microbiota showed that DME significantly up-regulated the abundance of Parvibacter, down-regulated the abundance of Paenalcaligenes, and regulated bile acid homeostasis. In terms of mRNA expression, DME significantly upregulated the mRNA levels of Nr1h4, Abcb11, Cyp7a1 and Slc10a1. Meanwhile, in terms of protein expression, DME significantly up-regulated the protein expression levels of FXR, BSEP, CYP7A1 and NTCP, which regulated bile acid homeostasis. Finally, the molecular docking results showed that the components of DME, such as Lumichrome, Daidzein and Folic acid, all had good binding ability with FXR, and the surface plasmon resonance (SPR) results also showed that both Lumichrome and Daidzein had a relatively high affinity with FXR. ConclusionDME alleviated CLD through the FXR pathway, and the mechanisms might be associated with the gut microbiota.

Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition.

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal FXR agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 weeks markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease.

Caffeoylquinic acids from Silphium perfoliatum L. show hepatoprotective effects on cholestatic mice by regulating enterohepatic circulation of bile acids

Ethnopharmacological relevanceThe incidence of cholestatic liver disease (CLD), which is primarily marked by abnormal bile acids (BAs) metabolism and can result in significant hepatic injury, is rising. Nevertheless, there remains a lack of effective treatments and drugs in clinical practice. Silphium perfoliatum L. (SP) is rich in various structural types of caffeoylquinic acid (CQA) compounds, and it is a traditional herb of North American Indians with hepatobiliary therapy effects. However, its therapeutic effect and mechanism of action on CLD have never been studied. Aim of the studyTo determine if SP-8, an extract rich in CQAs from SP, protects against cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) and to clarify its mechanism based on the farnesoid x receptor (FXR) signaling pathway and enterohepatic circulation of BAs. Materials and methodsThe therapeutic efficacy of SP-8 was evaluated by assessing the serum biochemical indices, inflammatory factors, and liver histopathology. Targeted metabolomics of the BAs was studied in the feces, liver, serum, and bile using UPLC-MS/MS. Additionally, a Western blot analysis was used to examine the expression levels of the peroxisome proliferator-activated receptor γ (PPARγ), the FXR, and proteins related to the synthesis and transport of BAs. 16S rRNA gene sequencing was performed to evaluate the gut microbiota (GM). Finally, molecular docking simulations were conducted to assess the interaction between seven types of CQAs from SP-8 with FXR and PPARγ. ResultsSP-8 significantly enhanced the health status of cholestatic mice induced by ANIT as evidenced by a notable reduction in the liver function indices and pro-inflammatory factors, restoration of liver pathological damage, and acceleration of BAs excretion through the feces. In addition, the levels of harmful secondary BAs in the liver and blood were significantly reduced by SP-8. Furthermore, the results of the study on the mechanism of action confirmed that SP-8 not only regulated FXR and PPARγ but also significantly ameliorated the GM structure, thereby promoting the enterohepatic circulation of BAs and achieving the homeostasis of the BAs in the blood and liver. In addition, SP-8 successfully reduced the inflammatory response by strongly suppressing the nuclear translocation of NF-κBp65. According to the molecular docking results, the extract's primary active ingredients could be the seven CQAs in SP-8, as they exhibited a strong affinity for both FXR and PPARγ. Finally, the Mantel test analysis revealed a significant correlation among cholestatic-associated parameters, the GM, and BAs. ConclusionIt was confirmed for the first time that the SP-8 extract of Silphium perfoliatum L. that is rich in seven CQAs had a strong therapeutic effect on ANIT-induced CLD. Its mechanism may involve the regulation of the FXR signaling pathway and the amelioration of the GM structure to promote the homeostasis of BAs enterohepatic circulation. This study provides a potential candidate medicinal herb and its components for the development of CLD therapeutic drugs.

Quality of Life in Primary Biliary Cholangitis - Advances in the Treatment

Quality of Life in Primary Biliary Cholangitis - Advances in the Treatment

Management of a Todani Type 1b Choledochal Cyst: Case report

This case report describes the management of a Todani Type 1b choledochal cyst in a 26-year-old woman who presented with chronic epigastric dyspepsia and acute epigastric pain. MRI revealed a cystic dilatation of the distal common bile duct. The patient underwent successful surgical excision of the cyst, cystic duct, and gallbladder, followed by reconstruction with a Roux-en-Y hepaticojejunostomy. The postoperative course was uneventful, with discharge on the sixth day. This case highlights the importance of timely diagnosis and surgical intervention to prevent complications such as biliary cirrhosis and malignancy.

Application of liver biopsy in etiological diagnosis of unexplained portal hypertension: Porto-sinusoidal vascular disease should not be ignored.

The diagnostic value of liver biopsy has been confirmed in patients with abnormal liver test results; however, little data are available on its application in patients with portal hypertension. This study aimed to investigate the utility of liver biopsy for the etiological diagnosis of unexplained portal hypertension, and explore the clinical and pathological characteristics of each etiology. A retrospective observational analysis was conducted on 1367 patients who underwent liver biopsy at the Second Hospital of Nanjing from 2017 to 2019. Of these, 188 patients with unexplained portal hypertension were enrolled. The clinical and pathological characteristics were collected and reassessed in a multidisciplinary team meeting. Among these patients, 174 (92.6%, 174/188) had a definite etiological diagnosis through liver biopsy. The main etiologies were autoimmune hepatitis in 47 patients (25%, 47/188), autoimmune hepatitis-primary biliary cirrhosis overlap syndrome in 41 patients (21.8%, 41/188), and porto-sinusoidal vascular disease (PSVD) in 40 patients (21.3%, 40/188). Compared to liver cirrhosis, PSVD patients were younger and the liver function damage of which was subtler. The widths of portal vein diameter were widest in PSVD but the liver stiffness measurement were almost normal. Splenomegaly was common in PSVD, but ascites were less frequent than in autoimmune hepatitis (25.0% vs 51.1%, P = .013). Based on the histological patterns, we found that cholestatic liver diseases such as primary biliary cirrhosis, autoimmune hepatitis-primary biliary cirrhosis overlap syndrome, and progressive familial intrahepatic cholestasis could lead to non-cirrhotic portal hypertension, while vascular liver diseases such as PSVD and Budd-Chiari syndrome could also show fibrous proliferation as the disease progresses. Liver biopsy is safe and valuable for etiological diagnosis of unexplained portal hypertension. Cirrhosis is the leading cause of portal hypertension, and porto-sinusoidal vascular diseases should also be considered. Clinical features may be helpful in suggesting the cause; however, pathological examination is still indispensable for disease diagnosis and progression assessment.

Predictors of survival in autoimmune liver disease overlap syndromes.

Survival in patients with autoimmune liver disease overlap syndromes (AILDOS) compared to those with single autoimmune liver disease is unclear. To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death. Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap (AIH-PBC) or autoimmune hepatitis and primary sclerosing cholangitis overlap (AIH-PSC) and were identified from three tertiary centres for this cohort study. Liver-related death or transplantation (liver-related mortality) was determined using a population-based data linkage system. Prognostic scores for liver-related death were compared for accuracy [including liver outcome score (LOS), Hepascore, Mayo Score, model for end-stage liver disease (MELD) score and MELD incorporated with serum sodium (MELD-Na) score]. Twenty-two AILDOS patients were followed for a median of 3.1 years (range, 0.35-7.7). Fourteen were female, the median age was 46.7 years (range, 17.8 to 82.1) and median Hepascore was 1 (range, 0.07-1). At five years post enrolment, 57% of patients remained free from liver-related mortality (74% AIH-PBC, 27% AIH-PSC). There was no significant difference in survival between AIH-PBC and AIH-PSC. LOS was a significant predictor of liver-related mortality (P < 0.05) in patients with AIH-PBC (n = 14) but not AIH-PSC (n = 8). A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients (P = 0.012, log-rank test, 100% sensitivity, 77.8% specificity) (Harrell's C-statistic 0.867). The MELD score, MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group. Survival in the rare, AILDOS is unclear. The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients. Further trials investigating predictors of survival in AILDOS are required.

The Outcomes of Liver Transplantation in Highly Dependent Incapacitated Patients with Intellectual and Developmental Disabilities.

Background/Objectives: Data regarding the outcomes of liver transplantation in disabled, highly dependent, and legally incapacitated adults are scarce, likely due to the infrequency of these procedures in such populations. Multicenter studies in adult transplant centers have shown that patients with coexisting intellectual and developmental disabilities (IDDs) may be denied transplantation because of their expected low longevity and the complexities associated with managing post-transplant care. We examined the long-term patient and graft outcomes in highly dependent, incapacitated patients with IDDs who underwent elective transplantation for chronic liver disease. Methods: Six adult patients who underwent liver transplantation for primary biliary cholangitis (n = 2), hepatitis C cirrhosis (n = 2), Wilson's disease (n = 1), and autoimmune hepatitis (n = 1) were included. The main causes of their disability were infantile cerebral palsy, myotonia, and Niemann-Pick disease. Results: Four of the six patients were women, with a median age of 26 (range: 23-36) years. Only one patient died during follow-up. Their 1- and 5-year survival rates were 100 and 75%, respectively, which were not statistically different from those of the general cohort of electively transplanted patients (95.8 and 90.1%, respectively) (p = 0.35). Conclusions: Adult patients who are highly dependent, disabled, or legally incapable should not be denied liver transplantation because of poor long-term survival rates. Physiological disorders and psychiatric comorbidities should not prevent patients from receiving life-saving surgeries due to poor postoperative compliance or low quality of life.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Primary Biliary Cholangitis in Men: A Case Report

Primary biliary cholangitis (PBC) is a rare chronic autoimmune liver disease, especially in men, that causes progressive inflammation and destruction of the intrahepatic bile ducts. This leads to hepatic fibrosis that can progress to cirrhosis. PBC diagnosis is suggested by cholestatic jaundice in the absence of abnormalities in intrahepatic and extrahepatic bile ducts, with alkaline phosphatases (ALP) &gt; 1.5 times the upper limit of normal and gamma-glutamyl transferase (GGT) &gt; 3 times the upper limit of normal, with or without elevated bilirubin levels. Confirmation is made through immunological tests, and liver biopsy (PBH) is necessary if tests are negative. The disease is often diagnosed at an advanced stage. Poor prognostic factors include early diagnosis, male gender, severe symptoms, and biological abnormalities such as elevated bilirubin levels. Specific autoantibodies, such as anti-gp210 and anti-sp100, also predict unfavorable disease progression. The first-line treatment is ursodeoxycholic acid (UDCA), which helps slow disease progression and improve symptoms. If UDCA is ineffective, other options include obeticholic acid (OCA) or fibrates like bezafibrate, often used in combination with UDCA. Liver transplantation is the only curative treatment for severe cases. Research is ongoing for new treatments, including PPAR agonists and bile acid transporter inhibitors.

Distinct characteristics of various autoimmune liver diseases: A 22‐year hospital‐based study in Taiwan

AbstractBackground and AimThe characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC‐AIH overlap syndrome (OS), have rarely been investigated and compared in Asia.MethodsAt the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC‐AIH OS patients (85.7% treated with UDCA and IST) were enrolled.ResultsCompared with AIH patients, PBC patients were older at baseline and had greater female‐to‐male sex ratios, alkaline phosphatase (ALP) and γ‐glutamyl transferase (γ‐GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22‐year all‐cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P &lt; 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC‐AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases.ConclusionsCompared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.

Current Landscape and Evolving Therapies for Primary Biliary Cholangitis

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Autoimmune diseases refractory to corticosteroids and immunosuppressants.

Corticosteroids and immunosuppressive drugs can alleviate the symptoms of most autoimmune diseases and induce remission by restraining the autoimmune attack and limiting the damage to the target tissues. However, four autoimmune non-degenerative diseases-adult advanced type 1 diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, and advanced primary biliary cholangitis-are refractory to these drugs. This article suggests that the refractoriness of certain autoimmune diseases is due to near-total loss of secreting cells coupled with the extremely low regenerative capacity of the affected tissues. The near-complete destruction of cells responsible for secreting insulin, thyroid hormones, or biliary HCO3 - diminishes the protective effects of immunosuppressants against further damage. The slow regeneration rate of these cells hinders tissue recovery, even after drug-induced immune suppression, thus preventing remission. Although the liver can fully regenerate after injury, severe primary biliary cholangitis may impair this ability, preventing liver recovery. Consequently, these four autoimmune diseases are resistant to immunosuppressive drugs and corticosteroids. In contrast, early stages of type 1 diabetes and early primary biliary cholangitis, where damage to secreting cells is partial, may benefit from immunosuppressant treatment. In contrast to these four diseases, chronic degenerative autoimmune conditions like multiple sclerosis may respond positively to corticosteroid use despite the limited regenerative potential of the affected tissue (the central nervous system). The opposite is true for acute autoimmune conditions like Guillain-Barré syndrome.

Leveraging large-scale genetic data to assess the causal impact of COVID-19 on multisystemic diseases

BackgroundThe long-term impacts of COVID-19 on human health are a major concern, yet comprehensive evaluations of its effects on various health conditions are lacking.MethodsThis study aims to evaluate the role of various diseases in relation to COVID-19 by analyzing genetic data from a large-scale population over 2,000,000 individuals. A bidirectional two-sample Mendelian randomization approach was used, with exposures including COVID-19 susceptibility, hospitalization, and severity, and outcomes encompassing 86 different diseases or traits. A reverse Mendelian randomization analysis was performed to assess the impact of these diseases on COVID-19.ResultsOur analysis identified causal relationships between COVID-19 susceptibility and several conditions, including breast cancer (OR = 1.0073, 95% CI = 1.0032–1.0114, p = 5 × 10 − 4), ER + breast cancer (OR = 0.5252, 95% CI = 0.3589–0.7685, p = 9 × 10 − 4), and heart failure (OR = 1.0026, 95% CI = 1.001–1.0042, p = 0.002). COVID-19 hospitalization was causally linked to heart failure (OR = 1.0017, 95% CI = 1.0006–1.0028, p = 0.002) and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). COVID-19 severity had causal effects on primary biliary cirrhosis (OR = 2.6333, 95% CI = 1.8274–3.7948, p = 2.059 × 10 − 7), celiac disease (OR = 0.0708, 95% CI = 0.0538–0.0932, p = 9.438 × 10–80), and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). Reverse MR analysis indicated that rheumatoid arthritis, diabetic nephropathy, multiple sclerosis, and total testosterone (female) influence COVID-19 outcomes. We assessed heterogeneity and horizontal pleiotropy to ensure result reliability and employed the Steiger directionality test to confirm the direction of causality.ConclusionsThis study provides a comprehensive analysis of the causal relationships between COVID-19 and diverse health conditions. Our findings highlight the long-term impacts of COVID-19 on human health, emphasizing the need for continuous monitoring and targeted interventions for affected individuals. Future research should explore these relationships to develop comprehensive healthcare strategies.

Gut microbiota-mediated C-sulfonate metabolism impairs the bioavailability and anti-cholestatic efficacy of andrographolide

ABSTRACT Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5’-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO4 2- to HSO3 −. HSO3 − subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.