Introduction

Mounting evidence supports an association between gut microbiota and cholestatic liver disease (CLD). However, the functional implications of the bacteria in the pathogenesis of this condition remain largely undefined. Here we investigated the functional role of gut microbiota–liver crosstalk for CLD murine model resembling human primary biliary cholangitis (PBC) and PSC.

Aims & Methods

​Male C57BL/6J mice received a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet for two weeks to induce cholestatic liver disease. Liver and gallbladder were collected and bacteria were identified in homogenates by culture procedures. Liver samples collected from eight PBC patients and three controls with hepatic cyst were analyzed by 16S ribosomal DNA sequencing. Next, the functional roles of the identified bacteria in CLD pathogenesis were studied by microbiota transfer experiments.

Results

Bacterial culture of livers and gallbladder in CLD mice isolated Ligilactobacillus murinus (L. murinus) and Lactococcus garvieae (L. garvieae), the former was prevalently detected in PBC patients and controls, the last was detected only in PBC patients but not in controls. Mice inoculated with L. garvieae but not L. murinus exhibited increased susceptibility to experimental CLD. Further experiments revealed that L. garvieae disrupts the intestinal barrier function through downregulation of tight junction proteins, which increased intestinal bacterial translocation and liver inflammatory responses. In vitro studies showed that L. garvieae significantly increased the expression of proinflammatory cytokines and chemokines in Raw264.7 cells and Intrahepatic bile duct epithelial cells. Strikingly, administration of L. garvieae significantly decreased the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum and increased serum BAs. Further experiments revealed that L. garvieae significantly increased the levels of taurine-conjugated BAs in serum, such as taurodeoxycholic acid (TDCA), and taurocholic acid (TCA), which was associated with reduced bile salt hydrolase (BSH) activity, thus reduced faecal BA excretion and enhances hepatic BA accumulation and liver fibrosis.

Conclusion

We demonstrate that L. garvieae contributes to the development of excessive BA-induced hepatobiliary injuries and liver fibrosis through promoting intestinal permeability and enhancing bile acid reabsorption, providing insights into the effect of gut-liver cross in CLD pathogenesis.

References

We demonstrate that L. garvieae contributes to the development of excessive BA-induced hepatobiliary injuries and liver fibrosis through promoting intestinal permeability and enhancing bile acid reabsorption, providing insights into the effect of gut-liver cross in CLD pathogenesis.

Disclosure

No conflict of interest

Introduction

Autoimmune cholestatic liver diseases (ACLD), including PBC and PSC, are chronic conditions causing bile acid accumulation, liver damage, and debilitating pruritus. Current treatments often fail to relieve symptoms, creating a need for new options. Ileal bile acid transporter (IBAT) inhibitors, such as maralixibat and linerixibat, offer a novel approach by reducing bile acid reabsorption. This meta-analysis evaluates their efficacy and safety in adults with ACLD.

Aims & Methods

To evaluate the efficacy and safety of ileal bile acid transporter (IBAT) inhibitors in adults with autoimmune cholestatic liver diseases (ACLD), specifically primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), focusing on patient-related and biochemical outcomes. We conducted a meta-analysis in accordance with PRISMA guidelines, registered on PROSPERO (ID: 621722). A comprehensive search of PubMed, Embase, and CENTRAL was performed from inception to January 2025 to identify randomized and observational studies evaluating IBAT inhibitors in adults with ACLD and pruritus, with a minimum follow-up of 12 weeks. The primary outcome was the change in pruritus severity measured by the 5-D Itch Scale. Secondary outcomes included: (1) changes in sleep quality assessed by the MOS Sleep Scale; (2) biochemical efficacy endpoints, including changes from baseline in serum bile acids (BA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TB), autotaxin (ATX), 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19); and (3) safety outcomes.

Results

Three studies (2 RCTs, 1 pilot study) comprising 180 patients (153 PBC, 27 PSC) were included. Treatment involved maralixibat (n=42) and linerixibat (n=138). Pruritus severity significantly improved with IBAT inhibitors (mean difference [MD] = -4.93; 95% CI [-6.26, -3.59]; p < 0.0001) with low heterogeneity (I² = 24.6%). IBAT inhibitors significantly improved sleep quality, as measured by the MOS Sleep Scale (MD = -8.12, 95% CI [-13.54, -2.70], p = 0.0033; I² = 0%). Regarding liver function, significant reductions were observed in AST (MD = -14.74, 95% CI [-24.22, -5.27], p = 0.0023) and GGT (MD = -50.34, 95% CI [-86.48, -14.20], p = 0.0063), while changes in ALT (MD = -6.45, 95% CI [-16.43, 3.53], p = 0.2055) and bilirubin (MD = 0.09, 95% CI [-0.03, 0.21], p = 0.15) were not statistically significant. Treatment led to significant reductions in serum BA (MD = -6.81, 95% CI [-9.34, -4.28], p < 0.0001), FGF19 (MD = -51.46, 95% CI [-73.30, -29.61], p < 0.0001), and ATX (MD = -74.41, 95% CI [-118.57, -30.26], p < 0.001), along with an increase in C4 levels (MD = 25.12, 95% CI [11.84, 38.41], p < 0.0002). Adverse events were reported in 89.7% of patients, most commonly diarrhea (22.7%), abdominal pain (18.2%), and nausea (12.2%), while serious adverse events were rare (2.2%). Treatment discontinuation occurred in 8.0% of cases.

Conclusion

IBAT inhibitors are associated with clinically meaningful improvements in pruritus and sleep quality in adults with ACLD. Although adverse events are common, serious events are infrequent, supporting a favorable safety profile. These findings highlight the promise of IBAT inhibitors as an emerging therapeutic option for cholestatic pruritus, though further high-quality studies are needed to confirm long-term benefits and safety across diverse patient populations.

Disclosure

GGLC has received a research grant from IPSEN. The other authors have no conflicts of interest to declare.

Introduction

Autoimmune liver diseases (AILDs) includes primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC), in which the immune system produces an inappropriate response to self-antigens leading to chronic liver disease. Gallstone disease is one of the most commonly occurring gastrointestinal disorders. The prevalence of gallbladder stones in patients with chronic liver disease is 22%-54%, higher than the general population¹. Chronic liver disease in most studies mainly refers to viral hepatitis and alcoholic liver disease, and there are no studies on AILDs complicating gallstones. Previous studies have shown that gallstones were associated with autoimmune disease² and were a common cause of secondary sclerosing cholangitis³, but the association between AIH, PBC and gallstones has not been reported yet. We have observed that the combination of AILDs and gallstones are a common phenomenon in clinical practice. Therefore, our study was intended to analyze the proportion and the clinical characteristics of gallstones in patients with AILDs as a reference for clinical decision making in patients with AILDs complicated by gallstones.

Aims & Methods

We investigated the comorbidity of gallstones and risk factors associated with gallstones in patients with AILDs. AILDs patients attending the General Hospital of Tianjin Medical University from November 2012 to October 2022 were retrospectively included. Analysis of the proportion of AILDs patients with gallstones (including patients who underwent cholecystectomy for gallstones), clinical characteristics, and laboratory test. Logistic regression analysis was used to assess the risk factors for the combination of gallstones in patients with AILDs.

Results

A total of 560 patients with AILDs were enrolled, including 207 patients with PBC, 289 with AIH and 64 with PBC-AIH overlap syndrome (PBC-AIH). The proportion of patients with AILDs, PBC, AIH and PBC-AIH complicated by gallstones was 32.50%, 35.75%, 28.37% and 40.63%, respectively. Multiple stones predominate in patients with AILDs complicated by gallstones (43.41%), followed by single stones (32.42%) and sludge (6.04%). Age at first visit (p=0.007) and serum biochemical markers associated with bile duct injury such as GGT (p=0.003) and ALP (p=0.001) were significantly higher in patients with AILDs complicated by gallstones compared to those without gallstones. Age (odd ratio [OR] = 1.024; 95% confidence interval [CI] =1.006-1.042 and serum ALP levels (OR = 1.001; 95% CI = 1-1.002) were independent risk factors for patients with AILDs complicated by gallstones, while serum GGT levels (OR = 1.002; 95% CI = 1-1.003) were independent risk factors for patients with AIH complicated by gallstones. Significantly higher prevalence of gallstones in patients with AILDs older than 61.5 years (p=0.003).

Conclusion

Gallstones are more common comorbidity in AILDs patients, predominantly multiple stones. Age and serum ALP levels were independent risk factors for patients with AILDs complicated by gallstones. Patients with AILDs complicated by gallstones present with significantly elevated serum biochemical parameters associated with bile duct injury. The comorbidity of gallstones tends to delay the initial diagnosis of patients with AILDs.

References

1 Li X, Gao P. Hepatitis C Virus Infection Increases Risk of Gallstone Disease in Elderly Chinese Patients with Chronic Liver Disease. Sci Rep. 2018;8(1):4636. Published 2018 Mar 15. doi:10.1038/s41598-018-22896-4
2 Chapman MH, Thorburn D, Hirschfield GM, et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019;68(8):1356-1378. doi:10.1136/gutjnl-2018-317993
3 Shabanzadeh DM, Linneberg A, Skaaby T, Sørensen LT, Jørgensen T. Screen-detected gallstone disease and autoimmune diseases - A cohort study. Dig Liver Dis. 2018;50(6):594-600. doi:10.1016/j.dld.2018.01.12
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