High prevalence of lower limb atherosclerosis is linked with the gut–liver axis in patients with primary biliary cholangitis

BACKGROUND AND AIMS: Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut–liver axis and systemic inflammation. METHODS: Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal‐sized groups of women with non‐alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow‐mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. RESULTS: PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM‐1 (p = .002), ICAM‐1 (p = .003), and TNF‐alpha (p = .04) serum levels, but only VCAM‐1 (OR 1.1, 95% CI 1.0–1.1; p = .04) and TNF‐alpha (OR 1.12, 95% CI 0.99–1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF‐alpha serum levels. Down‐regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched‐chain amino acids degradation was found in the functional gut metagenome of PBC women. CONCLUSIONS: LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut–liver axis.