Increased gut permeability and changes of the gut microbiota in secondary sclerosing cholangitis of critically ill patients (SSC-CIP)

Background and aims:

SSC-CIP is a progressive, cholestatic liver disease with enigmatic pathophysiology. Ischemic injury of the biliary system, bile cast formation and recurrent biliary infections are discussed as major factors. Since it occurs only in small proportion of patients surviving a critical illness, patient factors seem to be important in the pathogenesis. The aim of the study was to characterize gut microbiome composition and gut permeability in SSC-CIP patients in comparison to healthy controls.

Methods:

Serum and stool from 18 patients (mean age 59 ± 13, 5 women, 39% cirrhosis) with SSC-CIP from two centers in Austria and Germany and from 21 healthy controls were collected. Patients were included when they developed sclerosing cholangitis diagnosed by ERCP or MRCP after a critical illness. Gut permeability was assessed by diamino-oxidase (DAO, serum), zonulin and calprotectin (stool) using ELISA. sCD14 and lipopolysaccharide binding protein (LBP) as markers for endotoxemia were measured by ELISA in serum. 16S rDNA was isolated from stool, sequenced using Illumina technique and analysed using QIIME.

Results:

SSC-CIP patients had a significantly reduced alpha-diversity (chao1 p < 0.001). Significant differences in Beta Diversity could be shown using Bray-Curtis dissimilarity and Unifrac analysis. Patients with SSC-CIP showed significant oralisation of the microbiome as evidenced by an increase in Streptococcus, Rothia and Veillonella (p < 0.05). Faecalibacterium prausnitzii was significantly reduced in SSC-CIP patients. SSC-CIP patients had significantly impaired gut permeability as evidenced by higher levels of DAO in serum and zonulin in stool. sCD14 and LBP as markers of bacterial translocation were also elevated in SSC-CIP.

Summary and conclusions:

Patients with SSC-CIP showed dysbiosis with reduced diversity, oralisation, and loss of beneficial species. Biomarkers of gut permeability and endotoxemia were significantly elevated in SSC-CIP. Intestinal dysbiosis together with increased gut permeability point towards a critical role of bacterial translocation as trigger and/or booster of SSC-CIP.