Secondary Sclerosing Cholangitis in Critically Ill Patients Alters the Gut–Liver Axis: A Case Control Study

Abstract

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) occurs after long-term intensive care treatment. This study aimed to assess the gut–liver axis in SC-CIP. Stool microbiome composition, gut permeability, bacterial translocation and serum bile acid profiles of 18 SC-CIP patients compared to 11 patients after critical illness without liver disease (CIP controls), 21 patients with cirrhosis and 21 healthy controls were studied. 16S rDNA was isolated from stool and sequenced using the Illumina technique. Diamine oxidase, zonulin, soluble CD14 (sCD14) and lipopolysaccharide binding protein were measured in serum and calprotectin in stool. Serum bile acids were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Reduced microbiome alpha diversity and altered beta diversity were seen in SC-CIP, CIP controls and cirrhosis compared to healthy controls. SC-CIP patients showed a shift towards pathogenic taxa and an oralization. SC-CIP, CIP controls and cirrhotic patients presented with impaired gut permeability, and biomarkers of bacterial translocation were increased in SC-CIP and cirrhosis. Total serum bile acids were elevated in SC-CIP and cirrhosis and the bile acid profile was altered in SC-CIP, CIP controls and cirrhosis. In conclusions, observed alterations of the gut–liver axis in SC-CIP cannot solely be attributed to liver disease, but may also be secondary to long-term intensive care treatment.

The Gut-Liver Axis in Cholestatic Liver Diseases

“…Only little is known about bile acids in SC-CIP. We could recently demonstrate changes in the serum bile acids profile of patients with SC-CIP including an elevated total serum concentration of bile acids, same as already shown for PBC and PSC [ 18 , 156 , 157 ]. Furthermore, elevation of conjugated bile acids became evident in SC-CIP and may be caused by a reduction in microbiome diversity and antibiotic use [ 18 , 122 , 158 ].…”

“…Recently, we were the first to show that biomarkers of gut permeability and bacterial translocation are increased in SC-CIP with elevation of DAO and sCD14 compared to healthy controls. However, we found similar alterations in a group of patients with a history of a critical illness and intensive care treatment without development of SC-CIP [18]. This leaves room for discussion whether these changes are caused by the liver disease itself, by the experienced critical illness, or by an overlap of both.…”

“…In SC-CIP, we described the composition of the microbiome in fecal samples [ 18 ]. The gut microbiome of SC-CIP patients is characterized by reduced alpha diversity and dysbiosis with increase of the oral inhabitants Streptococcus parasanguinis and Rothia dentocariosa as well as Enterococcus faecium.…”

“…Because recurrence of the disease is possible after liver transplantation, extrahepatic drivers are likely to play a significant role in the pathogenesis [ 7 ]. SC-CIP is most likely triggered by ischemic injury of the biliary system during critical illness with consecutive formation of biliary casts and recurrent biliary infections [ 18 ]. PBC is a multifactorial disease and environmental triggers like infections (urinary tract infections, infections with mycobacteria, Epstein-Barr virus, chlamydia, Helicobacter pylori ) and smoking, as well as genetic predisposition and autoimmune factors have been described [ 5 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

High Rate of Gastrointestinal Bleeding in Patients with Secondary Sclerosing Cholangitis in Critically Ill Patients (SC-CIP)

“…The development of the disease seems to be favored by NOD2 gene variants [8]. Additionally, our group recently described alterations of the gut microbiome, intestinal permeability, and serum bile acid profiles in SC-CIP, which may not be caused by the liver disease alone, but seem to persist also from long-term intensive care treatment [9]. SC-CIP leads to destruction of the intra-and extrahepatic biliary tree with the development of biliary strictures that may lead to liver fibrosis and consequently to cirrhosis of the biliary type.…”