Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis

Abstract

BACKGROUND & AIMS:To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). METHODS: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion pairedend sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. RESULTS: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q fdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. CONCLUSIONS: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.

The Gut-Liver Axis in Cholestatic Liver Diseases

“…PSC patients showed reduced microbial gene richness and different abundance of several species in feces (Table 1). Furthermore, lower abundance of genes involved in vitamin B6 and branched-chain amino acids synthesis could be observed and reduced plasma levels of these metabolites could be correlated with lower liver transplantation-free survival suggesting a connection between disease course and microbiome functions [191]. In another study, PSC patients showed dysbiosis in fecal and salivary probes, independent of the co-existence of IBD in PSC patients.…”

“…On species level, PSC patients compared to healthy controls showed a decrease of the relative abundance of commensal bacteria and an increase of potentially pathogenic species [192]. In total, we identified 11 peer-reviewed full papers dealing with the microbiome in PSC patients [191][192][193][194][195][196][197][198][199][200][201] (Table 1). These papers present partly heterogenicity in findings, but several similarities can be summed up for the fecal microbiome: PSC patients present lower alpha diversity and dysbiosis compared to healthy controls.…”

The Gut Microbiota-Derived Immune Response in Chronic Liver Disease

“…In another study with two cohorts, the gut microbiomes of PSC patients revealed functional differences compared with those of the control group, including the microbial metabolism of essential nutrients [ 143 ]. Regarding epithelial barrier dysfunction, K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses in PSC patients.…”

Recurrent Primary Sclerosing Cholangitis: Current Understanding, Management, and Future Directions

“…A link between gut and liver pathology in PSC-IBD is likely and possibly related to the unique microbial and metabolic profiles seen in these patients. 62 In PSC-IBD, enteric pathogens and inappropriately activated lymphocytes are thought to translocate across a defective inflamed epithelial intestinal barrier, thus travelling to the liver via the portal circulation where they encounter a dysregulated immune environment, resulting in targeted biliary epithelial damage. 72 Subsequent sclerosing injury is thought to be augmented by a toxic bile acid milieu which is heavily influenced by the gut microbiome and enterohepatic circulation.…”

“…Recent data suggest important functional differences in the gut microbiome of PSC patients as compared with controls, with a recent study demonstrating that PSC patients have not only altered prevalence of bacterial species (e.g., Clostridium and Eubacterium species), but also reduced gene abundance relating to vitamin B6 synthesis and branched-chain amino acid synthesis, as well as reduced concentrations of these small molecules. 62 Ultimately, it is likely that biliary epithelial cells are damaged through a T-cell-driven process targeted at intraand/or extrahepatic biliary ducts, leading to fibro-obliterative duct destruction and progressive fibrosis. Strikingly, despite the implication of a dysregulated immune system in the pathophysiology of PSC and its recurrence, immunosuppressive agents have yet to prove successful in altering disease progression.…”