Mucosal immunity in primary sclerosing cholangitis: from the bowel to bile ducts and back again

Abstract

Purpose of reviewIn this article, we provide a contemporary overview on PSC pathogenesis, with a specific focus on the role of mucosal immunity. Recent findingsThe extent of enteric dysbiosis in PSC has been extensively quantified, with evidence of reduced bacterial diversity and enrichment of species capable of driving lymphocyte recruitment from the gut to the liver. Integrative pathway-based analysis and metagenomic sequencing indicate a reduction in butyrateproducing species, near absence of bacteria that activate the nuclear bile acid receptor FXR, and depletion of species that regulate the synthesis of vitamin B6 and branched-chain amino acids. Immunotyping of the cellular inflammatory infiltrate has identified a population of intrahepatic naive T cells, with tendency to acquire a Th17 polarisation state, paralleled by heightened responses to pathogen stimulation. Moreover, the search for antigen specificity has revealed the presence of overlapping nucleotide clonotypes across the gut and liver, highlighting the ability to recognize a common pool of epitopes bearing structural similarities across afflicted sites.

Primary sclerosing cholangitis and other risk factors for post-transplant lymphoproliferative disease after liver transplantation in adults

“…[12][13][14] Colonic dysbiosis, increased colonic permeability, FUT2 mutation, and immunological activity in mesenteric lymph nodes and liver are described in PSC, and are probably related to IBD. [15,16] Therefore, it is very well possible that in PSC immunological changes in the gut, abdominal lymph nodes, and liver contribute to the increased risk for PTLD after LT for PSC. The increased PTLD risk in LT for PSC may also indicate that EBV VL monitoring is even more important after LT for PSC compared to other LT indications.…”

“…An increased inflammatory state in PSC might play a role: although much is still unclear regarding the pathophysiology of PSC, the gut-liver axis with increased antigen load from gut to mesenteric lymph nodes and liver with concordant inflammation appears important 12-14 . Colonic dysbiosis, increased colonic permeability, FUT2 mutation, and immunological activity in mesenteric lymph nodes and liver are described in PSC, and are probably related to IBD 15,16 . Therefore, it is very well possible that in PSC immunological changes in the gut, abdominal lymph nodes, and liver contribute to the increased risk for PTLD after LT for PSC.…”

Gut Microbiota in Primary Sclerosing Cholangitis: From Prognostic Role to Therapeutic Implications

“…Once established the role of gut-induced immune dysregulation in the pathogenesis of PSC, with hyperactivation of Th17 and T memory cell recruited in the bile ducts through homing adhesion molecules, drugs targeting these molecules became an interesting therapeutic option to explore in PSC [75]. In particular, vedolizumab, which is an approved drug for IBDs, inhibits the α4β7 integrin-mucosal addressing cellular adhesion molecule-1 (MAdCAM-1) interaction, which blocks lymphocyte trafficking to the inflammation site in the gastrointestinal tract; therefore, considering the over-expression of MAdCAM-1 by hepatic endothelial cells in PSC, vedolizumab was expected to be a potential therapeutic candidate.…”

Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)—A European Society of Organ Transplantation (ESOT) Consensus Statement

“…The dominant clinical presentation of PSC is in association with gut inflammation, with 70%-80% of patients having inflammatory bowel disease (IBD). This relationship has driven several pathogenic hypotheses, in which enteric dysbiosis, dysregulated mucosal immune responses and altered bile acid metabolism are proposed to contribute [3,4]. Additionally, there is a growing body of evidence that the clinical course of liver disease can be affected by IBD activity; and in turn, the natural history of colitis may be affected by that of PSC [4].…”