Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis

Background and Aims The gut homing hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine the gut homing theory in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. Approach and Results Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of alpha 4 beta 7, alpha E beta 7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. beta 7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with beta 7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver. Conclusions These findings refute the widely accepted gut homing hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD.

Automated summary

The study found that the gut homing hypothesis is not the primary driver of PSC, and aberrant recruitment of gut-derived T cells to the liver is also seen in other chronic liver diseases. This finding provides a new understanding of the pathogenesis of PSC and CLD.