Hepatology. 2021 Oct 11. doi: 10.1002/hep.32193. Online ahead of print.
BACKGROUND & 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.
METHODS: Expression of MAdCAM-1, CCL25 and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from CLD patients undergoing orthotopic liver transplantation 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.
RESULTS: Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was upregulated in all CLDs compared to normal liver. There were no differences between disease groups. Frequencies of Î±4Î˛7, Î±EÎ˛7, CCR9 and GPR15 expressing hepatic T-cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. Î˛7 expressing hepatic T-cells displayed an increased inflammatory phenotype compared with Î˛7 negative cells, though 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 pan-aetiological feature of CLD.
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