Biomarkers of gut barrier dysfunction and risk of hepatocellular carcinoma in the REVEAL-HBV and REVEAL-HCV cohort studies.

Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut-derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV and REVEAL-HCV cohorts from Taiwan. REVEAL-HBV included 185 cases and 161 matched controls, and REVEAL-HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS-binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable-adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV-related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06-2.93; OR for LBP = 1.93, 95% CI: 1.10-3.38). None of the other markers were associated with an increased risk of HBV-related or HCV-related HCC. Results were similar when cases diagnosed in the first 5 years of follow-up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology.

Function, Regulation, and Pathophysiological Relevance of the POT Superfamily, Specifically PepT1 in Inflammatory Bowel Disease.

Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs and couple substrate translocation to the movement of H+ , with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di- and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug-delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731-760, 2018.