Fedirko, VeronikaTran, Hao QuangGewirtz, Andrew TStepien, MagdalenaTrichopoulou, AntoniaAleksandrova, KrasimiraOlsen, AnjaTjønneland, AnneOvervad, KimCarbonnel, FranckBoutron-Ruault, Marie-ChristineSeveri, GianlucaKühn, TilmanKaaks, RudolfBoeing, HeinerBamia, ChristinaLagiou, PagonaGrioni, SaraPanico, SalvatorePalli, DomenicoTumino, RosarioNaccarati, AlessioPeeters, Petra HBueno-de-Mesquita, H BWeiderpass, ElisabeteCastaño, José María HuertaBarricarte, AurelioSanchez-Perez, Maria-JoseDorronsoro, MirenQuirós, J RamónAgudo, AntonioSjöberg, KlasOhlsson, BodilHemmingsson, OskarWerner, MårtenBradbury, Kathryn EKhaw, Kay-TeeWareham, NickTsilidis, Konstantinos KAune, DagfinnScalbert, AugustinRomieu, IsabelleRiboli, ElioJenab, Mazda2023-01-252023-01-252017-04-04http://hdl.handle.net/10668/11045Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/EndotoxinsFlagellinHepatocellular carcinomaLipopolysaccharideProspective studiesAdultAgedCarcinoma, HepatocellularCase-Control StudiesCohort StudiesFemaleFlagellinHumansImmunoglobulin AImmunoglobulin GLipopolysaccharidesLiver NeoplasmsMaleMiddle AgedProspective StudiesRisk Factorsresearch article28372583open access10.1186/s12916-017-0830-81741-7015PMC5379669https://doi.org/10.1186/s12916-017-0830-8https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379669/pdf