Pre-diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case-control analysis of 12 prospective cohorts.

Authors

Watling CZ, Campbell PT, Graubard BI, Wang Y, Gewirtz AT, Zhang X, Barnett MJ, Buring JE, Chen Y, Eliassen AH, Gaziano JM, Hofmann JN, Huang WY, Kang JH, Koshiol J, Loftfield E, Lee IM, Moore SC, Mucci LA, Neuhouser ML, ...show more Newton CC, Purdue MP, Sesso HD, Shrubsole M, Sinha R, Tinker L, Triplette M, Um CY, Visvanathan K, Watts EL, Wactawski-Wende J, Willett W, Wu F, Zheng W, Barupal D, Petrick JL, McGlynn KA

Affiliations

• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
• Department of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, New York, USA.
• Applied Developmental Research Directorate, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
• Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
• School of Nursing, Yale University, New Haven, Connecticut, USA.
• Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
• Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
• Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA.
• Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
• Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case-control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23-1.79). Concentrations of anti-flagellin IgA (1.13, 1.01-1.28) and IgG (1.13, 1.01-1.28), anti-lipopolysaccharide IgG (1.20, 1.01-1.42), and soluble CD14 (1.12, 1.01-1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34-2.33) but not ICC (0.67, 0.37-1.22; p-heterogeneity = .003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.