Pre‐diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case–control analysis of 12 prospective cohorts
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.
Authors
- Howard D. Sesso (ORCID: https://orcid.org/0000-0002-9698-9954)
- J. Michael Gaziano
- Jae H. Kang (ORCID: https://orcid.org/0000-0003-4812-0557)
- A. Heather Eliassen (ORCID: https://orcid.org/0000-0002-3961-6609)
- Eleanor L. Watts (ORCID: https://orcid.org/0000-0001-9229-2589)
- Jean Wactawski‐Wende (ORCID: https://orcid.org/0000-0003-3096-9595)
- Jessica L. Petrick (ORCID: https://orcid.org/0000-0001-6580-450X)
- Andrew T. Gewirtz (ORCID: https://orcid.org/0000-0002-6338-7578)
- Mark P. Purdue (ORCID: https://orcid.org/0000-0003-1177-3108)
- Christina C. Newton (ORCID: https://orcid.org/0000-0003-1471-5608)
- Katherine A. McGlynn (ORCID: https://orcid.org/0000-0003-2329-9933)
- I‐Min Lee (ORCID: https://orcid.org/0000-0002-1083-6907)
- Erikka Loftfield (ORCID: https://orcid.org/0000-0002-3573-8748)
- Lorelei Ann Mucci (ORCID: https://orcid.org/0000-0002-2551-4927)
- Dinesh Kumar Barupal (ORCID: https://orcid.org/0000-0002-9954-8628)
- Rashmi Sinha
- Martha J. Shrubsole (ORCID: https://orcid.org/0000-0002-5591-7575)
- Fen Wu (ORCID: https://orcid.org/0000-0002-0563-5887)
- Peter T. Campbell (ORCID: https://orcid.org/0000-0002-5549-2036)
- Jonathan N. Hofmann (ORCID: https://orcid.org/0000-0002-1043-5812)
- Lesley F. Tinker (ORCID: https://orcid.org/0000-0003-2469-1929)
- Barry I. Graubard (ORCID: https://orcid.org/0000-0002-6787-1105)
- Matthew Triplette (ORCID: https://orcid.org/0000-0001-7421-4720)
- Cody Z. Watling (ORCID: https://orcid.org/0000-0002-6643-9660)
- Jill Koshiol (ORCID: https://orcid.org/0000-0002-3832-6204)
- Walter Churchill Willett (ORCID: https://orcid.org/0000-0003-1458-7597)
- Caroline Y. Um (ORCID: https://orcid.org/0000-0001-5449-6230)
- Julie E. Buring (ORCID: https://orcid.org/0000-0003-2648-8692)
- Steven C. Moore (ORCID: https://orcid.org/0000-0002-8169-1661)
- Yu Chen (ORCID: https://orcid.org/0000-0002-1519-4894)
- Xuehong Zhang (ORCID: https://orcid.org/0000-0003-4894-0555)
- Yanyu Wang (ORCID: https://orcid.org/0000-0003-3365-3262)
- Wei Zheng (ORCID: https://orcid.org/0000-0003-3193-2655)
- Wen‐Yi Huang (ORCID: https://orcid.org/0000-0002-4440-3368)
- Kala Visvanathan
- Matthew J Barnett
- Marian L Neuhouser
Institutions
- Boston University (US)
- Leidos (United States) (US)
- Brigham and Women's Hospital (US)
- American Cancer Society (US)
- Albert Einstein College of Medicine (US)
- Harvard University (US)
- Johns Hopkins University (US)
- Georgia State University (US)
- Vanderbilt University (US)
- Yale University (US)
- Fred Hutch Cancer Center (US)
- National Cancer Institute (US)
- Vanderbilt Health (US)
- Division of Cancer Epidemiology and Genetics
- New York University (US)
- University at Buffalo, State University of New York (US)
- Vanderbilt University Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- International Journal of Cancer
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1002/ijc.70201
- Primary Topic
- Hepatitis B Virus Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Health and Human Services
- Purdue University
- Washington State University
- National Institutes of Health
- Centers for Disease Control and Prevention
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute
- National Cancer Institute