Previously submitted to: JMIR Cancer (no longer under consideration since Jun 10, 2026)
Date Submitted: Oct 10, 2025
Open Peer Review Period: Oct 14, 2025 - Dec 9, 2025
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Exploring the Role of the Gut-Metabolic Syndrome Axis in Breast Cancer: a Case-Control Study Nested in the ORDET Cohort
ABSTRACT
Background:
Diet-induced metabolic endotoxemia contributes to the metabolic disturbances and systemic inflammation characteristic of metabolic syndrome (MetS), while MetS is a risk factor for postmenopausal breast cancer (BC).
Objective:
We investigated associations of metabolic endotoxemia (as elevated plasma lipopolysaccharide (LPS)) and plasma zonulin (marker of intestinal permeability) with risks of developing MetS or postmenopausal BC.
Methods:
We examined 54 matched case-control (BC-no BC) pairs who developed MetS, and 54 matched case-control pairs who did not develop MetS. The postmenopausal cases were chosen at random from those identified, by cancer registry linkage, in 3,666 women who had enrolled in both the ORDET and EPIC-Varese studies, and had data and plasma available at ORDET and EPIC recruitment (5 years apart). Associations of LPS and zonulin in plasma with MetS and BC were assessed by Bayesian logistic regression, with adjustment for inflammatory markers.
Results:
High LPS several years before BC diagnosis was associated with increased BC risk (OR = 1.38, 95% CI, 1.01-1.91). LPS closer to diagnosis, and longitudinal increase in LPS were not associated with BC. Longitudinal increase in LPS was associated with MetS (OR = 1.45, 95% CI, 1.01-2.06, adjusted model). Zonulin was not associated with BC or MetS.
Conclusions:
This appears to be the first study to associate high circulating LPS with increased BC risk several years later. Increase in LPS over time was also associated with increased MetS risk. These preliminary findings suggest that concurrent metabolic and gut perturbation may both affect postmenopausal BC risk and deserve further investigation. Clinical Trial: PNRR-MAD-2022-12376584
Citation
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