Markers of compromised gut epithelial barrier integrity increase during the menopause transition

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Abstract

BACKGROUND. In female murine models, one source of inflammation is a menopause-related increase in gut permeability. We examined whether the menopause transition (MT) in women is associated with an increase in markers of gut epithelial dysfunction and gut microbial product translocation, signals of compromised gut epithelial barrier integrity. METHODS. In 964 women, we measured markers of gut epithelial dysfunction (fatty acid binding protein 2, FABP2) and gut microbial antigen translocation (soluble CD14, sCD14) using sera collected before, during and after the MT. Multivariable mixed effects regressions fit piece-wise linear models to repeated FABP2 or sCD14 measures relative to time from final menstrual period (FMP). Covariates were age at FMP, race/ethnicity, and BMI. RESULTS. FABP2 and sCD14 did not change significantly until 2.5 years pre-FMP. At that point, FABP2 began rising; sCD14 began increasing 6 months later. FABP2 and sCD14 peaked 6 and 6.5 years post-FMP, respectively; subsequent levels remained stable. During the ~9-year interval of MT-related gain in gut barrier compromise markers, annual FABP2 and sCD14 increases were 2.6% (95% CI: 1.7 to 3.4%) and 0.8% (95% CI: 0.6 to 1.1%), respectively, among white women with sample-average BMI and age at FMP. FABP2 and sCD14 change rates did not differ significantly by race/ethnicity, BMI, or age at FMP. CONCLUSIONS. The MT is associated with a rise in markers of compromised gut barrier integrity, suggesting that this pathway of inflammation, previously described in animal models, occurs in humans. FUNDING. NIH U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, 5R01AR081794.

Authors

Albert Shieh, Marta Epeldegui, Arun S. Karlamangla, Rheinallt Jones, Roberto Pacifici, Gail A. Greendale