Temporal and regional intestinal changes in permeability, tight junction, and cytokine gene expression following ovariectomy-induced estrogen deficiency

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Abstract

Estrogen deficiency that occurs during menopause is associated with wide-ranging consequences, including effects on the gastrointestinal system. Although previous studies have implicated a role for estrogen in modulating colonic permeability and inflammatory gene expression, the kinetics of these changes following loss of estrogen and whether they are intestinal region specific are unknown. To test this, we performed sham or ovariectomy (OVX) surgery in BALB/c mice and examined permeability (in vivo and ex vivo) and gene expression changes in the duodenum, jejunum, ileum, and colon at 1, 4, and 8 weeks postsurgery. In vivo permeability, assessed by FITC-dextran gavage and subsequent measures of serum levels, indicated that OVX significantly increased whole intestinal permeability 1 week postsurgery before returning to sham levels at 4 and 8 weeks. Permeability of individual intestinal sections, measured ex vivo by Ussing chambers, revealed specific regional and temporal responses to OVX, with the most dynamic changes exhibited by the ileum. Analysis of gene expression, by qPCR and by mathematical modeling, revealed an OVX-specific effect with tight junction and inflammatory gene expression elevated and suppressed with both temporal and regional specificity. Furthermore, ileal and colonic expression of the tight junction protein occludin was found to be significantly correlated with expression of TNFα and IL-1β Together, our studies reveal previously unappreciated effects of estrogen deficiency in specific intestinal segments and further demonstrate temporal links between estrogen deficiency, inflammatory genes, and intestinal permeability.

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