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 TNF α 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.
Highlights
Natural menopause, the permanent cessation of the menstrual cycle following the loss of ovarian follicular activity, is a process that typically occurs in women between 47 and 52 years of age (Davis et al 2015)
Loss of estrogen is associated with intestinal changes that include decreased calcium absorption and changes in intestinal permeability which suggest that estrogen deficiency has direct effects on gastrointestinal homeostasis (Heaney et al 1989; Li et al 2016)
Transepithelial conductance (Gt) was recorded as a measure of tissue integrity, no significant change in Gt was observed in any of the segments during the time period of permeability measurements (Fig. 1C). These data suggest that changes in ileal permeability early after OVX surgery is likely responsible for the observed increase in in vivo overall gut permeability in the estrogen-deficient mice. These results demonstrate that the overall changes in intestinal permeability are time-dependent following estrogen deficiency, they are dependent on specific intestinal segments
Summary
The permanent cessation of the menstrual cycle following the loss of ovarian follicular activity, is a process that typically occurs in women between 47 and 52 years of age (Davis et al 2015). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Loss of estrogen is associated with intestinal changes that include decreased calcium absorption and changes in intestinal permeability which suggest that estrogen deficiency has direct effects on gastrointestinal homeostasis (Heaney et al 1989; Li et al 2016)
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