Abstract
Progesterone plays a protective role in preventing inflammation and preterm delivery during pregnancy. However, the mechanism involved is unknown. Microbial product translocation from a permeable mucosa is demonstrated as a driver of inflammation. To study the mechanism of the protective role of progesterone during pregnancy, we investigated the effect of physiologic concentrations of progesterone on tight junction protein occludin expression and human gut permeability in vitro and systemic microbial translocation in pregnant women in vivo. Plasma bacterial lipopolysaccharide (LPS), a representative marker of in vivo systemic microbial translocation was measured. We found that plasma LPS levels were significantly decreased during 24 to 28 weeks of gestation compared to 8 to 12 weeks of gestation. Moreover, plasma LPS levels were negatively correlated with plasma progesterone levels but positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels at 8 to 12 weeks of gestation but not at 24 to 28 weeks of gestation. Progesterone treatment increased intestinal trans-epithelial electrical resistance (TEER) in primary human colon tissues and Caco-2 cells in vitro through upregulating tight junction protein occludin expression. Furthermore, progesterone exhibited an inhibitory effect on nuclear factor kappa B (NF-κB) activation following LPS stimulation in Caco-2 cells. These results reveal a novel mechanism that progesterone may play an important role in decreasing mucosal permeability, systemic microbial translocation, and inflammation during pregnancy.
Highlights
Pregnancy is a period of considerable physiological adaptations[1]
We found there are no significant correlations between vitamin D and progesterone, LPS levels, gestation weeks and cytokines (TNF-α, IL-6 and IL-1β) (Supplemental Fig. 1B)
Higher levels of microbial translocation were observed in HIV-infected pregnant women and were associated with preterm delivery[36]
Summary
Pregnancy is a period of considerable physiological adaptations[1]. During this process, adaptations in maternal systemic immunity are presumed to be responsible for successful reproduction. The theory of general immune suppression has been widely accepted This suppression can reduce the likelihood of an antigen-specific response against the semi-allogeneic fetus during pregnancy[2,3]. The disruption of mucosal barriers results in an increase in microbial translocation and systemic immune activation[18]. Progesterone decreased NF-κB activation in response to LPS, and further decreased permeability in human primary colon tissues and Caco-2 cells through upregulating tight junction protein occludin expression in vitro. These results suggest that the increased levels of progesterone during pregnancy may contribute to decreases in mucosal permeability and microbial translocation and systemic inflammation
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