Abstract
Pregnancy is associated with adaptations of the immune response and with changes in the gutmicrobiota. We hypothesized the gut microbiota are involved in inducing (part of) the immunological adaptations during pregnancy. To test this hypothesis, we collected feces from pregnant conventional mice before and during pregnancy (days 7, 14, and 18) and microbiota were measured using 16S RNA sequencing. At day 18, mice were sacrificed and splenic (various Th cell populations) and blood immune cells (monocyte subsets) were measured by flow cytometry. The data were compared with splenic and blood immune cell populations from pregnant (day 18) germfree mice and non-pregnant conventional and germfree mice. Finally, the abundances of the individual gut bacteria in the microbiota of each conventional pregnant mouse were correlated to the parameters of the immune response of the same mouse. The microbiota of conventional mice were significantly different at the end of pregnancy (day 18) as compared with pre-pregnancy (Permanova, p < 0.05). The Shannon index was decreased and the Firmicutes/Bacteroidetes ratio was increased (Friedman followed by Dunn's test, p < 0.05), while abundances of various species (such as Allobaculum stercoricanis, Barnesiella intestihominis, and Roseburia faecis) were significantly different at day 18 compared with pre-pregnancy. In pregnant conventional mice, the percentage of Th1 cells was decreased, while the percentages of Treg cells and Th2 cells were or tended to be increased vs. non-pregnant mice. In germfree mice, only the percentage of Th1 cells was decreased in pregnant vs. non-pregnant mice, with no effect of pregnancy on Treg and Th2 cells. The percentages of monocyte subsets were affected by pregnancy similarly in conventional and germfree mice. However, the activation status of monocytes (expression of CD80 and MHCII) was affected by pregnancy mainly in conventional mice, and not in germfree mice. Correlation (Spearman's coefficient) of pregnancy affected microbiota with pregnancy affected immune cells, i.e., immune cells that were only affected differently in conventional mice and germfree mice, showed 4 clusters of bacteria and 4 clusters of immune cells, some of these clusters were correlated with each other. For instance, the microbiota in cluster 1 and 2 (in which there were various short chain fatty acid producing microbiota) are positively correlated with immune cells in cluster B, containing Treg cells and Th2 cells. Microbiota and immune cells are affected by pregnancy in mice. The different immunological adaptations to pregnancy between conventional and germfree mice, such as the increase in Treg and tendency to an increase in Th2 cells in conventional pregnant mice only, may suggest that the microbiota may play a role in adapting the maternal immune response to pregnancy.
Highlights
Pregnancy is characterized by many changes in the immune response in order to tolerate the semi-allogeneic fetus [1]
We found that Allobaculum stercoricanis, which significantly increased at day 18 vs. pre-pregnancy, explained 29 % of the variation between pre-pregnancy and day 18 of pregnancy
We showed that the presence of microbiota may be important in some of these adaptations of the maternal immune response to pregnancy, since we found different adaptations in immune cell numbers of pregnant germfree mice compared with pregnant conventional mice, i.e., the increase in the splenic percentage of Forkhead box P3+ (FoxP3)+ lymphocytes and the trend toward an increased Th2 percentage was only observed in pregnant conventional mice, not in pregnant germfree mice
Summary
Pregnancy is characterized by many changes in the immune response in order to tolerate the semi-allogeneic fetus [1]. Changes are observed in the peripheral immune response as well as locally at the maternal-fetal interface. Changes in the innate immune response can be found, such as an increased number monocytes and granulocytes during pregnancy [8, 9]. The innate immune response is further characterized by an increased activation monocytes and granulocytes [10, 11] and differences in cytokine production of these cells [9, 12]. Similar changes in the immune response have been observed in rodents [7]
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