Pregnancy as a perturbation principle of the intestinal microbiota: impact on intestinal inflammation and inflammation-associated cancer

妊娠是一种重要的暂时性生理状态，已被证明会引起肠道微生物区系的非生物变化，这可能会在妊娠晚期发挥局部促炎作用。这可能会导致代谢变化，如胰岛素抵抗，这反过来可能有利于胎儿的发育。母体宿主如何控制微生物群中与怀孕相关的变化的机制还知之甚少。肠道微生物区系失调和缺乏适应能力也是人类IBD的既定特征，通常表现在较年轻的个体中，因此最常影响女性的是其生殖寿命。一些研究表明，怀孕对个体病程的影响是复杂的，例如，与未怀孕的UC相比，患有溃疡性结肠炎(UC)的孕妇在怀孕期间和产后都更有可能复发。我们假设微生物群的改变和/或宿主对微生物区系变化的生理反应可能有助于疾病进程的调节，了解宿主-微生物在妊娠期间和之后的相互作用可能有助于确定以肠道微生物群为靶点的新的治疗原则。因此，我们在这里提出一个根本的问题，即如何控制妊娠期间管腔和粘膜相关微生物群的组成和代谢特性的变化。我们假设，上下文相关的信号作用于肠上皮细胞的功能，肠上皮细胞专门为怀孕期间观察到的微生物变化而选择。(I)我们将在功能上将这些变化与WT小鼠对肠道炎症(例如急性和慢性DSS结肠炎、恶唑酮结肠炎和TNFdeltaARE遗传模型)以及炎症诱导(AOM/DSS)癌症的易感性联系起来。(Ii)在第二步中，我们将利用携带肠上皮细胞(IEC)特异性IBD易感基因(NOD2、Atg16L1)敲除的小鼠来研究这些基因对妊娠相关宿主和微生物的生物失调和再生物过程的影响。(Iii)将招募和分析人类IBD-妊娠队列，以验证小鼠模型的研究结果。详细的患者数据(炎症临床参数、疾病活动性、血清微量营养素水平和妊娠/妊娠相关信息)将与获得的微生物数据相关联，冷冻粪便样本将用于灵芝转移实验，以确定观察到的影响是否可传播。我们假设，了解整个怀孕期间生态位的变化可能会引导我们找到治疗肠道炎症性疾病的靶点。此外，对怀孕期间和怀孕后促炎基调和粘膜微生物区系的修改的洞察可能有助于改善女性IBD患者的管理，作为未来的前景。

Pregnancy is an important transient physiological state that has been shown to cause dysbiotic alterations in the intestinal microbiota, which may exert local pro-inflammatory effects in the third trimester. This may contribute to metabolic alterations such as insulin resistance, which in turn might be favourable for fetal development. The mechanism how a maternal host is in control of pregnancy-associated changes in the microbiome is only poorly understood. Dysbiotic gut microbiota and lack of their resilience capacity are also established features of human IBD that often manifests in younger individuals, and as such affects females most often in their reproductive span of life. Several studies have shown a complex impact of pregnancies on the individual disease course, e.g. pregnant women with ulcerative colitis (UC) as compared to nonpregnant UC women are more likely to relapse both during pregnancy and postpartum. We here hypothesize that the microbial alterations and/or the host physiological response to microbiota shifts may contribute to the modulation of disease course and that understanding altered host-microbe interplay during and after pregnancy may help to identify novel therapeutic principles aiming at the intestinal microbiome as a target.Thus, we here ask the fundamental question how changes of composition and metabolic properties of luminal and mucosa-associated microbiota are controlled during pregnancy. We hypothesize that context-dependent signals act on the function of intestinal epithelial cells, which specifically select for the microbe shifts observed in pregnancy. (i) We will functionally relate these shifts to susceptibility to intestinal inflammation (e.g. acute vs. chronic DSS colitis, oxazolone colitis and the TNFdeltaARE genetic model) as well as inflammation-induced (AOM/DSS) cancer in WT mice. (ii) In a second step, we will use mice carrying intestinal epithelial cell (IEC)-specific knockouts of IBD susceptibility genes (NOD2, Atg16L1) to study the effects of such genes on pregnancy-related host and microbial dysbiosis and rebiosis processes. (iii) A human IBD – pregnancy cohort will be recruited and analyzed as validation of mouse model findings. Detailed patient data (inflammatory clinical parameters, disease activity, serum levels of micronutrients and pregnancy/gestation related information) will be correlated to acquired microbial data and frozen stool specimen will be used in gnotobiotic transfer experiments in order to identify whether the observed effects are transmissible. We hypothesize that understanding the alteration of ecological niches throughout pregnancy might guide us to therapeutically accessible targets for intestinal inflammatory diseases. Furthermore, insights into the modification of the pro-inflammatory tone and microbiota of the mucosa during and after pregnancy may help to improve the management of female IBD patients as a future perspective.