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

怀孕作为肠道微生物群的扰动原理：对肠道炎症和炎症相关癌症的影响

• 批准号: 436179961
• 负责人: Professor Dr. Philip Caspar Rosenstiel, Ph.D.
• 金额: --
• 依托单位: Institut für Klinische Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/436179961?language=en
• 关键词: Pregnancy; perturbation; principle; intestinal; microbiota

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.

妊娠是一种重要的短暂生理状态，已被证明会导致肠道微生物群的生态失调改变，这可能会在妊娠晚期发挥局部促炎作用。这可能有助于代谢改变，如胰岛素抵抗，这反过来可能有利于胎儿发育。母体宿主如何控制微生物组中与妊娠相关的变化的机制知之甚少。肠道菌群失调和缺乏恢复能力也是人类IBD的既定特征，通常表现在年轻个体中，因此最常影响女性的生殖寿命。几项研究表明，妊娠对个体疾病进程有复杂的影响，例如，与未妊娠的溃疡性结肠炎（UC）女性相比，妊娠女性更容易在妊娠期间和产后复发。我们在此假设，微生物改变和/或宿主对微生物群变化的生理反应可能有助于疾病进程的调节，并且理解怀孕期间和之后改变的宿主-微生物相互作用可能有助于确定针对肠道微生物组作为靶标的新治疗原则。我们在此提出了一个基本问题，即在怀孕期间如何控制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，环境依赖性信号作用于肠上皮细胞的功能，这些细胞专门选择在怀孕期间观察到的微生物变化。(i)我们将在功能上将这些变化与WT小鼠中对肠道炎症（例如急性vs.慢性DSS结肠炎、恶唑酮结肠炎和TNFDeltaARE遗传模型）以及炎症诱导的（AOM/DSS）癌症的易感性联系起来。(ii)在第二步中，我们将使用携带IBD易感基因（NOD 2，Atg 16 L1）的肠上皮细胞（IEC）特异性敲除的小鼠来研究这些基因对妊娠相关宿主和微生物生态失调和再生过程的影响。(iii)将招募人IBD -妊娠队列并进行分析，以验证小鼠模型结果。将详细的患者数据（炎症临床参数、疾病活动度、微量营养素血清水平和妊娠/妊娠相关信息）与获得的微生物数据相关联，并将冷冻粪便标本用于无菌转移实验，以确定观察到的效应是否具有传染性。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治疗肠道炎症性疾病的目标。此外，从未来的角度来看，对怀孕期间和怀孕后粘膜促炎性张力和微生物群的改变的深入了解可能有助于改善女性IBD患者的管理。