Functional analysis of gut microbiome-host interactions during the postnatal window of opportunity by a multiscale sequencing approach

通过多尺度测序方法对出生后机会窗口期间肠道微生物组与宿主相互作用的功能分析

• 批准号: 418004173
• 负责人: Professor Dr. Thomas Clavel
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418004173?language=en
• 关键词: Functional; analysis; gut; microbiome; host

Microbial colonization of the neonate gut is a dynamic process that contributes to the establishment of intestinal immunity and tolerance. Failure to reach a homeostatic host-microbial crosstalk during this time window influences the susceptibility to inflammatory, autoimmune, and metabolic diseases throughout life. Although this critical role of the postnatal period has been recognized, knowledge about underlying mechanisms is still scant. Here we join our expertise in microbiome research, phage biology and genomics, intestinal epithelium biology in neonates, and mucosal immunology to determine microbial colonization dynamics in the neonatal gut and the impact on innate and adaptive immune imprinting in mice. We propose a functional approach where colonization patterns and causal effects on the host are studied in gnotobiotic mice reconstituted with defined minimal consortia of cultured bacterial species. Particular emphasis is on characterizing (i) differential features of the neonatal and adult microbiota, and (ii) the effect of flagellated bacteria as part of the microbiota providing a dominant immunogenic antigen and innate immune stimulus. Lytic flagellotropic phages will be studied and use for precise manipulation of bacterial communities. In a multiscale sequencing approach including meta-transcriptomic and phageome analysis of microbiome colonization dynamics, single-cell (sc) RNAseq for tissue maturation and differentiation of intestinal epithelial cell (IEC) lineages, and lymphocyte receptor sequencing, we will provide novel insights into the functional importance of microbial colonization in early life.

新生儿肠道的微生物定植是一个动态过程，有助于建立肠道免疫和耐受性。在此时间窗口内未能达到宿主-微生物串扰的稳态会影响一生中对炎症、自身免疫和代谢疾病的易感性。尽管产后时期的这一关键作用已得到认可，但有关潜在机制的知识仍然很少。在这里，我们结合微生物组研究、噬菌体生物学和基因组学、新生儿肠上皮生物学和粘膜免疫学方面的专业知识，确定新生儿肠道中的微生物定植动态以及对小鼠先天性和适应性免疫印记的影响。我们提出了一种功能性方法，在用确定的最小培养细菌菌种重组的限生小鼠中研究定植模式和对宿主的因果影响。特别强调的是（i）新生儿和成人微生物群的差异特征，以及（ii）作为微生物群一部分的有鞭毛细菌的作用，提供主要的免疫原性抗原和先天免疫刺激。将研究裂解鞭毛噬菌体并将其用于细菌群落的精确操作。在多尺度测序方法中，包括微生物定植动态的元转录组学和噬菌体分析、用于组织成熟和肠上皮细胞 (IEC) 谱系分化的单细胞 (sc) RNAseq 以及淋巴细胞受体测序，我们将为微生物定植在生命早期的功能重要性提供新的见解。