Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA.
Nat Microbiol. 2023 Mar;8(3):424-440. doi: 10.1038/s41564-023-01326-w. Epub 2023 Feb 9.
The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
宿主遗传变异如何影响肠道微生物组的分子基础在很大程度上仍是未知的。在这里，我们使用了遗传多样性的小鼠群体，并应用系统遗传学策略来识别宿主和微生物表型之间的相互作用，包括微生物功能，使用粪便宏基因组学、小肠转录物和盲肠脂质来影响微生物-宿主动态。数量性状基因座 (QTL) 作图确定了与细菌分类群变化相关的鼠类基因组区域；细菌功能包括运动性、孢子形成和脂多糖产生以及细菌和宿主衍生脂质的水平。我们发现 Akkermansia muciniphila 的丰度和盲肠鸟氨酸脂质水平存在重叠的 QTL。随后的体外和体内研究表明，A. muciniphila 是肠道中这些脂质的主要来源，提供了证据表明鸟氨酸脂质具有免疫调节作用，并确定了与这些特征共同调节的肠道转录物，包括 Atf3，它编码一种转录因子，在调节代谢和免疫方面发挥着重要作用。总的来说，这些结果表明，鸟氨酸脂质可能对 A. muciniphila-宿主相互作用很重要，并支持宿主遗传作为对肠道微生物反应的决定因素的作用。
