Zhang Qijun, Hutchison Evan R, Pan Calvin, Warren Matthew F, Keller Mark P, Attie Alan D, Lusis Aldons J, Rey Federico E
Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
bioRxiv. 2024 Mar 3:2024.02.28.582610. doi: 10.1101/2024.02.28.582610.
The molecular basis for how host genetic variation impacts gut microbial community and bacterial metabolic niches remain largely unknown. We leveraged 90 inbred hyperlipidemic mouse strains from the Hybrid Mouse Diversity Panel (HMDP), previously studied for a variety of cardio-metabolic traits. Metagenomic analysis of cecal DNA followed by genome-wide association analysis identified genomic loci that were associated with microbial enterotypes in the gut. Among these we detected a genetic locus surrounding multiple amylase genes that was associated with abundances of Firmicutes ( family) and Bacteroidetes ( family) taxa encoding distinct starch and sugar metabolism functions. We also found that lower amylase gene number in the mouse genome was associated with higher gut levels. Previous work suggests that modulation of host amylase activity impacts the availability of carbohydrates to the host and potentially to gut bacteria. The genetic variants described above were associated with distinct gut microbial communities (enterotypes) with different predicted metabolic capacities for carbohydrate degradation. Mendelian randomization analysis revealed host phenotypes, including liver fibrosis and plasma HDL-cholesterol levels, that were associated with gut microbiome enterotypes. This work reveals novel relationships between host genetic variation, gut microbial enterotypes and host physiology/disease phenotypes in mice.
宿主基因变异如何影响肠道微生物群落和细菌代谢生态位的分子基础在很大程度上仍然未知。我们利用了来自杂交小鼠多样性面板（HMDP）的90个近交高脂血症小鼠品系，这些品系之前已针对多种心血管代谢性状进行过研究。对盲肠DNA进行宏基因组分析，随后进行全基因组关联分析，确定了与肠道微生物肠型相关的基因组位点。在这些位点中，我们检测到围绕多个淀粉酶基因的一个遗传位点，该位点与编码不同淀粉和糖代谢功能的厚壁菌门（科）和拟杆菌门（科）分类群的丰度相关。我们还发现，小鼠基因组中淀粉酶基因数量较少与较高的肠道水平相关。先前的研究表明，宿主淀粉酶活性的调节会影响宿主以及潜在地对肠道细菌的碳水化合物可用性。上述遗传变异与具有不同碳水化合物降解预测代谢能力的不同肠道微生物群落（肠型）相关。孟德尔随机化分析揭示了与肠道微生物群落肠型相关的宿主表型，包括肝纤维化和血浆高密度脂蛋白胆固醇水平。这项工作揭示了小鼠宿主基因变异、肠道微生物肠型与宿主生理/疾病表型之间的新关系。
