Gustafson Kevin L, Busi Susheel Bhanu, McAdams Zachary L, McCorkle Rachael E, Khodakivskyi Pavlo, Bivens Nathan J, Davis Daniel J, Raju Murugesan, Coghill Lyndon M, Goun Elena A, Amos-Landgraf James, Franklin Craig L, Wilmes Paul, Cortese Rene, Ericsson Aaron C
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65201, USA.
UK Centre for Ecology and Hydrology, Wallingford, Oxfordshire, OX10 8BB, UK.
bioRxiv. 2024 Oct 22:2024.04.12.589237. doi: 10.1101/2024.04.12.589237.
The microorganisms colonizing the gastrointestinal tract of animals, collectively referred to as the gut microbiome, affect numerous host behaviors dependent on the central nervous system (CNS). Studies comparing germ-free mice to normally colonized mice have demonstrated influences of the microbiome on anxiety-related behaviors, voluntary activity, and gene expression in the CNS. Additionally, there is epidemiologic evidence supporting an intergenerational influence of the maternal microbiome on neurodevelopment of offspring and behavior later in life. There is limited experimental evidence however directly linking the maternal microbiome to long-term neurodevelopmental outcomes, or knowledge regarding mechanisms responsible for such effects.
Here we show that that the maternal microbiome has a dominant influence on several offspring phenotypes including anxiety-related behavior, voluntary activity, and body weight. Adverse outcomes in offspring were associated with features of the maternal microbiome including bile salt hydrolase activity gene expression (), abundance of certain bile acids, and hepatic expression of . In cross-foster experiments, offspring resembled their birth dam phenotypically, despite faithful colonization in the postnatal period with the surrogate dam microbiome. Genome-wide methylation analysis of hippocampal DNA identified microbiome-associated differences in methylation of 196 loci in total, 176 of which show conserved profiles between mother and offspring. Further, single-cell transcriptional analysis revealed accompanying differences in expression of several differentially methylated genes within certain hippocampal cell clusters, and vascular expression of genes associated with bile acid transport. Inferred cell-to-cell communication in the hippocampus based on coordinated ligand-receptor expression revealed differences in expression of neuropeptides associated with satiety.
Collectively, these data provide proof-of-principle that the maternal gut microbiome has a dominant influence on the neurodevelopment underlying certain offspring behaviors and activities, and selectively affects genome methylation and gene expression in the offspring CNS in conjunction with that neurodevelopment.
定殖于动物胃肠道的微生物统称为肠道微生物群，会影响许多依赖中枢神经系统（CNS）的宿主行为。将无菌小鼠与正常定殖小鼠进行比较的研究表明，微生物群对焦虑相关行为、自主活动以及CNS中的基因表达有影响。此外，有流行病学证据支持母体微生物群对后代神经发育和后期行为的代际影响。然而，直接将母体微生物群与长期神经发育结果联系起来的实验证据有限，关于此类影响的作用机制的知识也很有限。
我们在此表明，母体微生物群对几种后代表型具有主要影响，包括焦虑相关行为、自主活动和体重。后代的不良结果与母体微生物群的特征相关，包括胆汁盐水解酶活性基因表达、某些胆汁酸的丰度以及肝脏表达。在交叉寄养实验中，尽管后代在出生后忠实地定殖了代孕母鼠的微生物群，但在表型上与它们的生母相似。对海马DNA进行全基因组甲基化分析发现，总共196个位点的甲基化存在与微生物群相关的差异，其中176个位点在母亲和后代之间显示出保守的图谱。此外，单细胞转录分析揭示了某些海马细胞簇内几个差异甲基化基因的表达存在伴随差异，以及与胆汁酸转运相关的基因的血管表达。基于协调的配体 - 受体表达推断海马中的细胞间通讯，发现与饱腹感相关的神经肽表达存在差异。
总体而言，这些数据提供了原理证明，即母体肠道微生物群对某些后代行为和活动背后的神经发育具有主要影响，并与该神经发育一起选择性地影响后代CNS中的基因组甲基化和基因表达。
