Huda M Nazmul, Kelly Emer, Barron Keri, Xue Jing, Valdar William, Tarantino Lisa M, Schoenrock Sarah, Ideraabdullah Folami Y, Bennett Brian J
Department of Nutrition, University of California Davis, Davis, CA, USA.
Obesity and Metabolism Research Unit, Western Human Nutrition Research Center, ARS, USDA, Davis, CA, 95616, USA.
Microbiome. 2025 Jun 16;13(1):143. doi: 10.1186/s40168-025-02130-w.
Early-life exposure to environmental factors can have long-lasting impacts on offspring health into adulthood and therefore is an emerging public health concern. In particular, the impact of maternal environmental exposures such as diet and antibiotic use on the establishment of the offspring gut microbiome has been recently highlighted as a potential link to disease risk. However, the long-term effects are poorly understood. Moreover, interindividual host genetic differences have also been implicated in modulating the gut microbiome, suggesting that these differences may modulate susceptibility to environmentally induced dysbiosis and exacerbate related health outcomes. Our understanding of how the developmental environment and genetics interact to modulate offspring long-term gut microbiota and health is still limited.
In this study, we investigated the effects of early exposure to known or putative dietary insults on the microbiome (antibiotic exposure, protein deficiency, and vitamin D deficiency) in a novel population of mice. Dams were maintained on purified AIN93G antibiotic-containing (AC), low-protein (LP), low-vitamin D (LVD), or mouse control (CON) diets from 5 weeks prior to pregnancy until the end of lactation. After weaning, mice were transferred to new cages and fed a standardized chow diet. The parent-of-origin (PO) effect was determined via F1 offspring from reciprocal crosses of recombinant inbred intercross (RIX) of Collaborative Cross (CC) mice, where all F1 offspring within a reciprocal pair were genetically identical except for the X- and Y-chromosomes and mitochondrial genomes. We assayed offspring bodyweight and the gut bacterial microbiota via 16S rRNA gene sequencing at 8 weeks of age.
Our study revealed that early developmental exposure to antibiotics, protein deficiency, and vitamin D deficiency had long-lasting effects on offspring bodyweight and gut microbial diversity and composition, depending on the genetic background. Several bacterial genera and ASVs, including Bacteroides, Muribaculaceae, Akkermansia, and Bifidobacterium, are influenced by developmental insults. We also observed a significant effect of PO on offspring gut microbiota and growth. For example, the offspring of CC011xCC001 mice had increased bodyweight, microbial diversity indices, and several differential bacterial abundances, including those of Faecalibaculum, compared with those of the corresponding reciprocal cross CC001xCC011.
Our results show that maternal exposure to nutritional deficiencies and antibiotics during gestation and lactation has a lasting impact on offspring gut microbiota composition. The specific responses to a diet or antibiotic can vary among F1 strains and may be driven by maternal genetics. Video Abstract.
生命早期暴露于环境因素会对后代成年后的健康产生长期影响，因此这是一个新出现的公共卫生问题。特别是，母体环境暴露，如饮食和抗生素使用，对后代肠道微生物群建立的影响最近被强调为与疾病风险的潜在联系。然而，其长期影响仍知之甚少。此外，个体宿主基因差异也与调节肠道微生物群有关，这表明这些差异可能调节对环境诱导的生态失调的易感性，并加剧相关的健康结果。我们对发育环境和基因如何相互作用以调节后代长期肠道微生物群和健康的理解仍然有限。
在本研究中，我们在一个新的小鼠群体中研究了早期暴露于已知或假定的饮食损伤（抗生素暴露、蛋白质缺乏和维生素D缺乏）对微生物群的影响。从怀孕前5周直到哺乳期结束，将母鼠维持在纯化的含AIN93G抗生素（AC）、低蛋白（LP）、低维生素D（LVD）或小鼠对照（CON）饮食中。断奶后，将小鼠转移到新笼子中，并喂食标准化的普通饲料。通过协作杂交（CC）小鼠的重组近交杂交（RIX）的正反交产生的F1后代来确定亲本来源（PO）效应，在正反交对中的所有F1后代除了X和Y染色体以及线粒体基因组外，基因都是相同的。我们在8周龄时通过16S rRNA基因测序测定后代体重和肠道细菌微生物群。
我们的研究表明，早期发育暴露于抗生素、蛋白质缺乏和维生素D缺乏对后代体重以及肠道微生物多样性和组成具有长期影响，这取决于基因背景。包括拟杆菌属、毛螺菌科、阿克曼氏菌属和双歧杆菌属在内的几个细菌属和ASV受到发育损伤的影响。我们还观察到PO对后代肠道微生物群和生长有显著影响。例如，与相应的反交CC001xCC011相比，CC011xCC001小鼠的后代体重增加、微生物多样性指数增加，并且有几种不同的细菌丰度增加，包括粪便杆菌属。
我们的结果表明，母体在妊娠和哺乳期暴露于营养缺乏和抗生素会对后代肠道微生物群组成产生持久影响。对饮食或抗生素的具体反应在F1品系之间可能有所不同，并且可能由母体基因驱动。视频摘要。
