PDF(Pubmed)
Abstract：
The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory \'gut-germline axis\' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.
摘要：
肠道微生物群在宿主-环境相互作用的界面上起作用，以影响人类的稳态和代谢网络1-4。因此，使肠道微生物生态系统失衡的环境因素可以影响整个体细胞组织的生理和疾病相关反应5-9。然而,肠道微生物组对种系以及由此产生的F1后代的系统性影响尚未被发现10。在这里，我们表明肠道微生物群是父系受孕前环境和小鼠代际健康之间的关键接口。对未来父亲的肠道微生物群的扰动增加了其后代出现低出生体重的可能性，严重的生长限制和过早死亡。疾病风险的传播是通过种系发生的，并且是由普遍的肠道微生物群扰动引起的。包括不可吸收的抗生素或渗透性泻药，但是通过在受孕前恢复父系微生物群来拯救。这种效应与男性生殖系统中诱导的菌群失调的动态反应有关，包括瘦素信号受损，改变睾丸代谢物谱并重新映射精子中的小RNA有效载荷。因此,营养不良的父亲会引发子宫内胎盘功能不全的风险升高，揭示了哺乳动物代际效应的胎盘起源。我们的研究定义了男性的肠道-种线轴，它对环境暴露敏感，并通过影响胎盘功能来规划后代的健康。
