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作者：SCI天天读
SCI
13 May 2024
Paternal microbiome perturbations impact offspring fitness
（IF: NATURE, 64.8）
Argaw-Denboba A, Schmidt TSB, Di Giacomo M, Ranjan B, Devendran S, Mastrorilli E, Lloyd CT, Pugliese D, Paribeni V, Dabin J, Pisaniello A, Espinola S, Crevenna A, Ghosh S, Humphreys N, Boruc O, Sarkies P, Zimmermann M, Bork P, Hackett JA. Paternal microbiome perturbations impact offspring fitness. Nature. 2024 May 1.
Correspondence: jamie.hackett@embl.it
The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues. 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.
肠道微生物群在宿主-环境相互作用的界面上发挥作用，影响着人类的体内平衡和代谢网络。因此，肠道微生物生态系统失衡的环境因素可以影响体细胞组织的生理和疾病相关反应。然而，肠道微生物群对生殖系的系统性影响，以及对由此产生的对第一代后代的影响尚未被探究。在这里，我们证明了肠道微生物群是小鼠父系孕前环境和代际健康之间的关键界面。准父亲肠道微生物群的扰动会增加其后代出现低出生体重、严重生长受限和过早死亡的可能性。疾病风险的传播是通过生殖系发生的，并且是由肠道微生物群的广泛扰动引起的，包括不可吸收的抗生素或渗透性泻药，但在受孕前恢复父系微生物群可以挽救。这种效应与男性生殖系统对诱导的失调的动态反应相关，包括瘦素信号传导受损、睾丸代谢产物谱的改变以及精子中小RNA有效载荷的重新映射。因此，失调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调节“肠道-生殖系轴”，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状况。
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