Masson Bethany A, Kiridena Pamudika, Lu Da, Kleeman Elizabeth A, Reisinger Sonali N, Qin Wendy, Davies William J, Muralitharan Rikeish R, Jama Hamdi A, Antonacci Simona, Marques Francine Z, Gubert Carolina, Hannan Anthony J
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
Brain Behav Immun. 2025 Jan;123:290-305. doi: 10.1016/j.bbi.2024.09.020. Epub 2024 Sep 16.
The paternal environment prior to conception has been demonstrated to influence offspring physiology and behavior, with the sperm epigenome (including noncoding RNAs) proposed as a potential facilitator of non-genetic inheritance. Whilst the maternal gut microbiome has been established as an important influence on offspring development, the impact of the paternal gut microbiome on offspring development, health and behavior is largely unknown. Gut microbiota have major influences on immunity, and thus we hypothesized that they may be relevant to paternal immune activation (PIA) modulating epigenetic inheritance in mice. Therefore, male C57BL/6J mice (F0) were orally administered non-absorbable antibiotics via drinking water in order to substantially deplete their gut microbiome. Four weeks after administration of the antibiotics (gut microbiome depletion), F0 male mice were then mated with naïve female mice. The F1 offspring of the microbiome-depleted males had reduced body weight as well as altered gut morphology (shortened colon length). F1 females showed significant alterations in affective behaviors, including measures of anxiety and depressive-like behaviors, indicating altered development. Analysis of small noncoding RNAs in the sperm of F0 mice revealed that gut microbiome depletion is associated with differential expression of 8 different PIWI-interacting RNAs (piRNAs), each of which has the potential to modulate the expression of multiple downstream gene targets, and thus influence epigenetic inheritance and offspring development. This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors. These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans.
受孕前的父本环境已被证明会影响后代的生理和行为，精子表观基因组（包括非编码RNA）被认为是非遗传继承的潜在促进因素。虽然母本肠道微生物群已被确认为对后代发育有重要影响，但父本肠道微生物群对后代发育、健康和行为的影响在很大程度上尚不清楚。肠道微生物群对免疫有重大影响，因此我们推测它们可能与父本免疫激活（PIA）调节小鼠的表观遗传继承有关。因此，通过饮用水给雄性C57BL/6J小鼠（F0）口服不可吸收的抗生素，以大幅减少其肠道微生物群。在给予抗生素（肠道微生物群耗竭）四周后，F0雄性小鼠与未接触过的雌性小鼠交配。肠道微生物群耗竭的雄性小鼠的F1后代体重减轻，肠道形态也发生改变（结肠长度缩短）。F1雌性小鼠在情感行为方面表现出显著变化，包括焦虑和抑郁样行为的测量指标，表明发育发生了改变。对F0小鼠精子中的小非编码RNA进行分析发现，肠道微生物群耗竭与8种不同的PIWI相互作用RNA（piRNA）的差异表达有关，每种piRNA都有可能调节多个下游基因靶点的表达，从而影响表观遗传继承和后代发育。这项研究表明，肠道-生殖系轴影响精子小RNA谱和后代生理，对后代的情感和/或应对行为有特定影响。这些发现可能对具有类似肠道微生物群、代际表观遗传学和发育生物学的其他动物物种（包括人类）有更广泛的意义。
