Bethany A. Masson , Pamudika Kiridena , Da Lu , Elizabeth A. Kleeman , Sonali N. Reisinger , Wendy Qin , William J. Davies , Rikeish R. Muralitharan , Hamdi A. Jama , Simona Antonacci , Francine Z. Marques , Carolina Gubert , Anthony J. Hannan
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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. 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引用次数: 0
摘要
受孕前的父方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)被认为是非遗传的潜在促进因素。母体肠道微生物群对后代发育的重要影响已被证实,但父体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还不为人所知。肠道微生物群对免疫有重大影响,因此我们假设它可能与父系免疫激活调节小鼠表观遗传有关。因此,我们通过饮用水给雄性 C57BL/6J 小鼠(F0)口服非吸收性抗生素,以大量消耗其肠道微生物群。在服用抗生素(肠道微生物群耗竭)四周后,F0 雄性小鼠再与天真雌性小鼠交配。微生物群耗竭的雄性小鼠的 F1 后代体重减轻,肠道形态也发生了改变(结肠长度缩短)。F1雌性小鼠的情感行为(包括焦虑和抑郁样行为)发生了显著变化,这表明它们的发育发生了改变。对F0小鼠精子中的小非编码RNA分析表明,肠道微生物组的耗竭与8种不同的PIWI-interacting RNA(πRNA)的差异表达有关,每种RNA都有可能调节多个下游基因靶标的表达,从而影响表观遗传和后代发育。这项研究表明,肠道-生殖系轴影响精子小 RNA 图谱和后代生理,并对后代的情感和/或应对行为产生具体影响。这些发现可能会对其他具有相似肠道微生物群、代际表观遗传学和发育生物学的动物物种(包括人类)产生更广泛的影响。
Depletion of the paternal gut microbiome alters sperm small RNAs and impacts offspring physiology and behavior in mice
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.
期刊介绍:
Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals.
As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.