Sisk-Hackworth Laura, Akhavan Shayan R, Krutkin Dennis D, Kelley Scott T, Thackray Varykina G
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
Department of Biology, San Diego State University, San Diego, CA, USA.
bioRxiv. 2024 Jul 2:2024.07.01.601610. doi: 10.1101/2024.07.01.601610.
The gut microbiome plays a key role in human health and gut dysbiosis is linked to many sex-specific diseases including autoimmune, metabolic, and neurological disorders. Activation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty leads to sexual maturation and development of sex differences through the action of gonadal sex steroids. While the gut microbiome also undergoes sex differentiation, the mechanisms involved remain poorly understood. Using a genetic hypogonadal (hpg) mouse model, we sampled the fecal microbiome of male and female wild-type and hpg mutant mice before and after puberty to determine how microbial taxonomy and function are influenced by age, sex, and the HPG axis. We showed that HPG axis activation during puberty is required for sexual maturation of the gut microbiota composition, community structure, and metabolic functions. We also demonstrated that some sex differences in taxonomic composition and amine metabolism developed independently of the HPG axis, indicating that sex chromosomes are sufficient for certain sex differences in the gut microbiome. In addition, we showed that age, independent of HPG axis activation, led to some aspects of pubertal maturation of the gut microbiota community composition and putative functions. These results have implications for microbiome-based treatments, indicating that sex, hormonal status, and age should be considered when designing microbiome-based therapeutics.
肠道微生物群在人类健康中起着关键作用，肠道生态失调与许多性别特异性疾病有关，包括自身免疫性疾病、代谢性疾病和神经疾病。青春期下丘脑-垂体-性腺（HPG）轴的激活通过性腺性类固醇的作用导致性成熟和性别差异的发展。虽然肠道微生物群也会发生性别分化，但其涉及的机制仍知之甚少。我们使用基因性腺功能减退（hpg）小鼠模型，在青春期前后对雄性和雌性野生型及hpg突变小鼠的粪便微生物群进行采样，以确定微生物分类学和功能如何受到年龄、性别和HPG轴的影响。我们发现，青春期期间HPG轴的激活是肠道微生物群组成、群落结构和代谢功能性成熟所必需的。我们还证明，分类组成和胺代谢中的一些性别差异独立于HPG轴而产生，这表明性染色体足以导致肠道微生物群中某些性别差异。此外，我们表明，年龄独立于HPG轴的激活，会导致肠道微生物群落组成和假定功能的青春期成熟的某些方面。这些结果对基于微生物群的治疗具有启示意义，表明在设计基于微生物群的治疗方法时应考虑性别、激素状态和年龄。
