Singh Salma, Abu Yaa, Antoine Danielle, Gomez Daniel, Tao Junyi, Truitt Bridget, Roy Sabita
Department of Surgery, School of Medicine, University of Miami Miller, Miami, USA.
Department of Neuroscience, School of Medicine, University of Miami Miller, Miami, USA.
Gut Microbes. 2025 Dec;17(1):2464942. doi: 10.1080/19490976.2025.2464942. Epub 2025 Feb 14.
The gut microbiome has emerged as a promising target for modulating adverse effects of opioid exposure due to its significant role in health and disease. Opioid use disorder (OUD) has become increasingly prevalent, specifically in women of reproductive age, contributing to an increased incidence of offspring exposed to opioids in utero. Recent studies have shown that prenatal opioid exposure (POE) is associated with notable changes to the maternal gut microbiome, with subsequent implications for the offspring's microbiome and other adverse outcomes. However, the role of the gut microbiome in mediating sex-based differences in pain sensitivity has not yet been investigated. In this study, both male and female C57BL/6 offspring were used to determine sex-based differences in nociception and gut microbial composition as a result of POE. Our data reveals significant sex-based differences in offspring prenatally exposed to opioids. The gut microbiome of opioid-exposed females showed an enrichment of commensal bacteria including compared to opioid-exposed males. Additionally, POE females demonstrated decreased nociceptive sensitivity, while males demonstrated increased nociceptive sensitivity. RNA sequencing of the prefrontal cortex showed sex-based differences in several canonical pathways, including an increase in the opioid signaling pathway of opioid-exposed females, which was not observed in males. Microbiome modification via maternal probiotic supplementation attenuated sex-based differences throughout the early stages of life. Together, our study provides further insight on sex-based differences arising from POE and highlights the pivotal role of the gut microbiome as a modifiable target for mitigating its negative effects.
由于肠道微生物群在健康和疾病中发挥着重要作用，它已成为调节阿片类药物暴露不良反应的一个有前景的靶点。阿片类药物使用障碍（OUD）日益普遍，尤其是在育龄女性中，导致子宫内接触阿片类药物的后代发病率增加。最近的研究表明，产前阿片类药物暴露（POE）与母体肠道微生物群的显著变化有关，进而对后代的微生物群和其他不良后果产生影响。然而，肠道微生物群在介导疼痛敏感性的性别差异方面的作用尚未得到研究。在本研究中，使用雄性和雌性C57BL/6后代来确定POE导致的伤害感受和肠道微生物组成的性别差异。我们的数据揭示了产前暴露于阿片类药物的后代存在显著的性别差异。与暴露于阿片类药物的雄性相比，暴露于阿片类药物的雌性的肠道微生物群显示共生细菌富集。此外，POE雌性表现出伤害感受敏感性降低，而雄性表现出伤害感受敏感性增加。前额叶皮层的RNA测序显示在几个经典通路中存在性别差异，包括暴露于阿片类药物的雌性的阿片类信号通路增加，而在雄性中未观察到。通过母体补充益生菌进行微生物群修饰可在生命早期阶段减弱性别差异。总之，我们的研究进一步深入了解了POE引起的性别差异，并强调了肠道微生物群作为减轻其负面影响的可调节靶点的关键作用。
