De Cillis Floriana, Petrillo Giulia, D'Aprile Ilari, Marizzoni Moira, Saleri Samantha, Mazzelli Monica, Zonca Valentina, Di Benedetto Maria Grazia, Riva Marco Andrea, Cattaneo Annamaria
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.
Nutrients. 2025 Aug 29;17(17):2812. doi: 10.3390/nu17172812.
The gut microbiota and the gut epithelium play a central role in maintaining systemic and brain homeostasis from early life. Stressful experiences during sensitive developmental windows can disrupt this balance, increasing long-term susceptibility to psychiatric disorders. However, the mechanisms through which early-life alterations in the microbiota influence brain development and function remain poorly understood. Here, the sex-specific impact of prenatal stress (PNS) on gut integrity and microbial composition in adult offspring was explored. Thirty dams were mated and randomly assigned to PNS or control. Offspring microbiota was analysed through 16S rRNA sequencing, intestinal morphology with morphometric analyses, and tight junctions using qPCR and immunofluorescence. Exposure to PNS was associated with reduced intestinal surface area in males and shortened crypts in females. In both sexes, PNS caused a decrease in the expression of ZO-1, suggesting impaired gut barrier integrity. 16S rRNA sequencing revealed, furthermore, that PNS exposure was associated with a decrease in beneficial genera, including in males and in females, along with an increase in the pro-inflammatory genus , regardless of sex. Notably, some of these alterations were more pronounced in PNS-exposed animals that showed impaired sociability, highlighting gut microbiota inter-individual variability in the response to early-life adversity. Moreover, selected microbial changes show significant correlations with the behavioural outcomes, as well as with intestinal morphology or brain inflammatory markers. Together, these findings pinpoint the gut as a central player in stress vulnerability and highlight specific microbial signatures as promising biomarkers and therapeutic targets for stress-related disorders.
从生命早期开始，肠道微生物群和肠道上皮在维持全身和大脑的稳态中发挥着核心作用。敏感发育阶段的应激经历会破坏这种平衡，增加患精神疾病的长期易感性。然而，微生物群在生命早期的改变影响大脑发育和功能的机制仍知之甚少。在此，研究了产前应激（PNS）对成年后代肠道完整性和微生物组成的性别特异性影响。30只母鼠交配后随机分为PNS组或对照组。通过16S rRNA测序分析后代微生物群，通过形态计量分析评估肠道形态，并使用qPCR和免疫荧光检测紧密连接。暴露于PNS与雄性肠道表面积减少和雌性隐窝缩短有关。在两性中，PNS均导致ZO-1表达降低，表明肠道屏障完整性受损。此外，16S rRNA测序显示，暴露于PNS与有益菌属减少有关，包括雄性中的 和雌性中的 ，同时促炎菌属 增加，且与性别无关。值得注意的是，这些改变中的一些在社交能力受损的PNS暴露动物中更为明显，突出了肠道微生物群在对生命早期逆境反应中的个体间差异。此外，选定的微生物变化与行为结果以及肠道形态或脑部炎症标志物显示出显著相关性。总之，这些发现指出肠道是应激易感性的核心因素，并突出特定的微生物特征作为应激相关疾病有前景的生物标志物和治疗靶点。
