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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. Methods: 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. Results: 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 Akkermansia in males and Clostridia vadinBB60 in females, along with an increase in the pro-inflammatory genus Anaerotruncus, 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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/nu17172812","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:25:57Z","timestamp":1756470357000},"page":"2812","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prenatal Stress Rewires the Gut\u2013Brain Axis: Long-Term, Sex-Specific Effects on Microbiota, Intestinal Barrier, and Hippocampal Inflammation"],"prefix":"10.3390","volume":"17","author":[{"given":"Floriana","family":"De Cillis","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Petrillo","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilari","family":"D\u2019Aprile","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-2988","authenticated-orcid":false,"given":"Moira","family":"Marizzoni","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2900-7794","authenticated-orcid":false,"given":"Samantha","family":"Saleri","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4892-7716","authenticated-orcid":false,"given":"Monica","family":"Mazzelli","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Zonca","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3165-0044","authenticated-orcid":false,"given":"Maria Grazia","family":"Di Benedetto","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-5060","authenticated-orcid":false,"given":"Marco Andrea","family":"Riva","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"},{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"},{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nakama, N., Usui, N., Doi, M., and Shimada, S. 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