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Herein, we explored whether prebiotics administration during chronic stress prevented depression\u2010like and anxiety\u2010like behavior in a sex\u2010specific manner and the mechanism of behavioral differences caused by sex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Female and male C57 BL\/J mice on normal diet were supplemented with or without a combination of fructo\u2010oligosaccharides (FOS) and galacto\u2010oligosaccharides (GOS) during 3\u2010 and 4\u2010week chronic restraint stress (CRS) treatment, respectively. C57 BL\/J mice on normal diet without CRS were used as controls. Behavior consequences, gut microbiota, dysfunction of gut and brain\u2013blood barriers, and inflammatory profiles were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the 3rd week, FOS\u2009+\u2009GOS administration attenuated stress\u2010induced anxiety\u2010like behavior in female, but not in male mice, and the anxiolytic effects in males were observed until the 4th week. However, protective effects of prebiotics on CRS\u2010induced depression were not observed. Changes in the gene expression of tight junction proteins in the distal colon and hippocampus, and decreased number of colon goblet cells following CRS were restored by prebiotics only in females. In both female and male mice, prebiotics alleviated stress\u2010induced BBB dysfunction and elevation in pro\u2010inflammatory cytokines levels, and modulated gut microbiota caused by stress. Furthermore, correlation analysis revealed that anxiety\u2010like behaviors were significantly correlated with levels of pro\u2010inflammatory cytokines and gene expression of tight junction proteins in the hippocampus of female mice, and the abundance of specific gut microbes was also correlated with anxiety\u2010like behaviors, pro\u2010inflammatory cytokines, and gene expression of tight junction proteins in the hippocampus of female mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Female mice were more vulnerable to stress and prebiotics than males. The gut microbiota, gut and blood\u2013brain barrier, and inflammatory response may mediate the protective effects of prebiotics on anxiety\u2010like behaviors in female mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14091","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T04:56:53Z","timestamp":1674017813000},"page":"115-128","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Sex difference in prebiotics on gut and blood\u2013brain barrier dysfunction underlying stress\u2010induced anxiety and depression"],"prefix":"10.1111","volume":"29","author":[{"given":"Jiajun","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Psychiatry, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)  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