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However, the molecular basis underlying these sex-specific differences remains insufficiently understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three-week-old male and female C57BL\/6J mice were administered 0.4% \u03b2-aminopropionitrile (BAPN) in drinking water for 28 d to induce AD. After the induction period, fecal samples, serum, and aortic tissues were collected from all surviving animals. Integrated analyses included strand-specific transcriptomic sequencing of aortic tissues, untargeted serum metabolomics, and full-length 16\u00a0S rRNA sequencing of fecal samples to characterize sex-related differences across transcriptomic, metabolic, and microbiome layers. Inter-omics correlations were further assessed using bioinformatic approaches. Furthermore, in vivo experiments were conducted to validate the impact of key metabolites on the progression of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Female mice exhibited significantly lower susceptibility to BAPN-induced AD, including reduced rates of aortic rupture, lower incidence of AD or aneurysm (AAD), and attenuated aortic dilation. Transcriptomic analysis revealed that female non-dissected mice (FeNonAD) displayed diminished induction of inflammation-related genes and lower predicted immune cell infiltration. Metabolomic profiling revealed significant elevations of tryptophan\u2013indole pathway metabolites\u2014such as indolepyruvate, indole-3-acetic acid, and indolepropionic acid\u2014in both FeNonAD and AAD groups. Microbiome analysis further revealed a higher relative abundance of tryptophan-metabolizing taxa, particularly key\n                      <jats:italic>Clostridium<\/jats:italic>\n                      species, in the intestinal tract of FeNonAD mice, accompanied by significant upregulation of key functional genes (\n                      <jats:italic>tyrB<\/jats:italic>\n                      and\n                      <jats:italic>aspC<\/jats:italic>\n                      ) associated with indolepyruvate synthesis. Weighted gene co-expression network analysis (WGCNA)-based integration identified strong negative correlations between indolepyruvate and indole-3-acetic acid sodium salt levels and aortic gene modules linked to immune-inflammatory activation. Further in vivo experiments demonstrated that treatment with indolepyruvate delayed AD progression in male mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights a central \u201cgut microbiota\u2013tryptophan metabolism\u2013aortic inflammation\u201d axis that contributes to sexual dimorphism in BAPN-induced AD. These findings provide new molecular insights into sex-specific disease mechanisms and offer a conceptual basis for developing sex-tailored diagnostic and therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00925-6","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:55:16Z","timestamp":1779238516000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated multi-omics analysis reveals a gut microbiota\u2013tryptophan metabolism axis contributes to sex differences in a \u03b2-aminopropionitrile-induced aortic dissection mouse model"],"prefix":"10.1186","volume":"17","author":[{"given":"Shuai","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"925_CR1","doi-asserted-by":"publisher","first-page":"101814","DOI":"10.3390\/genes13101814","volume":"13","author":"Z Zhou","year":"2022","unstructured":"Zhou Z, Cecchi AC, Prakash SK, Milewicz DM. 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All animal experimental protocols received approval from the Zhengzhou University Laboratory Animal Welfare and Ethics Committee (approval number: ZZU-LAC20231229 [\n                      \n                      ]). This study adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"133"}}