Integrated multi-omics analysis reveals a gut microbiota–tryptophan metabolism axis contributes to sex differences in a β-aminopropionitrile-induced aortic dissection mouse model
Shuai Cheng, Xinyu Hao, et al. • Biology of Sex Differences • 2026
This study highlights a central 'gut microbiota–tryptophan metabolism–aortic inflammation' axis that contributes to sexual dimorphism in BAPN-induced aortic dissection, with female mice showing higher levels of protective indole metabolites produced by tryptophan-metabolizing gut bacteria, and indolepyruvate treatment delaying AD progression in male mice.
Key Findings
Results
Female mice exhibited significantly lower susceptibility to BAPN-induced aortic dissection than male mice, including reduced rates of aortic rupture, lower incidence of AD or aneurysm, and attenuated aortic dilation.
Three-week-old C57BL/6J mice of both sexes were administered 0.4% β-aminopropionitrile (BAPN) in drinking water for 28 days to induce AD.
Female mice showed reduced rates of aortic rupture compared to males.
Female mice demonstrated lower incidence of aortic dissection or aneurysm (AAD) and attenuated aortic dilation.
The model used integrated analyses across transcriptomic, metabolic, and microbiome layers to characterize sex-related differences.
Results
Transcriptomic analysis revealed that female non-dissected mice (FeNonAD) displayed diminished induction of inflammation-related genes and lower predicted immune cell infiltration in aortic tissues.
Strand-specific transcriptomic sequencing was performed on aortic tissues collected after the 28-day induction period.
FeNonAD mice showed diminished induction of inflammation-related genes compared to male counterparts.
Lower predicted immune cell infiltration was observed in aortic tissues of FeNonAD mice.
Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules linked to immune-inflammatory activation.
Results
Metabolomic profiling revealed significant elevations of tryptophan–indole pathway metabolites in both FeNonAD and AAD groups.
Untargeted serum metabolomics was performed on serum samples collected after the induction period.
Specifically elevated metabolites included indolepyruvate, indole-3-acetic acid, and indolepropionic acid.
These elevations were observed in both female non-dissected mice (FeNonAD) and AAD groups.
Indole metabolites are known to modulate immune responses and support healthy cell function.
Results
Female non-dissected mice had a higher relative abundance of tryptophan-metabolizing gut bacteria, particularly key Clostridium species, compared to male mice.
Full-length 16S rRNA sequencing of fecal samples was used to characterize the gut microbiome.
Key Clostridium species were identified as particularly enriched in the intestinal tract of FeNonAD mice.
Significant upregulation of key functional genes tyrB and aspC associated with indolepyruvate synthesis was observed in FeNonAD mice.
These findings suggest that female gut microbiota are more actively converting tryptophan into protective indole compounds.
Results
WGCNA-based inter-omics integration identified strong negative correlations between indolepyruvate and indole-3-acetic acid sodium salt levels and aortic gene modules linked to immune-inflammatory activation.
Bioinformatic approaches were used to assess inter-omics correlations across transcriptomic, metabolic, and microbiome data.
Indole-3-acetic acid sodium salt levels similarly showed strong negative correlations with these gene modules.
This integration revealed a functional link between circulating indole metabolites and suppression of vascular inflammation.
Results
In vivo treatment with indolepyruvate delayed aortic dissection progression in male mice.
Further in vivo experiments were conducted to validate the impact of key metabolites on AD progression.
Indolepyruvate supplementation was administered to male mice in the BAPN-induced AD model.
Treatment with indolepyruvate reduced the incidence of aortic dissection in male mice.
The findings were consistent with the identified negative correlation between indolepyruvate and aortic inflammation-related gene expression.
Conclusions
The study identified a 'gut microbiota–tryptophan metabolism–aortic inflammation' axis as a contributor to sexual dimorphism in BAPN-induced aortic dissection.
The axis links higher abundance of tryptophan-metabolizing gut bacteria in females to elevated circulating indole metabolites.
Elevated indole metabolites were associated with reduced immune-inflammatory gene activation in the aorta.
The integrated multi-omics approach spanned transcriptomics, serum metabolomics, and 16S rRNA microbiome sequencing.
The authors propose this axis as a conceptual basis for developing sex-tailored diagnostic and therapeutic strategies for aortic dissection.
What This Means
This research suggests that the well-known difference in aortic dissection risk between males and females may be partly explained by differences in gut bacteria and how they process a dietary amino acid called tryptophan. Using a mouse model where aortic dissection is induced by a chemical (BAPN), the researchers found that female mice were significantly more protected from the disease than males—they had fewer vessel ruptures, less ballooning of the aorta, and less inflammation in the vessel wall. By simultaneously examining gene activity in the aorta, chemicals circulating in the blood, and bacteria in the gut, the researchers found that female mice had higher blood levels of molecules called indole metabolites, which are made from tryptophan by certain gut bacteria. Female mice had more of the specific gut bacteria (particularly Clostridium species) capable of converting tryptophan into these protective indole compounds, and the bacterial genes responsible for this conversion were more active in females.
The study further found that these indole metabolites were statistically linked to lower activity of inflammation-promoting genes in the aortic wall. When the researchers directly gave male mice one of these indole metabolites, indolepyruvate, it reduced the rate of aortic dissection in those animals. This suggests that the gut–tryptophan–aorta communication pathway plays a functional role in protecting against the disease, not just a correlational one.
This research suggests that gut microbiome composition and tryptophan metabolism may be important factors in why aortic dissection is more common and more severe in males. These findings open potential avenues for new approaches to prevention or treatment that account for biological sex, including the possibility that modifying gut bacteria or supplementing with indole metabolites could reduce disease risk. However, this work was conducted in mice, and further research would be needed to determine whether these mechanisms apply in humans.
Shuai Cheng, Xinyu Hao, Shirui Liu, Linfeng Zhang, Shuai Zhang, Yutian Chen, et al.. (2026). Integrated multi-omics analysis reveals a gut microbiota–tryptophan metabolism axis contributes to sex differences in a β-aminopropionitrile-induced aortic dissection mouse model. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00925-6