Integrated multi-omics analysis reveals a gut microbiota-tryptophan metabolism axis contributes to sex differences in a β-aminopropionitrile-induced aortic dissection mouse model.

内容摘要

Sex differences in aortic dissection (AD) have been consistently reported in epidemiological studies and experimental mouse models, with males showing markedly higher susceptibility. However, the molecular basis underlying these sex-specific differences remains insufficiently understood. Three-week-old male and female C57BL/6J mice were administered 0.4% β-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 S 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. 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-indole pathway metabolites-such as indolepyruvate, indole-3-acetic acid, and indolepropionic acid-in both FeNonAD and AAD groups. Microbiome analysis further revealed a higher relative abundance of tryptophan-metabolizing taxa, particularly key Clostridium species, in the intestinal tract of FeNonAD mice, accompanied by significant upregulation of key functional genes (tyrB and aspC) 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. This study highlights a central "gut microbiota-tryptophan metabolism-aortic inflammation" 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. Aortic dissection is a dangerous condition, in which the wall of the main artery leaving the heart suddenly tears. It leads to internal bleeding and can be fatal. Doctors have long known that men develop this condition more often than women, but the reasons behind this difference have remained unclear.We used a mouse model to investigate why females appear to be better protected against aortic dissection. We examined several layers of biology simultaneously, including gene activity in the aorta, circulating chemicals, and bacteria in the gut. We aimed to understand how the body responds before and during disease.Female mice showed fewer signs of inflammation in the aorta and were less prone to vessel rupture. Their blood also contained higher levels of certain molecules made from the amino acid tryptophan. These molecules, called indole metabolites, are known to modulate immune responses and support healthy cell function. We discovered that female mice produced more of these protective molecules because their gut bacteria were better at converting tryptophan into indole compounds. In further experiments, supplementing male mice with indolepyruvate, an indole metabolite, reduced the incidence of aortic dissection.We found that these indole metabolites were associated with reduced activation of inflammation-related genes in the aorta. This suggests that communication between the gut and the blood vessel wall may help protect females from disease.Our findings highlight a gut–body pathway that may explain why females are less vulnerable to aortic dissection and point to new possibilities for prevention or treatment.