Nat Comm . . . Chen's team reveals the mechanism by which human intestinal microbiome disorders contribute to the onset of intracranial aneurysms and provides new intervention strategies.

The global prevalence of unruptured intracranial aneurysms is 3.2%. Community surveys in China show that the prevalence of unruptured intracranial aneurysms is as high as 7% in Chinese adults.intracranial aneurysm is a very dangerous cerebrovascular disease. Once ruptured, its early mortality rate is 40-50%.there is a consensus that endovascular treatment or surgical treatment is necessary for ruptured intracranial aneurysms. However, the treatment of unruptured intracranial aneurysms is still controversial. Even if endovascular treatment or surgical treatment is carried out for ruptured intracranial aneurysms, there is still a greater risk of bleeding and complications.therefore, it is very important to strengthen the clinical and basic research of unruptured intracranial aneurysms, identify the risk factors of intracranial aneurysms, analyze the pathogenesis and find new intervention measures.intracranial aneurysms are the result of the joint action of environmental factors and genetic factors. At present, a large amount of evidence shows that intestinal flora, as an important mediator, metabolizes various substances ingested by human body and produces small molecule metabolites such as TMAO and inflammatory factors, which play an important role in complex diseases.so far, is the occurrence of human intracranial aneurysms related to intestinal flora? If so, is it possible to take this as a breakthrough to find new interventions? None of the above issues are clear.recently, nature Communications published the latest research paper entitled "alternations of gut microbiota contribution to the progress of unruptured internal aneurysms" by Professor Chen Jingzhou of Fuwai Hospital, Chinese Academy of Medical Sciences.this study revealed for the first time the relationship between human intracranial aneurysms and intestinal flora, analyzed the mechanism of intestinal flora in the occurrence of intracranial aneurysms, and provided a new intervention method.the team first sequenced the intestinal flora between unruptured intracranial aneurysms and controls in two case-control studies, and found that the structural heterogeneity of intestinal flora in patients with intracranial aneurysms was significantly reduced.there were 145 genera with different abundance between the two groups.among them, Bacteroides, rubinococcus and blautia were enriched in the intestinal tract of patients with intracranial aneurysms, while faecalibacterium, eucharaterium, collinella and lactobacillus were enriched in the intestines of normal controls.species level analysis showed that the abundance of 47 species was significantly different between the two groups, and 38 species were enriched in the intracranial aneurysm group.species of the genus Bacteroides such as B. thetaiotaomicron, B. massiliensis, B. nordii, B. intellectualis and B. cellulosilyticus were significantly enriched in the intracranial aneurysm group.odoribacter Splanchnicus is a group of species that has been reported to have a positive correlation distribution between red meat intake and a negative correlation distribution with vegetable and horizontal uptake.in addition, the team found that a group of Clostridium species, including C. bartlettii, C. nexile and C. bolteae, were significantly enriched in the intracranial aneurysm group.however, C. hathewai (officially renamed hungatella hathewai in 2014) is the only member of the Clostridium genus with reduced abundance in the intestinal tract of intracranial aneurysms.among the 47 species, 8 species (17.0%) still had significant differences in the second population. in order to further explore the diagnostic value of intestinal flora disorder in intracranial aneurysm disease, the team constructed a random forest classifier based on the changes of intestinal flora in the first population. 47 species with different abundance in the two groups identified by metaphlan2 method were trained in the first population, and the area under the curve (AUC) reached 0.86. further tests were carried out in the second population. The results showed that the 47 species still had good disease prediction value in the second population, and the AUC reached 0.72, indicating that the difference of intestinal flora has the potential to diagnose intracranial aneurysms. functional annotation and pathway analysis showed that unsaturated fatty acid biosynthesis, amino acid (methionine, tryptophan, pyruvate and isoleucine) metabolism and glycolysis pathway may be related to intracranial aneurysms. among them, isoleucine biosynthesis and methionine biosynthesis were significantly enriched in the normal control group, suggesting that there was a significant difference in the ability of the two groups to synthesize branched chain amino acids and aromatic amino acids in intestinal flora. this finding is similar to the results of intestinal Metagenomics in obese patients and obese mice. these results suggest that the disturbance of intestinal flora in intracranial aneurysms may play a role through the changes of amino acid and fatty acid metabolism. therefore, the team further carried out quantitative detection on the levels of amino acids and fatty acids in the plasma of the two groups through targeted metabonomics, and found that there were significant differences in the levels of 7 fatty acids and 12 amino acids between the two groups. further analysis of the correlation between these 19 metabolites and 47 different intestinal bacteria showed that the abundance of phenylalanine acid in the plasma of patients with intracranial aneurysms was increased, and the levels of taurine, taurine, L-histidine and citrulline were significantly decreased in patients with intracranial aneurysms, and there was a strong correlation between the 19 metabolites and 47 different intestinal bacteria. it is suggested that intestinal flora may promote the occurrence and development of intracranial aneurysm disease by regulating the levels of plasma amino acids and fatty acids. in order to further explore whether the changes of intestinal flora directly lead to the development of intracranial aneurysms, the team conducted a mouse fecal transplantation experiment. compared with mice transplanted with normal control feces, the overall incidence of intracranial aneurysms in mice transplanted with feces from patients with intracranial aneurysms was significantly increased. in addition, Kaplan Meier analysis showed that there were significant differences in asymptomatic survival curves between the two groups, indicating that intestinal flora disturbance can directly affect the formation and rupture of intracranial aneurysms in the host. transcriptome sequencing of the cerebral blood vessels of the recipient mice showed that 850 genes were significantly up-regulated in the aneurysm receptor mice and 362 genes were significantly up-regulated in the normal control recipient mice. then, these differentially expressed genes were compared with the transcriptome data of another human intracranial aneurysm (gse26969). It was found that the transcriptome changes induced by intestinal flora transplantation in mice were similar to those in human intracranial aneurysms, suggesting that they have great translational medical value. in addition, bioinformatics analysis found that these differential genes could enrich in the signal pathways closely related to intracranial aneurysms, such as apoptosis and inflammation related pathways, suggesting that intestinal flora may affect the vascular lesions of intracranial aneurysms through these pathways. in order to determine the effect of intestinal flora on plasma metabolites in mice, the team conducted plasma metabonomics tests on mice after fecal transplantation. the results showed that there were significant differences between the two groups in plasma of 2 fatty acids and 8 amino acids. among them, taurine, L-histidine and linoleic acid showed the same changes as those of human intracranial aneurysms and controls. based on this, the team further explored whether exogenous supplementation of the above three metabolites in mice could reduce the formation and rupture of intracranial aneurysms. the results showed that exogenous taurine supplementation after transplantation significantly reduced the overall incidence of intracranial aneurysms compared with mice transplanted with faeces from patients with aneurysms. Kaplan Meier analysis further confirmed that taurine supplementation did reduce the risk of rupture of intracranial aneurysms. it is worth noting that taurine supplementation did not significantly reduce blood pressure in mice, suggesting that the protective effect of taurine does not depend on blood pressure regulation. supplementation with L-histidine and linoleic acid did not show any protective effect. mechanism studies found that taurine supplementation reduced the formation rate and rupture rate of intracranial aneurysms by reducing inflammatory reaction, reducing extracellular matrix remodeling and maintaining the integrity of cerebral vascular structure. in order to further clarify which intestinal flora is related to plasma taurine level, Spearman's correlation analysis was used to study the correlation between different intestinal bacteria and plasma metabolites in the two groups after fecal transplantation. the results showed that there was a positive correlation between the abundance of five strains and taurine content, and a negative correlation between the abundance of one strain and the taurine content. among the six strains closely related to taurine, H. hathewai is the only strain that is also associated with taurine in the study of intracranial aneurysm population, and the change trend of H. hathewai in two populations, fecal transplantation human donors and transplant recipient mice is the same - that is, the abundance of H. hathewai is significantly reduced in the state of intracranial aneurysm disease. therefore, in order to clarify whether H. hathewai is related to the changes of plasma taurine level and the occurrence of intracranial aneurysm disease, the team gave H. hathewai intragastric administration after fecal transplantation in mice, and found that H. hathewai feeding could restore H. hathewai level. it is important that H. hathewai supplementation can also significantly restore plasma taurine levels. in addition, H. hathewai supplementation significantly reduced the overall incidence of intracranial aneurysms compared with mice transplanted with faeces from patients with aneurysms alone. Kaplan Meier analysis further confirmed that H. hathewai supplementation reduced the risk of rupture of intracranial aneurysms. in addition, H. hathewai supplementation also inhibited cerebrovascular inflammatory response, extracellular matrix remodeling, MMP-9 activity and apoptosis of cerebral vascular smooth muscle cells. the above results fully indicate that H. hathewai participates in the synthesis of taurine, increases the plasma taurine level, and finally reduces the incidence and rupture rate of intracranial aneurysms. this study is the first time to clarify the relationship between human intracranial aneurysms and intestinal flora, analyze the mechanism of intestinal flora in the occurrence of intracranial aneurysms, and provide new intervention measures (taurine or H The results of this research team provide a new and potentially effective intervention for patients with unruptured intracranial aneurysms who are not suitable for surgery (including intervention and surgical treatment) or with high risk of surgical complications. the study was jointly completed by Fuwai Hospital of Chinese Academy of Medical Sciences, Tiantan Hospital Affiliated to Capital Medical University, Cangzhou Central Hospital, Tsinghua University, Beijing Nuohe Zhiyuan Technology Co., Ltd. and PLA General Hospital. Prof. Chen Jingzhou, Fuwai Hospital, Chinese Academy of Medical Sciences, is the corresponding author of this paper. Li Hao, associate researcher of Fuwai Hospital, postdoctoral Xu HaoChen, chief physician Li Youxiang and associate chief physician Jiang Yuhua of Tiantan Hospital are co authors of this paper. <br