Letter by Teng et al Regarding Article, “Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms”

HomeCirculationVol. 148, No. 8Letter by Teng et al Regarding Article, "Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Teng et al Regarding Article, "Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms" Zhenqing Teng, Xiang Ma and Yitong Ma Zhenqing TengZhenqing Teng https://orcid.org/0000-0003-0228-7212 Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China. , Xiang MaXiang Ma https://orcid.org/0000-0001-6528-3599 Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China. and Yitong MaYitong Ma Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China. Originally published21 Aug 2023https://doi.org/10.1161/CIRCULATIONAHA.123.065557Circulation. 2023;148:701–702To the Editor:We congratulate Benson et al1 on the recent publication of their article in Circulation. The authors comprehensively reported that the disruption of the metaorganismal production of trimethylamine N-oxide (TMAO) by targeting either the gut microbiome or the liver enzyme flavin-containing monooxygenase 3 (FMO3) of the host organism decreases circulating TMAO and protects mice from abdominal aortic aneurysm development in 2 independent mouse models. However, further research on the use of plasma TMAO and associated analytes as predictive biomarkers for both the incidence and growth rate of abdominal aortic aneurysms from the laboratory to bedside setting is needed.Some studies have suggested that TMAO might act through a G-protein–coupled receptor on the cell surface to alter signaling and to promote inflammation.2 In this study, it was shown that binary choice supplementation and TMAO elevation also increased macrophage infiltration. It can be indicated that TMAO may directly cause aortic vascular injury. However, gut microbiome dysbiosis also contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation.3 We concluded that the direct damage of TMAO to the aortic vessels needs further consideration because intestinal flora can also cause metabolic abnormalities of the body and neutrophil traps generated by chronic inflammation, which affect aortic homeostasis and promote the occurrence and rupture of abdominal aortic aneurysm.Studies have previously identified FMO3 as a potential link between cardiovascular disease and other components of the metabolic syndrome, and the knockdown of fmo3 entirely prevents hyperglycemia, hyperlipidemia, and atherosclerosis in insulin-resistant mice.2 The detrimental effects of FMO3 might be mediated by one of its other products, and TMAO might simply be a marker of excess FMO3 activity. Moreover, in this study, although the choline diet increased plasma trimethylamine and TMAO in female mice, abdominal aortic aneurysm diameter and incidence were not significantly different in angiotensin II–infused female mice. Therefore, we concluded that the function of FMO3 is what affects aortic vascular homeostasis rather than TMAO.It was also indicated that TMAO exacerbates aortic injury and is enriched in response to endoplasmic reticulum stress and PERK. The endoplasmic reticulum communicates with neighboring organelles, including endosomes, mitochondria, and the plasma membrane, all of which are essential for facilitating lipid metabolism, Ca2+ homeostasis, and the exchange of various ions between organelles.4 Some studies also indicated that mitochondrial and STING signaling dysfunction aggravates aortic degeneration and aortic aneurysm and dissection development.5 Therefore, we concluded that TMAO damage to the aorta is due to the dual effects of metabolic abnormalities and inflammation. Thus, further investigation must be conducted to identify intercellular communication between the TMAO-damaged vascular cells using single-cell sequencing along with cell pseudotemporal development. In this article, as shown in Figure 2, aortic injury was evident at the thoracic and abdominal aortas. Therefore, it is necessary to consider validating the production of TMAO and the metabolic pathway of related proteins through spatial transcriptome and metabolomics, which have different cell trajectories for the development of aortic vascular cells at different anatomic locations and can be associated with the mechanism for aneurysm and dissection.ARTICLE INFORMATIONAcknowledgmentsThe authors thank Qi Wang, Shipeng Guo, Xiaocui Chen, Xiaojie Ma, Fen Liu , Xue Zhang, Qi Wang, Zexin Zhou, and all members of the GZDlab for participating in the discussion of this letter with the first author and for their help and support.Sources of FundingXiang Ma was supported by the Key Research and Development Task of Xinjiang Uygur Autonomous Region (No.2022B03022 and No. 2022B03022-3), Key Project of Natural Science Foundation of Xinjiang Uygur Autonomous Region (No. 2022D01D66), and the National Natural Science Foundation of China (No. 81960097).Disclosures None.Footnotes*X. Ma and Y. Ma contributed equally.Circulation is available at www.ahajournals.org/journal/circREFERENCES1. Benson TW, Conrad KA, Li XS, Wang Z, Helsley RN, Schugar RC, Coughlin TM, Wadding-Lee C, Fleifil S, Russell HM, et al. Gut microbiota–derived trimethylamine N-oxide contributes to abdominal aortic aneurysm through inflammatory and apoptotic mechanisms.Circulation. 2023; 147:1079–1096. doi: 10.1161/CIRCULATIONAHA.122.060573LinkGoogle Scholar2. Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, et al. Trimethylamine N-oxide binds and activates PERK to promote metabolic dysfunction.Cell Metab. 2019; 30:1141–1151.e5. doi: 10.1016/j.cmet.2019.08.021CrossrefMedlineGoogle Scholar3. Tian Z, Zhang Y, Zheng Z, Zhang M, Zhang T, Jin J, Zhang X, Yao G, Kong D, Zhang C, et al. Gut Microbiome dysbiosis contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation.Cell Host Microbe. 2022; 30:1450–1463.e8. doi: 10.1016/j.chom.2022.09.004CrossrefMedlineGoogle Scholar4. Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases.Nat Rev Cardiol. 2021; 18:499–521. doi: 10.1038/s41569-021-00511-wCrossrefMedlineGoogle Scholar5. Luo W, Wang Y, Zhang L, Ren P, Zhang C, Li Y, Azares AR, Zhang M, Guo J, Ghaghada KB, et al. Critical role of cytosolic DNA and its sensing adaptor STING in aortic degeneration, dissection, and rupture.Circulation. 2020; 141:42–66. doi: 10.1161/CIRCULATIONAHA.119.041460LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails August 22, 2023Vol 148, Issue 8 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.123.065557PMID: 37603602 Originally publishedAugust 21, 2023 PDF download Advertisement SubjectsAneurysmEthics and PolicyVascular Disease