05fcdd0a46c45e3166ba2a88ad2d4a4d pmc_9916030.pdf e87a90f7a9e863f70d7baa562d6c318001981ff1 pmc_9916030.pdf 9b7e368f06190d7a5c6de8d9f1eb9529d7c578e52f5077f844cfdadf670e2bc7 pmc_9916030.pdf Title: Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease? Subject: Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study. Keywords: atherosclerosis; TMAO; mortality; CVD; renal function; prospective Author: Marina Canyelles, Carla Borràs, Noemí Rotllan, Mireia Tondo, Joan Carles Escolà-Gil and Francisco Blanco-Vaca Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Feb 9 07:33:49 2023 CET ModDate: Thu Feb 9 07:36:39 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 965311 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GXRZWQ+VnURWPalladioL Type 1 Custom yes yes no 10 0 INQOPQ+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 BIKWOX+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 CKUGXT+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 PYPZKK+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 SZMMWU+EURM10 Type 1 Builtin yes yes no 71 0 GKBKEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 81 0 GKBKFF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 87 0 GKBKIF+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 93 0 GKBKIG+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 99 0 GKBKIH+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 102 0 GKBKII+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 105 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 116 0 EILUJF+CMSY10 Type 1 Builtin yes yes no 120 0 GKBKEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 142 0 GKBKFF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 148 0 GKBKIF+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 154 0 GKBKIG+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 160 0 GKBKIH+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 163 0 GKBKII+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 166 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-03-31 02:28:51 CEST RepresentationInformation: pmc_9916030.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-30 02:15:42 CEST Size: 965311 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 470 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Trimethylamine-N-Oxide (TMAO) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Microbial Pathways Leading to TMA Production in the Gut Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Dietary Precursors of TMA and TMAO Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: TMAO Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: TMAO in Prospective Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: TMAO in Genetic Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Mechanisms Related to TMAO Atherogenic Effect Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: TMAO, Cholesterol Metabolism Disruption, and Atherosclerotic Plaque Formation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: TMAO, Inflammation, and Endothelial Dysfunction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: TMAO, Platelet Activation, and Thrombosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease? Author: Marina Canyelles, Carla Borràs, Noemí Rotllan, Mireia Tondo, Joan Carles Escolà-Gil and Francisco Blanco-Vaca Subject: Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which at least in part could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study. 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