The Microbiome and Endothelial Function
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 9 Linguagem: Inglês
10.1161/circresaha.118.313813
ISSN1524-4571
AutoresJhansi L. Leslie, Brian H. Annex,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoHomeCirculation ResearchVol. 123, No. 9The Microbiome and Endothelial Function Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Microbiome and Endothelial FunctionAn Investigative Fountain or Analytical Morass Jhansi L. Leslie and Brian H. Annex Jhansi L. LeslieJhansi L. Leslie From the Division of Infectious Disease (J.L.L.), University of Virginia, Charlottesville. and Brian H. AnnexBrian H. Annex Correspondence to Brian H. Annex, MD, Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22901. Email E-mail Address: [email protected] Department of Medicine, Robert M. Berne Cardiovascular Research Center (B.H.A.), University of Virginia, Charlottesville. Division of Cardiovascular Medicine, Department of Medicine (B.H.A.), University of Virginia, Charlottesville. Originally published11 Oct 2018https://doi.org/10.1161/CIRCRESAHA.118.313813Circulation Research. 2018;123:1015–1016This article is a commentary on the followingLactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery DiseaseThe gut microbiome, a term that describes the entire intestinal habitat, including resident microorganisms (the microbiota) and their metabolic byproducts, has a profound impact on systemic health ranging from immune development, metabolism, and protection from infection.1–4 The innovative use of the 16S ribosomal RNA gene for phylogenic analysis, paired with the decreasing cost of sequencing paved the way for numerous surveys describing the composition of human bacterial microbiota.5,6 The ability to characterize bacterial membership at various body sites beyond our limited capacity to culture organisms has enabled us to find associations between the microbiota and many human diseases.Article, see p 1091The role of the microbiome in cardiovascular disease has only been investigated in a small number of human studies that have primarily linked differences in the composition of microbiota to various disease processes associated with cardiovascular disease.7 For example, taxa abundant in atherosclerotic plaques were also increase in patient oral cavities.8 Studies in both animal models and humans have demonstrated a link between microbial metabolism of diet-derived metabolites and increased levels of trimethylamine N-oxide.9 Together, these studies point tantalizingly toward the promise of modulation of microbiome for treatment of cardiovascular disease.In this issue of Circulation Research, Malik et al10 sought to move microbiome studies from observation to intervention by examining whether Lactobacillus plantarum 229v altered vascular endothelial function in men with stable coronary artery disease. To completely meet these goals the following questions must be asked: Did the intervention alter the gut microbiome? Did the intervention alter measures of vascular disease? Are the vascular measures a reliable clinical surrogate?The study used G3 PhyloChip to assess the effect of oral L plantarum 229v on the microbiota though PhyloChip does not, as stated, rely on 16S rDNAsequencing but rather is a microarray-based approach. To the best of our knowledge, no recent articles have benchmarked G3 PhyloChip relative to Illumina 16S rRNA (ribosomal RNA) gene sequencing, so it is difficult to compare the 2 methods. The microarray-based approach enables detection of taxa from both Bacteria and Archaea.11 Archaea are an understudied minority member of the gut microbiota which has been proposed as a potential means to decrease trimethylamine levels in the gut.12 The authors reported that Lplantarum 229v did not result in significant differences in the overall microbiota, including the number of observed species (richness), but they noted significant differences in the relative abundance of 70 operational taxonomic units between the pre and post-treatment samples with an enrichment of Lactobacillus spp. in the post-treatment samples. However, these findings were not significant after correcting for multiple comparisons. Perhaps other analytical methods like machine learning based models might be better able to parse the differences between samples.13,14 Overall, the findings from this study are in line with other works, which have seen minimal effects of probiotic supplementation on community structure.15,16 Plasma levels of acetic, propionic, and butyric acid, which are derivatives of microbial-derived short-chain fatty acids, were measured as a surrogate to determine if Lplantarum 229v supplementation altered the microbiome.17 After supplementation, levels of acetic acid significantly decreased, whereas levels of propionic acid increased. This result begs the question if the changes reflect Lplantarum 229v metabolism or if they reflect changes in metabolism of other members of the microbiota from the dietary supplementation. Others have found that although no significant alterations in the community structure were observed during probiotic therapy, the gut microbial transcriptional program was significantly changed.15 This suggests that future studies seeking to determine the effects of an intervention on the microbiota should move beyond metrics of community structure (who is there) and instead focus on what the microbes are doing.After the probiotic supplementation, the outcome measures included change in brachial artery flow-mediated dilation from 3.55±1.96 to 4.73±2.32 with no change in resting vessel diameter, hyperemic shear stress, or vascular smooth muscle mediated vasodilation. They then took plasma from 4 subjects and tested the net/bulk effects on adipose arterioles. There were reductions in IL (interleukin)-8 and IL-12, and again, effects were limited to the endothelium because the effects were smooth muscle independent and blocked by l-NAME (L-nitroarginine methyl ester). Direct measures of bioavailable nitric oxide (NO) are feasible but were not made.18 After a washout period, a subset of patients also took oral vancomycin because the authors had previously seen a therapeutic effect in animal models.19 Vancomycin did not result in a significant change in brachial artery flow-mediated dilation post-treatment. It is tempting to speculate that this result lends support for more targeted microbial therapeutics; however, the value of vancomycin as an intervention control for the specificity of the probiotic therapy is yet to be determined.The role of NO as the key factor in the maintenance of endothelial function, overall vascular health, and arterial tone is an established paradigm and central theme of translational vascular biology. Though brachial artery flow-mediated dilation is technically challenging, it does provide the best noninvasive assessment and is a frequently used accepted biomarker of the state of NO bioavailability in the endothelium. Changes in flow-mediated dilation suggest that the response of the endothelium can be inversely related to disease progression, although even in this space, brachial artery reactivity serves more as a marker for prediction of risk, and its role is less clear as a response to therapy.It is quite likely that the gut microbiome can influence the balance of vascular homeostasis (Figure) in critical features like NO production, inflammation, and thrombosis. Variations in baseline and alterations within the microbiome should be considered as an important and influential factor. Studies of the microbiome within and outside cardiovascular medicine are likely to, and indeed should, increase. In parallel, we will see an increase in the complexity of the analytic tools needed to fully establish the absolute and relative importance of this area on vascular health.Download figureDownload PowerPointFigure. The gut microbiome (bottom) can serve as a fulcrum in the ongoing battle of vascular injury and repair that determines overall endothelial health.Sources of FundingDr Leslie received support from T32 AI 7496-23. Dr Annex is supported by RO1HL16455, HL121635, and HL101200.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Brian H. Annex, MD, Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22901. Email [email protected]eduReferences1. Marchesi JR, Ravel J. The vocabulary of microbiome research: a proposal.Microbiome. 2015; 3:31. doi: 10.1186/s40168-015-0094-5CrossrefMedlineGoogle Scholar2. Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota.Immunity. 2017; 46:562–576. doi: 10.1016/j.immuni.2017.04.008CrossrefMedlineGoogle Scholar3. Leslie JL, Young VB. The rest of the story: the microbiome and gastrointestinal infections.Curr Opin Microbiol. 2015; 23:121–125. doi: 10.1016/j.mib.2014.11.010CrossrefMedlineGoogle Scholar4. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, Tuohy K. Gut microbiota functions: metabolism of nutrients and other food components.Eur J Nutr. 2018; 57:1–24. doi: 10.1007/s00394-017-1445-8CrossrefMedlineGoogle Scholar5. Woese CR, Fox GE. Phylogenetic structure of the prokaryotic domain: the primary kingdoms.Proc Natl Acad Sci USA. 1977; 74:5088–5090.CrossrefMedlineGoogle Scholar6. Huttenhower C, Gevers D, Knight R, et al; The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome.Nature. 2012; 486:207–214. doi: 10.1038/nature11234CrossrefMedlineGoogle Scholar7. Fåk F, Tremaroli V, Bergström G, Bäckhed F. Oral microbiota in patients with atherosclerosis.Atherosclerosis. 2015; 243:573–578. doi: 10.1016/j.atherosclerosis.2015.10.097CrossrefMedlineGoogle Scholar8. Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE, Bäckhed F. Human oral, gut, and plaque microbiota in patients with atherosclerosis.Proc Natl Acad Sci USA. 2011; 108:4592–4598.CrossrefMedlineGoogle Scholar9. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472:57–63. doi: 10.1038/nature09922CrossrefMedlineGoogle Scholar10. Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R, Tanner MJ, Kakarla M, Baker JE, Widlansky ME. Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease.Circ Res. 2018; 123:1091–1102. doi: 10.1161/CIRCRESAHA.118.313565LinkGoogle Scholar11. 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Plasma nitrite response and arterial reactivity differentiate vascular health and performance.Nitric Oxide. 2009; 20:231–237. doi: 10.1016/j.niox.2009.01.002CrossrefMedlineGoogle Scholar19. Lam V, Su J, Hsu A, Gross GJ, Salzman NH, Baker JE. Intestinal microbial metabolites are linked to severity of myocardial infarction in rats.PLoS One. 2016; 11:e0160840. doi: 10.1371/journal.pone.0160840CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Haywood N, Luk C, Bridge K, Drozd M, Makava N, Skromna A, Maccannell A, Ozber C, Warmke N, Wilkinson C, Watt N, Koch‐Paszkowski J, Teh I, Boyle J, Smart S, Schneider J, Yuldasheva N, Roberts L, Beech D, Sukumar P, Wheatcroft S, Cubbon R and Kearney M (2021) Endothelial IGF‐1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity, EMBO reports, 10.15252/embr.202050767, 22:5, Online publication date: 5-May-2021. Bouman Chen Z and Kaur Malhi N (2021) Endothelium–gut communication: IGF‐1Rs crosstalk with microbiota, EMBO reports, 10.15252/embr.202152896, 22:5, Online publication date: 5-May-2021. Related articlesLactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery DiseaseMobin Malik, et al. Circulation Research. 2018;123:1091-1102 October 12, 2018Vol 123, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313813PMID: 30355167 Originally publishedOctober 11, 2018 KeywordshumansmicrobiotaEditorialsendotheliumtrimethylaminePDF download Advertisement
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