Advertisement
Heart, Lung and Circulation

The Gut Microbiota and Their Metabolites in Human Arterial Stiffness

Published:August 24, 2021DOI:https://doi.org/10.1016/j.hlc.2021.07.022

      Aim

      Gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) have vasodilator properties in animal and human ex vivo arteries. However, the role of the gut microbiota and SCFAs in arterial stiffness in humans is still unclear. Here we aimed to determine associations between the gut microbiome, SCFA and their G-protein coupled sensing receptors (GPCRs) in relation to human arterial stiffness.

      Methods

      Ambulatory arterial stiffness index (AASI) was determined from ambulatory blood pressure (BP) monitoring in 69 participants from regional and metropolitan regions in Australia (55.1% women; mean, 59.8± SD, 7.26 years of age). The gut microbiome was determined by 16S rRNA sequencing, SCFA levels by gas chromatography, and GPCR expression in circulating immune cells by real-time PCR.

      Results

      There was no association between metrics of bacterial α and β diversity and AASI or AASI quartiles in men and women. We identified two main bacteria taxa that were associated with AASI quartiles: Lactobacillus spp. was only present in the lowest quartile, while Clostridium spp. was present in all quartiles but the lowest. AASI was positively associated with higher levels of plasma, but not faecal, butyrate. Finally, we identified that the expression of GPR43 (FFAR2) and GPR41 (FFAR3) in circulating immune cells were negatively associated with AASI.

      Conclusions

      Our results suggest that arterial stiffness is associated with lower levels of the metabolite-sensing receptors GPR41/GPR43 in humans, blunting its response to BP-lowering metabolites such as butyrate. The role of Lactobacillus spp. and Clostridium spp., as well as butyrate-sensing receptors GPR41/GPR43, in human arterial stiffness needs to be determined.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Avolio A.
        Arterial stiffness.
        Pulse (Basel). 2013; 1: 14-28
        • Ogola B.O.
        • Zimmerman M.A.
        • Clark G.L.
        • Abshire C.M.
        • Gentry K.M.
        • Miller K.S.
        • et al.
        New insights into arterial stiffening: does sex matter?.
        Am J Physiol Heart Circ Physiol. 2018; 315: H1073-H1087
        • Muralitharan R.R.
        • Jama H.A.
        • Xie L.
        • Peh A.
        • Snelson M.
        • Marques F.Z.
        Microbial peer pressure: the role of the gut microbiota in hypertension and its complications.
        Hypertension. 2020; 76: 1674-1687
        • Marques F.Z.
        • Mackay C.R.
        • Kaye D.M.
        Beyond gut feelings: how the gut microbiota regulates blood pressure.
        Nat Rev Cardiol. 2018; 15: 20-32
        • Petersen C.
        • Round J.L.
        Defining dysbiosis and its influence on host immunity and disease.
        Cell Microbiol. 2014; 16: 1024-1033
        • Cani P.D.
        • Bibiloni R.
        • Knauf C.
        • Waget A.
        • Neyrinck A.M.
        • Delzenne N.M.
        • et al.
        Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.
        Diabetes. 2008; 57: 1470-1481
        • Koeth R.A.
        • Wang Z.
        • Levison B.S.
        • Buffa J.A.
        • Org E.
        • Sheehy B.T.
        • et al.
        Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
        Nat Med. 2013; 19: 576-585
        • Jama H.
        • Beale A.
        • Shihata W.A.
        • Marques F.Z.
        The effect of diet on hypertensive pathology: is there a link via gut microbiota-driven immune-metabolism?.
        Cardiovasc Res. 2019; 115: 1435-1447
        • Kaye D.M.
        • Shihata W.
        • Jama H.A.
        • Tsyganov K.
        • Ziemann M.
        • Kiriazis H.
        • et al.
        Deficiency of prebiotic fibre and insufficient signalling through gut metabolite sensing receptors leads to cardiovascular disease.
        Circulation. 2020; : 1393-1403
        • Li J.
        • Zhao F.
        • Wang Y.
        • Chen J.
        • Tao J.
        • Tian G.
        • et al.
        Gut microbiota dysbiosis contributes to the development of hypertension.
        Microbiome. 2017; 5: 14
        • Marques F.Z.
        • Nelson E.
        • Chu P.Y.
        • Horlock D.
        • Fiedler A.
        • Ziemann M.
        • et al.
        High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice.
        Circulation. 2017; 135: 964-977
        • Mortensen F.V.
        • Nielsen H.
        • Mulvany M.J.
        • Hessov I.
        Short chain fatty acids dilate isolated human colonic resistance arteries.
        Gut. 1990; 31: 1391-1394
        • Natarajan N.
        • Hori D.
        • Flavahan S.
        • Steppan J.
        • Flavahan N.A.
        • Berkowitz D.E.
        • et al.
        Microbial short chain fatty acid metabolites lower blood pressure via endothelial G-protein coupled receptor 41.
        Physiol Genomics. 2016; 48: 826-834
        • Kim S.
        • Goel R.
        • Kumar A.
        • Qi Y.
        • Lobaton G.
        • Hosaka K.
        • et al.
        Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure.
        Clin Sci (Lond). 2018; 132: 701-718
        • Rhys-Jones D.
        • Climie R.
        • Jama H.
        • Gill P.A.
        • Head G.A.
        • Gibson P.
        • et al.
        Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomised cross-over placebo controlled trial.
        Pre-Print in Research Square. 2021; (doi:1021203/rs3rs-149397/v1)
        • Li Y.
        • Wang J.G.
        • Dolan E.
        • Gao P.J.
        • Guo H.F.
        • Nawrot T.
        • et al.
        Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring.
        Hypertension. 2006; 47: 359-364
        • Nakai M.E.
        • Ribeiro R.V.
        • Stevens B.R.
        • Gill P.A.
        • Muralitharan R.R.
        • Yiallourou S.
        • et al.
        Essential hypertension is associated with changes in gut microbial metabolic pathways: a multi-site analysis of ambulatory blood pressure.
        Hypertension. 2021; (Accepted on 2/07/2021. Pre-print available at)
        • Marques F.Z.
        • Jama H.A.
        • Tsyganov K.
        • Gill P.A.
        • Rhys-Jones D.
        • Muralitharan R.R.
        • et al.
        Guidelines for transparency on gut microbiome studies in essential and experimental hypertension.
        Hypertension. 2019; 74: 1279-1293
        • Mirzayi C.
        • Renson A.
        • Zohra F.
        • Elsafoury S.
        • Geistlinger L.
        • Kasselman L.
        • et al.
        Strengthening the Organization and Reporting of Microbiome Studies (STORMS): a reporting checklist for human microbiome research.
        BioRvix. 2021; https://doi.org/10.1101/2020.06.24.167353
        • Bolyen E.
        • Rideout J.R.
        • Dillon M.R.
        • Bokulich N.A.
        • Abnet C.C.
        • Al-Ghalith G.A.
        • et al.
        Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.
        Nat Biotechnol. 2019; 37: 852-857
        • Segata N.
        • Izard J.
        • Waldron L.
        • Gevers D.
        • Miropolsky L.
        • Garrett W.S.
        • et al.
        Metagenomic biomarker discovery and explanation.
        Genome Biol. 2011; 12: R60
        • Chong J.
        • Liu P.
        • Zhou G.
        • Xia J.
        Using MicrobiomeAnalyst for comprehensive statistical, functional, and meta-analysis of microbiome data.
        Nat Protoc. 2020; 15: 799-821
        • Dhariwal A.
        • Chong J.
        • Habib S.
        • King I.L.
        • Agellon L.B.
        • Xia J.
        MicrobiomeAnalyst: a web-based tool for comprehensive statistical, visual and meta-analysis of microbiome data.
        Nucleic Acids Res. 2017; 45: W180-W188
        • Chen L.
        • Reeve J.
        • Zhang L.
        • Huang S.
        • Wang X.
        • Chen J.
        GMPR: a robust normalization method for zero-inflated count data with application to microbiome sequencing data.
        PeerJ. 2018; 6: e4600
        • So D.
        • Yao C.K.
        • Gill P.A.
        • Pillai N.
        • Gibson P.R.
        • Muir J.G.
        Screening dietary fibres for fermentation characteristics and metabolic profiles using a rapid in vitro approach: implications for irritable bowel syndrome.
        Br J Nutr. 2020; : 1-11
        • Gill P.A.
        • van Zelm M.C.
        • Ffrench R.A.
        • Muir J.G.
        • Gibson P.R.
        Successful elevation of circulating acetate and propionate by dietary modulation does not alter T-regulatory cell or cytokine profiles in healthy humans: a pilot study.
        Eur J Nutr. 2020; 59: 2651-2661
        • Muralitharan R.R.
        • Marques F.Z.
        Diet-related gut microbial metabolites and sensing in hypertension.
        J Hum Hypertens. 2021; : 162-169
        • Menni C.
        • Lin C.
        • Cecelja M.
        • Mangino M.
        • Matey-Hernandez M.L.
        • Keehn L.
        • et al.
        Gut microbial diversity is associated with lower arterial stiffness in women.
        Eur Heart J. 2018; 39: 2390-2397
        • Sata Y.
        • Marques F.Z.
        • Kaye D.M.
        The emerging role of gut dysbiosis in cardio-metabolic risk factors for heart failure.
        Curr Hypertens Rep. 2020; 22: 38
        • Beale A.L.
        • Kaye D.M.
        • Marques F.Z.
        The role of the gut microbiome in sex differences in arterial pressure.
        Biology of Sex Differences. 2019; 10: 22
        • Do K.A.
        • Treloar S.A.
        • Pandeya N.
        • Purdie D.
        • Green A.C.
        • Heath A.C.
        • et al.
        Predictive factors of age at menopause in a large Australian twin study.
        Hum Biol. 1998; 70: 1073-1091
        • Takahashi K.
        • Miura S.
        • Mori-Abe A.
        • Kawagoe J.
        • Takata K.
        • Ohmichi M.
        • et al.
        Impact of menopause on the augmentation of arterial stiffness with aging.
        Gynecol Obstet Invest. 2005; 60: 162-166
        • Wilck N.
        • Matus M.G.
        • Kearney S.M.
        • Olesen S.W.
        • Forslund K.
        • Bartolomaeus H.
        • et al.
        Salt-responsive gut commensal modulates T(H)17 axis and disease.
        Nature. 2017; 551: 585-589
        • Sun S.
        • Lulla A.
        • Sioda M.
        • Winglee K.
        • Wu M.C.
        • Jacobs Jr., D.R.,
        • et al.
        Gut microbiota composition and blood pressure.
        Hypertension. 2019; 73: 998-1006
        • Yan Q.
        • Gu Y.
        • Li X.
        • Yang W.
        • Jia L.
        • Chen C.
        • et al.
        Alterations of the gut microbiome in hypertension.
        frontiers in cellular and infection microbiology. 2017; 7: 381
        • Parada Venegas D.
        • De la Fuente M.K.
        • Landskron G.
        • González M.J.
        • Quera R.
        • Dijkstra G.
        • et al.
        Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases.
        Frontiers in Immunology. 2019; 10: 277
        • Tan J.K.
        • McKenzie C.
        • Marino E.
        • Macia L.
        • Mackay C.R.
        Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation.
        Annu Rev Immunol. 2017; 35: 371-402
        • Smith P.M.
        • Howitt M.R.
        • Panikov N.
        • Michaud M.
        • Gallini C.A.
        • Bohlooly Y.M.
        • et al.
        The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
        Science. 2013; 341: 569-573
        • Barhoumi T.
        • Kasal D.A.
        • Li M.W.
        • Shbat L.
        • Laurant P.
        • Neves M.F.
        • et al.
        T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.
        Hypertension. 2011; 57: 469-476
        • Liu X.
        • Zhang Q.
        • Wu H.
        • Du H.
        • Liu L.
        • Shi H.
        • et al.
        Blood neutrophil to lymphocyte ratio as a predictor of hypertension.
        Am J Hypertens. 2015; 28: 1339-1346