Improvement of intestinal flora: accompany with the antihypertensive effect of electroacupuncture on stage 1 hypertension

Jun-Meng Wang, Ming-Xiao Yang, Qiao-Feng Wu, Ji Chen, Shu-Fang Deng, Lin Chen, Da-Neng Wei, Fan-Rong Liang, Jun-Meng Wang, Ming-Xiao Yang, Qiao-Feng Wu, Ji Chen, Shu-Fang Deng, Lin Chen, Da-Neng Wei, Fan-Rong Liang

Abstract

Background: Increasing evidence have indicated the relationship between intestinal dysbiosis and hypertension. We aimed to evaluate the effect of the electroacupuncture (EA) on intestinal microbiota in patients with stage 1 hypertension.

Methods: 93 hypertensive patients and 15 healthy subjects were enrolled in this study. Applying a highly accurate oscillometric device to evaluate the antihypertensive effect of EA. 16S rRNA sequencing was used to profile stool microbial communities from Healthy group, Before treatment (BT) group and After treatment (AT) group, and various multivariate analysis approaches were used to assess diversity, composition and abundance of intestinal microbiota.

Results: In this study, EA significantly decreased the blood pressure (BP) of hypertensive patients. Higher abundance of Firmicutes and lower Bacteroidetes abundance were observed in the BT group compared to the Healthy group. And EA treatment significantly decreased the Firmicutes/Bacteroidetes ratio compared to the BT group. Moreover, at the genus level, there was an increased abundance of Escherichia-Shigella in patients with hypertension, while Blautia were decreased, and EA reversed these changes.

Conclusions: Our study indicates that EA can effectively lower BP and improve the structure of intestinal microbiota which are correlate with the alteration of blood pressure by electroacupuncture.

Trial registration: Clinicaltrial.gov, NCT01701726. Registered 5 October 2012, https://ichgcp.net/clinical-trials-registry/NCT01701726.

Keywords: Dysbiosis; Electro-acupuncture; Intestinal flora; Stage 1 hypertension.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Influence of EA on the diversity and richness of gut microbiota. a Simpson and b Shannon index represent community diversity of OTUs. c Ace and d Chao1 index represent community richness of OTUs. There was no significant difference in Alpha diversity among three groups
Fig. 2
Fig. 2
PLS-DA analysis for fecal microbiota of healthy group, before treatment group and after treatment group. a PLS-DA score plot for healthy group, before treatment group and after treatment group. b PLS-DA score plot for healthy group and before treatment group. c PLS-DA score plot for before treatment group and after treatment group. d PLS-DA score plot for healthy group and after treatment group. PLS-DA showed clear separation between Healthy and hypertension, and AT group showed a tendency toward the Healthy group
Fig. 3
Fig. 3
Modulation of the composition of gut microbiota by EA. a Venn diagrams demonstrate the number of OTUs shared between the Healthy, BT and AT group by the overlap. b Bar chart depicts the variability in phylum-level composition in each group. c Pie chart shows the proportion of reads in genus for the Healthy, BT and AT group
Fig. 4
Fig. 4
Influence of EA on the relative abundance of microbiota at each level. a The ratio of Firmicutes to Bacteroidetes ratio, and bd differences at each taxonomic level (phylum, family and genus). All data were expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 5
Fig. 5
Spearman correlation plots between bacterial at family and genus level and BP values. R in different colors to show, the right side of the legend is the color range of different R values. *P < 0.05, **P < 0.01

References

    1. Wang Z, Chen Z, Zhang L, Wang X, Hao G, Zhang Z, et al. Status of hypertension in China: results from the China hypertension survey, 2012–2015. Circulation. 2018;137(22):2344–2356. doi: 10.1161/CIRCULATIONAHA.117.032380.
    1. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–1401. doi: 10.1056/NEJMoa1402670.
    1. Viera AJ, Hawes EM. Management of mild hypertension in adults. BMJ. 2016 doi: 10.1136/bmj.i5719.
    1. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957–967. doi: 10.1016/S0140-6736(15)01225-8.
    1. Cho L, Kim P. 2017 ACC/AHA blood pressure classification and cardiovascular disease in 15 million adults of age 20–94 years. J Clin Med. 2019;8(11):1832. doi: 10.3390/jcm8111832.
    1. Liu N, Yang JJ, Meng R, Pan X-F, Zhang X, He M, et al. Associations of blood pressure categories defined by 2017 ACC/AHA guidelines with mortality in China: pooled results from three prospective cohorts. Eur J Prev Cardiol. 2017 doi: 10.1177/2047487319862066.
    1. Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S, et al. Blood pressure and incidence of twelve cardiovascular diseases: Lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet. 2014;383(9932):1899–1911. doi: 10.1016/S0140-6736(14)60685-1.
    1. Yano Y, Reis JP, Colangelo LA, Shimbo D, Viera AJ, Allen NB, et al. Association of blood pressure classification in young adults Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Cardiovascular Events Later in Life. JAMA. 2018;320(17):1774. doi: 10.1001/jama.2018.13551.
    1. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Syst Rev. 2012 doi: 10.1002/14651858.CD006742.pub2.
    1. Sheppard JP, Stevens S, Stevens R, Martin U, Mant J, Hobbs FDR, et al. Benefits and harms of antihypertensive treatment in low-risk patients with mild hypertension. JAMA Intern Med. 2018;178(12):1626–1634. doi: 10.1001/jamainternmed.2018.4684.
    1. Tan X, Pan Y, Su W, Gong S, Zhu H, Chen H, et al. Acupuncture therapy for essential hypertension: a network meta-analysis. Ann Transl Med. 2019;7(12):266–266. doi: 10.21037/atm.2019.05.59.
    1. Liu Y, Park JE, Shin KM, Lee M, Jung HJ, Kim AR, et al. Acupuncture lowers blood pressure in mild hypertension patients: a randomized, controlled, assessor-blinded pilot trial. Complement Ther Med. 2015 doi: 10.1016/j.ctim.2015.06.014.
    1. Yang M, Yu Z, Chen X, Guo Z, Deng S, Chen L, et al. Active acupoints differ from inactive acupoints in modulating key plasmatic metabolites of hypertension: a targeted metabolomics study. Sci Rep. 2018;8(1):17824. doi: 10.1038/s41598-018-36199-1.
    1. Kang Y, Cai Y. Gut microbiota and hypertension: From pathogenesis to new therapeutic strategies. Clin Res Hepatol Gastroenterol. 2018;42(2):110–117. doi: 10.1016/j.clinre.2017.09.006.
    1. Niskanen L, Laaksonen DE, Nyyssönen K, Punnonen K, Valkonen VP, Fuentes R, et al. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension. 2004;44(6):859–865. doi: 10.1161/01.HYP.0000146691.51307.84.
    1. 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 doi: 10.1186/s40168-016-0222-x.
    1. Bartolomaeus H, Balogh A, Yakoub M, Homann S, Markó L, Höges S, et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation. 2019;139(11):1407–1421. doi: 10.1161/CIRCULATIONAHA.118.036652.
    1. Felizardo RJF, Mizuno Watanabe IK, Dardi P, Venturini Rossoni L, Olsen Saraiva Câmara N. The interplay among gut microbiota, hypertension and kidney diseases: the role of short-chain fatty acids. Pharmacol Res. 2019;141:366–377. doi: 10.1016/j.phrs.2019.01.019.
    1. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165(1):111–124. doi: 10.1016/j.cell.2016.02.011.
    1. Zhao L, Li D, Zheng H, Chang X, Cui J, Wang R, et al. Acupuncture as adjunctive therapy for chronic stable angina. JAMA Intern Med. 2019;179:1–12. doi: 10.1001/jamainternmed.2019.2407.
    1. Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65(6):1331–1340. doi: 10.1161/HYPERTENSIONAHA.115.05315.
    1. Sircana A, De Michieli F, Parente R, Framarin L, Leone N, Berrutti M, et al. Gut microbiota, hypertension and chronic kidney disease: recent advances. Pharmacol Res. 2019;144:390–408. doi: 10.1016/j.phrs.2018.01.013.
    1. Mushtaq N, Hussain S, Zhang S, Yuan L, Li H, Ullah S, et al. Molecular characterization of alterations in the intestinal microbiota of patients with grade 3 hypertension. Int J Mol Med. 2019;44(2):513–522.
    1. Macklin EA, Wayne PM, Kalish LA, Valaskatgis P, Thompson J, Pian-Smith MCM, et al. Stop Hypertension with the Acupuncture Research Program (SHARP): results of a randomized, controlled clinical trial. Hypertension. 2006;48(5):838–845. doi: 10.1161/01.HYP.0000241090.28070.4c.
    1. Flachskampf FA, Gallasch J, Gefeller O, Gan J, Mao J, Pfahlberg AB, et al. Randomized trial of acupuncture to lower blood pressure. Circulation. 2007;115(24):3121–3129. doi: 10.1161/CIRCULATIONAHA.106.661140.
    1. Brook RD, Appel LJ, Rubenfire M, Ogedegbe G, Bisognano JD, Elliott WJ, et al. Beyond medications and diet: alternative approaches to lowering blood pressure: a scientific statement from the American Heart Association. Hypertension. 2013;61(6):1360–1383. doi: 10.1161/HYP.0b013e318293645f.
    1. Yin CS, Seo BK, Park HJ, Cho M, Jung WS, Choue R, et al. Acupuncture, a promising adjunctive therapy for essential hypertension: A double-blind, randomized, controlled trial. Neurol Res. 2007 doi: 10.1179/016164107X172220.
    1. Endres M, Heuschmann PU, Laufs U, Hakim AM. Primary prevention of stroke: Blood pressure, lipids, and heart failure. Eur Heart J. 2011;32:545–555. doi: 10.1093/eurheartj/ehq472.
    1. Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA, et al. Primary prevention of hypertension: clinical and public health advisory from the National High Blood Pressure Education Program. J Am Med Assoc. 2002;288(15):1882–1888. doi: 10.1001/jama.288.15.1882.
    1. Zheng H, Li J, Li Y, Zhao L, Wu X, Chen J, et al. Acupuncture for patients with mild hypertension: a randomized controlled trial. J Clin Hypertens. 2019;21(3):412–420. doi: 10.1111/jch.13490.
    1. Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019 doi: 10.1016/j.jacc.2019.03.024.
    1. 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. 2018;132(6):701–718. doi: 10.1042/CS20180087.
    1. Jama HA, Kaye DM, Marques FZ. The gut microbiota and blood pressure in experimental models. Curr Opin Nephrol Hypertens. 2019;28:97–104. doi: 10.1097/MNH.0000000000000476.
    1. Adnan S, Nelson JW, Ajami NJ, Venna VR, Petrosino JF, Bryan RM, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics. 2017;49(2):96–104. doi: 10.1152/physiolgenomics.00081.2016.
    1. Mell B, Jala VR, Mathew AV, Byun J, Waghulde H, Zhang Y, et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics. 2015;47(6):187–197. doi: 10.1152/physiolgenomics.00136.2014.
    1. Durgan DJ, Ganesh BP, Cope JL, Ajami NJ, Phillips SC, Petrosino JF, et al. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension. 2016;67(2):469–474. doi: 10.1161/HYPERTENSIONAHA.115.06672.
    1. Marques FZ, Nelson E. High-fiber diet and acetate supplementation development of hypertension and heart failure in hypertensive mice. Circulation. 2017;135:964–977. doi: 10.1161/CIRCULATIONAHA.116.024545.
    1. Martínez I, Lattimer JM, Hubach KL, Case JA, Yang J, Weber CG, et al. Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME J. 2013;7(2):269–280. doi: 10.1038/ismej.2012.104.
    1. Reichardt N, Vollmer M, Holtrop G, Farquharson FM, Wefers D, Bunzel M, et al. Specific substrate-driven changes in human faecal microbiota composition contrast with functional redundancy in short-chain fatty acid production. ISME J. 2018;12(2):610–622. doi: 10.1038/ismej.2017.196.
    1. Liu C, Finegold SM, Song Y, Lawson PA. Reclassification of Clostridium coccoides, Ruminococcus hansenii, Ruminococcus hydrogenotrophicus, Ruminococcus luti, Ruminococcus productus and Ruminococcus schinkii as Blautia coccoides gen. nov., comb. nov., Blautia hansenii comb. nov., Blautia hydrogenotrophica comb. nov., Blautia luti comb. nov., Blautia producta comb. nov., Blautia schinkii comb. nov. and description of Blautia wexlerae. Int J Syst Evol Microbiol. 2008;58(8):1896–1902. doi: 10.1099/ijs.0.65208-0.
    1. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17(5):662–671. doi: 10.1016/j.chom.2015.03.005.
    1. Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, et al. Olfactory receptor responding to gut microbiotaderived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A. 2013;110(11):4410–4415. doi: 10.1073/pnas.1215927110.
    1. Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol Genomics. 2016;48(11):826–834. doi: 10.1152/physiolgenomics.00089.2016.
    1. Pluznick JL. Microbial short-chain fatty acids and blood pressure regulation. Curr Hypertens Rep. 2017;19(4):25. doi: 10.1007/s11906-017-0722-5.
    1. Chang Y, Chen Y, Zhou Q, Wang C, Chen L, Di W, et al. Short-chain fatty acids accompanying changes in the gut microbiome contribute to the development of hypertension in patients with preeclampsia. Clin Sci (Lond) 2020;134(2):289–302. doi: 10.1042/CS20191253.
    1. Queipo-Ortuño MI, Boto-Ordóñez M, Murri M, Gomez-Zumaquero JM, Clemente-Postigo M, Estruch R, et al. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am J Clin Nutr. 2012;95(6):1323–1334. doi: 10.3945/ajcn.111.027847.
    1. Toral M, Robles-Vera I, De La Visitación N, Romero M, Yang T, Sánchez M, et al. Critical role of the interaction gut microbiota-sympathetic nervous system in the regulation of blood pressure. Front Physiol. 2019 doi: 10.3389/fphys.2019.00231.
    1. Yin X, Peng J, Zhao L, Yu Y, Zhang X, Liu P, et al. Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula. Syst Appl Microbiol. 2013;36(3):188–196. doi: 10.1016/j.syapm.2012.12.009.
    1. Beutler B. TLR4 as the mammalian endotoxin sensor. Curr Top Microbiol Immunol. 2002 doi: 10.1007/978-3-642-59430-4_7.
    1. Lamping N, Dettmer R, Schröder NWJ, Pfeil D, Hallatschek W, Burger R, et al. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest. 1998;101(10):2065–2071. doi: 10.1172/JCI2338.
    1. Zhou CH, Meng YT, Xu JJ, Fang X, Zhao JL, Zhou W, et al. Altered diversity and composition of gut microbiota in Chinese patients with chronic pancreatitis: gut microbiota alterations in chronic pancreatitis. Pancreatology. 2020;20(1):16–24. doi: 10.1016/j.pan.2019.11.013.
    1. Bomfim GF, dos Santos RA, Oliveira MA, Giachini FR, Akamine EH, Tostes RC, et al. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin Sci. 2012;122(11):535–543. doi: 10.1042/CS20110523.
    1. Hernanz R, Martínez-Revelles S, Palacios R, Martín A, Cachofeiro V, Aguado A, et al. Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension. Br J Pharmacol. 2015;172(12):3159–3176. doi: 10.1111/bph.13117.
    1. Conte MP, Schippa S, Zamboni I, Penta M, Chiarini F, Seganti L, et al. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut. 2006;55(12):1760–1767. doi: 10.1136/gut.2005.078824.
    1. Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513(7516):59–64. doi: 10.1038/nature13568.
    1. Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011;108(SUPPL. 1):4592–4598. doi: 10.1073/pnas.1011383107.
    1. Engels C, Ruscheweyh HJ, Beerenwinkel N, Lacroix C, Schwab C. The common gut microbe Eubacterium hallii also contributes to intestinal propionate formation. Front Microbiol. 2016 doi: 10.3389/fmicb.2016.00713.
    1. Duncan SH, Louis P, Flint HJ. Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. Appl Environ Microbiol. 2004;70(10):5810–5817. doi: 10.1128/AEM.70.10.5810-5817.2004.
    1. Udayappan S, Manneras-Holm L, Chaplin-Scott A, Belzer C, Herrema H, Dallinga-Thie GM, et al. Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice. NPJ Biofilms Microbiomes. 2016 doi: 10.1038/npjbiofilms.2016.9.
    1. Zhang J, Song L, Wang Y, Liu C, Zhang L, Zhu S, et al. Beneficial effect of butyrate-producing Lachnospiraceae on stress-induced visceral hypersensitivity in rats. J Gastroenterol Hepatol. 2019;34(8):1368–1376. doi: 10.1111/jgh.14536.
    1. Groot HE, Van De VYJ, Verweij N, Lipsic E, Karper JC. Human genetic determinants of the gut microbiome and their associations with health and disease : a phenome - wide association study. Sci Rep. 2020 doi: 10.1038/s41598-020-70724-5.
    1. Calderón-pérez L, Gosalbes MJ, Yuste S, Valls RM, Pedret A, Llauradó E, et al. Gut metagenomic and short chain fatty acids signature in hypertension : a cross-sectional study. Sci Rep. 2020;10:1–16. doi: 10.1038/s41598-020-63475-w.
    1. John OD, Mouatt P, Majzoub ME, Thomas T, Panchal SK, Brown L. Physiological and metabolic effects of yellow mangosteen (Garcinia dulcis) rind in rats with diet-induced metabolic syndrome. Int J Mol Sci. 2020;21(1):272. doi: 10.3390/ijms21010272.
    1. Receptor P. Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome. Mol Cell Biol. 2013;33(7):1303–1316. doi: 10.1128/MCB.00858-12.
    1. Infirmary R. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21:793–798. doi: 10.1136/gut.21.9.793.
    1. Donohoe DR, Garge N, Zhang X, Sun W, Connell TMO, Bunger MK, et al. Article The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon. Cell Metab. 2011;13(5):517–526. doi: 10.1016/j.cmet.2011.02.018.
    1. Duszka K, Oresic M, Le MC, König J. PPAR γ Modulates Long Chain Fatty Acid Processing in the Intestinal Epithelium. Int J Mol Sci. 2017;18(12):2559. doi: 10.3390/ijms18122559.
    1. Byndloss MX, Olsan EE, Rivera-chávez F, Tiffany CR, Cevallos SA, Lokken KL, et al. Microbiota-activated PPAR- g signaling inhibits dysbiotic Enterobacteriaceae expansion. Int J Hypertens. 2017;575(August):570–575.
    1. Li J, Sun M, Ye J, Li Y, Zheng H, Liang F, et al. The mechanism of acupuncture in treating essential hypertension : a narrative review. Int J Hypertens. 2019;2019:8676490.
    1. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555(7695):210–215. doi: 10.1038/nature25973.

Source: PubMed

3
Se inscrever