Untapped potential of gut microbiome for hypertension management

Figures & data

Figure 1. The gut microbiota derived or modified metabolites in the regulation of blood pressure. Five groups of metabolites have diverse effects five major systems to contribute to the blood pressure regulation. Red arrows indicate blood pressure-increasing effect; blue arrows indicate blood pressure-lowering effect; black arrows indicate mixed effects on blood pressure.

Table 1. Mechanisms of microbiota-derived metabolites in blood pressure regulation.

Metabolite		Blood pressure change	Mechanisms
Short chain fatty acids	Acetate	Lower	1. Activate Treg cells, enhance mRNA levels of Tjp1.^Citation24 2. Reduced expression of IL17a and IL6.^Citation24
	Propionate	Increase or Lower	1. Activate Olfr78 to raise blood pressure,^Citation30 while activate Gpr41 to lower blood pressure.^Citation28 2. Attenuate T cells responses to Ang II, and reduce Th17 and memory T cells, leading to a decrease in blood pressure.^Citation26
	Butyrate	Lower	1. Enhance β-oxidation of the intestinal mucosa.^Citation32 2. Alleviate immune inflammatory reactions.^Citation32
Trimethylamine-N-oxide		Increase	1. Enhance the pro-hypertensive effect of Ang II.^Citation36 2. Decrease vascular compliance, induce endothelial dysfunction, and atherosclerosis.^Citation38
Bile acid		Lower	1. Lower succinate, a pro-hypertensive metabolite.^Citation40 2. Activate multiple receptors, including FXR, PXR, VDR, and TGR5.^Citation42,Citation43
H2S		Lower	1. Dilate peripheral vessel through K-ATP channels.^Citation58 2. Attenuate Ang II-dependent autonomic dysfunction.^Citation59 3. Improve endothelial by activating the PPARδ/eNOS pathway.^Citation60 4. Inhibit renin synthesis and release.^Citation61
Serotonin		Increase or Lower	1.Activate vagal nerve and strong vasoconstriction.^Citation62,Citation63 2.Collaborate with enteric nervous system and the autonomic nervous system.^Citation64

Table 2. Effectiveness of antibiotics and the associated microbiota in different experimental animals.

Antibiotic	Object of study	Blood pressure change	Gut microbial change	Reference
Minocycline	Ang II-infused Sprague-Dawley rats	Lower	↑Akkermansia, Bacteroides, Enterorhabdus, and Marvinbryantia	^Citation100
	high fructose diet-induced Sprague-Dawley rats	Increase	↑Akkermansia ↓Lactobacillus, Ruminococcus, and Odoribacte	^Citation102
	Dahl salt‐sensitive rats	Increase	↑Firmicutes, Proteobacteria, and Verrucomicrobia, ↓Actinobacteria, Bacteroidetes, Cyanobacteria, Deferribacteres, TM7, and Tenericutes	^Citation101
	SHR	Lower	↑Actinobacteria, Cyanobacteria, Deferribacteres, and Firmicutes ↓Bacteroidetes, Proteobacteria, TM7, and Tenericutes	^Citation101
Vancomycin	Dahl salt‐sensitive rats	Increase	↑Bacteroidetes, Cyanobacteria, Elusimicrobia, Fusobacteria, Proteobacteria, and Verrucomicrobia ↓Actinobacteria, Deferribacteres, Firmicutes, TM7, and Tenericutes	^Citation101
	SHR	Lower	↑Bacteroidetes, Cyanobacteria, Proteobacteria, and Verrucomicrobia, ↓Firmicutes, TM7, and Tenericutes	^Citation101
Neomycin	Dahl salt‐sensitive rats	Increase	↑Bacteroidetes, Cyanobacteria, Fusobacteria, and Verrucomicrobia, ↓Actinobacteria, Deferribacteres, Firmicutes, Proteobacteria, TM7, and Tenericutes	^Citation101
	SHR	No change	↑Bacteroidetes, Cyanobacteria, Elusimicrobia, and Verrucomicrobia ↓Firmicutes, Proteobacteria, TM7, and Tenericutes	^Citation101
	Corticosterone-induced Sprague-Dawley rats	Lower	Not mentioned.	^Citation99
Amoxicillin	Dahl salt‐sensitive rats	Lower	↓Ruminococcus, Oscillospira, Anaerovibrio, Lactobacillus, Pseudomonas, Coprococcus, Dorea, Clostridium, Roseburia, Turicibacter, and Prevotella ↑Blautia, Prevotella, Enterobacter, Enterococcus, Klebsiella, Sutterella, and Bacteroides	^Citation101

Chen H, Li J, Li N, Liu H, Tang J. Increased circulating trimethylamine N-oxide plays a contributory role in the development of endothelial dysfunction and hypertension in the RUPP rat model of preeclampsia. Hypertens Pregnancy. 2019;38(2):96–104. doi:10.1080/10641955.2019.1584630.

 PubMed Web of Science ®Google Scholar

Xiao L, Dong JH, Teng X, Jin S, Xue HM, Liu SY, Guo Q, Shen W, Ni XC, Wu YM. Hydrogen sulfide improves endothelial dysfunction in hypertension by activating peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase signaling. J Hypertens. 2018;36(3):651–665. doi:10.1097/HJH.0000000000001605.

 PubMed Web of Science ®Google Scholar

Tomasova L, Dobrowolski L, Jurkowska H, Wróbel M, Huc T, Ondrias K, Ostaszewski R, Ufnal M. Intracolonic hydrogen sulfide lowers blood pressure in rats. Nitric Oxide. 2016;60:50–58. doi:10.1016/j.niox.2016.09.007.

 PubMed Web of Science ®Google Scholar

Li C, Yang J, Wang Y, Qi Y, Yang W, Li Y. Farnesoid X receptor agonists as therapeutic target for cardiometabolic diseases. Front Pharmacol. 2020;11:1247. doi:10.3389/fphar.2020.01247.

 PubMed Web of Science ®Google Scholar

Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–276. doi:10.1016/j.cell.2015.02.047.

 PubMed Web of Science ®Google Scholar

He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Li X. et al. Short-chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci. 2020;21(17):6356. doi:10.3390/ijms21176356.

 PubMed Web of Science ®Google Scholar

Yang T, Magee KL, Colon-Perez LM, Larkin R, Liao YS, Balazic E, Cowart JR, Arocha R, Redler T, Febo M. et al. Impaired butyrate absorption in the proximal colon, low serum butyrate and diminished central effects of butyrate on blood pressure in spontaneously hypertensive rats. Acta Physiol (Oxf). 2019;226(2):e13256. doi:10.1111/apha.13256.

 PubMed Web of Science ®Google Scholar

Calderón-Pérez L, Gosalbes MJ, Yuste S, Valls RM, Pedret A, Llauradó E, Jimenez-Hernandez N, Artacho A, Pla-Pagà L, Companys J. et al. Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study. Sci Rep. 2020;10(1):6436. doi:10.1038/s41598-020-63475-w.

 PubMed Web of Science ®Google Scholar

Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, Pluznick JL. 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.

 PubMed Web of Science ®Google Scholar

Felizardo RJF, de Almeida DC, Pereira RL, Watanabe IKM, Doimo NTS, Ribeiro WR, Cenedeze MA, Hiyane MI, Amano MT, Braga TT. et al. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. FASEB J. 2019;33(11):11894–11908. doi:10.1096/fj.201901080R.

 PubMed Web of Science ®Google Scholar

Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Treviño-Villarreal JH, Mejia P, Ozaki CK. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015;160(1–2):132–144. doi:10.1016/j.cell.2014.11.048.

 PubMed Web of Science ®Google Scholar

Rose P, Moore PK, Whiteman M, Kirk C, Zhu YZ. Diet and hydrogen sulfide production in mammals. Antioxid Redox Signal. 2021;34(17):1378–1393. doi:10.1089/ars.2020.8217.

 PubMed Web of Science ®Google Scholar

Magee EA, Richardson CJ, Hughes R, Cummings JH. Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans. Am J Clin Nutr. 2000;72(6):1488–1494. doi:10.1093/ajcn/72.6.1488.

 PubMed Web of Science ®Google Scholar

Tomasova L, Konopelski P, Ufnal M. Gut bacteria and hydrogen sulfide: The new old players in circulatory system homeostasis. Molecules. 2016;21(11):1558. doi:10.3390/molecules21111558.

 PubMed Web of Science ®Google Scholar

Szlęzak D, Bronowicka-Adamska P, Hutsch T, Ufnal M, Wróbel M. Hypertension and aging affect liver sulfur metabolism in rats. Cells. 2021;10(5):1238. doi:10.3390/cells10051238.

 PubMed Web of Science ®Google Scholar

Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S. et al. H 2 S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine γ-lyase. Science. 2008;322(5901):587–590. doi:10.1126/science.1162667.

 PubMed Web of Science ®Google Scholar

Huc T, Jurkowska H, Wróbel M, Jaworska K, Onyszkiewicz M, Ufnal M. Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats. Exp Biol Med (Maywood). 2018;243(1):96–106. doi:10.1177/1535370217741869.

 PubMed Web of Science ®Google Scholar

Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, Zadeh M, Gong M, Qi Y, Zubcevic J. et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65(6):1331–1340. doi:10.1161/hypertensionaha.115.05315.

 PubMed Web of Science ®Google Scholar

Hsu CN, Chan JYH, Klh W, Yu HR, Lee WC, Hou CY, Tain YL. Altered gut microbiota and its metabolites in hypertension of developmental origins: exploring differences between fructose and antibiotics exposure. Int J Mol Sci. 2021;22(5):22. doi:10.3390/ijms22052674.

 Web of Science ®Google Scholar

Galla S, Chakraborty S, Cheng X, Yeo JY, Mell B, Chiu N, Wenceslau CF, Vijay-Kumar M, Joe B. Exposure to amoxicillin in early life is associated with changes in gut microbiota and reduction in blood pressure: findings from a study on rat dams and offspring. J Am Heart Assoc. 2020;9(2):e014373. doi:10.1161/JAHA.119.014373.

 PubMed Web of Science ®Google Scholar

Honour J. The possible involvement of intestinal bacteria in steroidal hypertension. Endocrinology. 1982;110(1):285–287. doi:10.1210/endo-110-1-285.

 PubMed Web of Science ®Google Scholar

Data availability statement

Data sharing not applicable – no new data generated.