Gut Microbiota in Hypertension

Pedro A. Jose; Dominic Raj


Curr Opin Nephrol Hypertens. 2015;24(5):403-409. 

In This Article

Gut Microbiota and Hypertension

The gut microbiota, dominated to a large extent by Firmicutes and Bacteroidetes and to a lesser extent by Actinobacteria and Proteobacteria,[45] constantly adapt to lifestyle modifications, such as diet[46,47] and even exercise.[48] The gut microbiota can regulate about 10% of the host's transcriptome, especially those genes related to immunity, cell proliferation, and metabolism.[49,50] The gut microbiota may play a role in the development of cardiovascular disease, including arteriosclerosis and hypertension. Female C57BL/6J Apoe−/− mice develop atherosclerosis related to increased trimethylamine N-oxide (TMAO) levels following fecal microbial transplantation from atherosclerosis-prone C57BL/6J mice fed choline diet.[51] Toxic metabolites, such as p-cresol, indoxyl sulfate, and TMAO, are produced following fermentation of protein by gut microbiota.[52–54] Chronic kidney disease patients have elevated plasma levels of TMAO that are derived from the metabolism of dietary choline, phosphatidylcholine (lecithin), and l-carnitine by microbiota.[55] This elevation in plasma TMAO levels is probably mainly due to gut microbial action, because genes play a minor role in determining TMAO levels in humans.[56]

Short-chain fatty acids (SCFAs) produced by the gut microbiota[40] influence blood pressure that is related to renal sensory nerves.[43,57] These SCFAs activate two orphan G protein-coupled receptors – GPR41 (also known as free fatty acid receptor 3), GPR43 (also known as free fatty acid receptor 2), and olfactory receptor 78 (Olfr78). The increase in blood pressure caused by SCFA-induced renin release from the afferent arteriole is mediated by Olfr78. This, in turn, can be counteracted by the vasodilatory action of GPR43.[43,57] SCFA, via GPR43, also suppresses insulin signaling in adipocytes, improving metabolism, in part, by inhibiting the accumulation of fat in adipose tissue.[58] By contrast, GPR41 increases energy expenditure by stimulating the sympathetic nervous system, but this could also lead to an increase in blood pressure.[59]

Chronic low-grade inflammation can be a cause or consequence of hypertension.[60] Low-grade inflammation can be the result of a reduction in microbial gene richness.[61] Preeclampsia is associated with hypertension and inflammation, the incidence of which is decreased by chronic intake of probiotics.[62] Changes in the ratio of the microbes Firmicutes and Bacteroidetes have been used as a biomarker for pathological conditions. The Firmicutes and Bacteroidetes ratio was recently reported to be increased in spontaneously hypertensive rats, angiotensin II-induced hypertension in rats, and small group of humans with essential hypertension. The oral administration of minocycline normalized the Firmicutes and Bacteroidetes ratio and blood pressure of spontaneously hypertensive rats and rats with angiotensin II-induced hypertension.[63] Angiotensin-converting enzyme type 2 (ACE2)-mediated regulation of gut microbiota is important in epithelial immunity.[64]Lactobacilli also produce biologically active peptides capable of inhibiting ACE1;[65] ACE2-mediated production of angiotensin 1–7 decreases, whereas ACE1-mediated production of angiotensin II increases blood pressure.[28]

Consumption of milk fermented with Lactobacilli lowered blood pressure in hypertensive humans.[66] The antihypertensive effect of blueberries may also be due to Lactobacilli in the gut.[67] Oral administration of sour milk to spontaneously hypertensive rats has been reported to lower SBP. Phenylacetyl glutamine is a gut microbial metabolite that is negatively associated with pulse wave velocity and SBP.[68] A meta-analysis of randomized, controlled trials in humans showed that probiotic consumption modestly decreased both SBP and DBP, with a greater effect when at least 1011 colony-forming units are taken for at least 8 weeks, and if multiple species of probiotics are consumed.[69]

The role of a particular species of gut microbiota on blood pressure regulation needs to be sorted. For example, both the Dahl salt-sensitive and salt-resistant rats on a high salt diet have more Firmicutes than Bacteroidetes but the ratio may be the same in these two Dahl rat strains. This is in contrast to the aforementioned increased Firmicutes and Bacteroidetes ratio in spontaneously hypertensive rats, angiotensin II-induced hypertension in rats, and hypertensive humans.[63] The amount of Bacteroidetes, especially the S24–7 family, and the family Veillonellaceae of the Firmicutes phylum was higher in Dahl salt-sensitive than Dahl salt-resistant rats. Dahl salt-sensitive rats given cecal content from Dahl salt-resistant rats had higher blood pressure, higher Veillonellaceae, higher plasma acetate and heptanoate, lower sodium excretion, and shorter life span that those that received cecal content from Dahl salt-sensitive rats.[70] These effects were not found in Dahl salt-sensitive rats fed a low-salt diet or antibiotics. By contrast, the blood pressures of Dahl salt-resistant rats on high-salt diet were not affected by cecal content from Dahl salt-sensitive or salt-resistant rats. There are also no differences in Olfr78 and Gpr41 sequences between these two rat strains.[70] However, antibiotic treatment resulting in a reduction in the biomass of the gut microbiota elevated the blood pressure in Olfr78 knockout but not wild-type mice.[43] Thus, the influence of that gut microbiota on blood pressure is modulated by genetics.