Gut Microbiota in Hypertension

Pedro A. Jose; Dominic Raj


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

In This Article

Gut Microbiota, Epigenetics, Hypertension, and Salt Sensitivity

Genome-wide association studies (GWAS), which have identified only 2% of the genetic factors believed to influence blood pressure variation,[3,5,6,108] did not report GRK4 or SLC4A5 to be associated with hypertension. However, the failure to identify GRK4 and SLC4A5 in GWAS does not, by itself, eliminate GRK4 and SLC4A5 gene variants or any particular gene as causative of hypertension or salt sensitivity (or any phenotype). The current presentation of GWAS data often fails to report all truly associating variants if they do not meet arbitrary P value cut-offs.[5,109] Moreover, the chips may not contain the gene of interest. For example, SLC4A5 rs10177833 is not in any of the Affymetrix chips and rs7571842 is found in only three of the six Affymetrix chips. Illumina chips have both variants only in Human1M-Duo-v3 and each variant in only one of the seven chips. Affymetrix chips do not have GRK4142V and the only Affymetrix chip that has GRK4486V is Genomewide 6. The Illumina chips, except for Illumina Human 1M-Duo-v3, do not have GRK4486V ; not all the chips have GRK465L . The failure of GWAS to identify the association of GRK4 or other genes with hypertension in some studies[109–112] may also be due to a failure to examine gene–gene and gene–environment (salt sensitivity) interaction.

The lack of powerful genetic association in essential hypertension, especially salt-sensitive hypertension, as with type 2 diabetes and metabolic syndrome, may indicate the importance of gene modifiers, such as epigenetics, especially resulting from environmental influence.[113–115] Diet, including salt and gut microbiota, can influence epigenetics;[116–119] salt can increase oxidative stress[120,121] and oxidative stress can influence epigenetics (e.g. histone deacetylase activity).[122] Lysine-specific demethylase 1 regulates histone methylation by demethylating histone H3 at lysine residues 4 and 9, and is involved in salt-sensitive hypertension.[7,8,114,118,123] Certain miRs have been implicated in salt sensitivity and inverse salt sensitivity of blood pressure.[114,124–128] For example, miR-320 and miR-26b are increased in the aorta, whereas miR-21 and miR-1331 are decreased in the aorta and myocardium, respectively, in Dahl salt-sensitive rats fed a high-salt diet.[125,126] Several miRs in human renal proximal tubule cells were found to distinguish salt-resistant from salt-sensitive humans, including miR-3661, miR-3126, miR-3183, and miR-615–5p, whereas miR-4516 was able to distinguish salt sensitivity from inverse salt sensitivity.[127] Mir-124 expression is also increased in urinary exosomes of salt-sensitive individuals[127] and can regulate avian myelocytomatosis viral oncogene homolog (c-Myc).[128,129] C-Myc, being a proto-oncogene,[129,130] is of interest because there is a positive association of hypertension and cancer, at least in men,[131] and increased dietary salt intake increases the risk of gastric cancer.[132]