Hypertension alters Gut Microbial Metabolites

Abstract

Hypertension is a global public health challenge. Although multiple host signaling pathways have been discovered to play a role in hypertension, recent studies have revealed an important role of the commensal gut microbiota in contributing to blood pressure regulation. The gut microbiota can affect the host through the production of metabolites which activate signaling pathways in the host; these metabolites include those thought to largely promote host health, such as short chain fatty acids, as well as metabolites which are known to be uremic toxins (p‐cresol sulphate, indoxyl sulphate). In this study, we hypothesized that hypertension would alter gut microbial metabolite production. Furthermore, we hypothesized that an unbiased screen for changes in gut microbial metabolites would allow us to identify novel microbial metabolites. To pursue these hypotheses, six week old C57BL/6 conventional (conv, n=6) and germ‐free (GF, n=6) mice were infused with angiotensin‐II (AngII) for 4 weeks (400ng.kg−1.min−1; Alzet 1004); in parallel control groups, conv (n=6) and GF (n=6) mice received saline via minipumps. The inclusion of the GF group allows us to distinguish changes in host metabolites from changes in microbial metabolites. Following minipump implantation, animals were housed singly to prevent cross‐contamination of microbiota. At the end of fourth week, feces and blood was collected from mice. Both plasma and feces samples were processed and analyzed by using Liquid Chromatography‐Tandem Mass Spectroscopy (LC‐MS/MS) for metabolite detection (Metabalon). In feces, 33 of the top 35 metabolites which were significantly upregulated after angiotensin‐II treatment in conventional mice (saline‐conv vs. AngII‐conv) either were not detected or did not change in germ‐free mice (saline‐GF vs. AngII‐GF), indicating that they are of microbial origin. The most significant among them are choline phosphate (phospholipid metabolite, p ≤0.0029), taurohyodeoxycholic acid (bile acid metabolite, p ≤0.0203), taurolithocholate (bile acid metabolite, p ≤0.0093), and taurodeoxy cholate (bile acid metabolite, p ≤0.0166). In plasma, there were 11 metabolites which were significantly upregulated in AngII‐conv vs. saline‐conv; none of these 11 metabolites were upregulated by AngII in GF mice (saline‐GF vs. AngII‐GF). These metabolites include 4‐ethylphenylsulphate (benzoate metabolism, p ≤0.0001), p‐cresol sulfate (benzoate metabolism, known uremic toxin, p ≤0.0026), p‐cresol glucuronide (Tyrosine metabolism, p ≤0.0001), and taurodeoxycholate (Bile acid metabolite, p ≤0.0273). In summary, these data indicate that the great majority of metabolites which are upregulated in hypertension are gut microbial in origin, further strengthening the argument that the gut microbiome plays an important role in influencing host physiology in hypertension.Support or Funding InformationAmerican Heart Association (AHA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.