Gut Microbiota Plays a Central Role to Modulate the Plasma and Fecal Metabolomes in Response to Angiotensin II

Gut microbial metabolites have been implicated in contributing to blood pressure regulation; however, only a few microbial metabolites have been examined to date. In this study, we hypothesized that an unbiased screen for changes in gut microbial metabolites in a chronic Ang II (angiotensin II) infusion model would identify novel microbial metabolites associated with blood pressure regulation. To accomplish this, we used both conventional and germ-free mice, which had been implanted with minipumps to infuse either saline or Ang II. Our aim was to identify metabolites that were altered with Ang II treatment in conventional mice, but not in germ-free mice, indicating that they are dependent on the gut microbiota. Both plasma and feces samples were processed and analyzed using liquid chromatography-tandem mass spectroscopy. In plasma, we identified 4 metabolites that were significantly upregulated and 8 metabolites that were significantly downregulated with Ang II treatment in conventional mice; none of these metabolites changed in germ-free mice. Similarly, in feces, we identified 25 metabolites that were significantly upregulated and 71 metabolites that were significantly downregulated with Ang II treatment in conventional mice; none of these metabolites changed in germ-free mice. Finally, fecal 16S sequencing revealed significant shifts in the microbiome of conventional mice with Ang II treatment, including sex-specific changes. These data demonstrate that the metabolites that are differentially regulated with Ang II are dependent on the gut microbiome.