I ncreased Host Energy Metabolism in the Proximal Colon‐Microbiota Interface Elevates Blood Pressure

Abstract

Introduction : Hypertensive subjects present with alterations in gut microbiota and short chain fatty acids (SCFAs). SCFAs are the major metabolic products of bacterial fermentation in the intestine. While acetate and propionate are energy sources for peripheral tissues, butyrate is the primary energy source for the host colonic epithelium via β-oxidation or glycolysis. Since butyrate is known to elevate blood pressure (BP), we hypothesized that the mechanism of gut microbial butyrate-mediated elevation in BP is linked with an increased energy metabolism in the proximal colon. Methods : To test this hypothesis, 7 weeks old concomitantly raised male germ-free Sprague Dawley rats (GF, n=5-6) were compared with GF acquiring microbiota acutely for 10 days (germ-free conventionalized rats, GFC, n=6) for (1) BP, (2) cecal butyrate by proton nuclear magnetic resonance (1-H NMR), (3) microbial profiling by 16S RNA sequencing and (4) proximal colonic transcriptomic signatures for energy metabolism by real time qRT-PCR. Results : GFC rats acquired microbiota successfully (Figure 1 C and D) and represented an energy-repleted state with a marked increase of the colonic energy substrate, butyrate (Figure 1E). Interestingly, GFC rats had a significant increase in systolic and diastolic BP compared to GF rats (Figure 1 A and B, p<0.05). This increase in BP was associated with a significant upregulation of all 11 genes tested by qRT-PCR for energy metabolism pathways for β-oxidation and glycolysis in the colon of the GFC rats compared to GF rats (Figure 1F). These genes are: peroxisome proliferator activated receptor γ (Pparγ), free fatty acid receptor 2 (Ffar2), acyl-CoA synthetase short chain family member 1(Acss1), acyl-CoA dehydrogenase long chain(Acadl), carnitine palmitoyltransferase 2(Cpt2), hexokinase 2(Hk2), phosphofructokinase, platelet(Pfkp), phosphoglycerate mutase 1(Pgam1), glycerol-3-phosphate dehydrogenase 2(Gpd2), sirtuin 3(Sirt3)and carnitine O-acetyltransferase(Crat). Conclusion : Collectively our data reported here is the first to provide evidence for a direct relationship between host energy metabolism at the proximal gut-microbiota interface and BP regulation. Further, our studies suggest that butyrate, which is a predominant colonic energy metabolite, contributes to the mechanism governing this relationship between energy metabolism in the proximal colon with BP regulation.