Acute Administration of Gut Microbial Metabolites Reduces Blood Pressure and Cardiac Contractility

Abstract

Metabolites produced by the gut microbiota can affect host physiology; one class of these metabolites are short chain fatty acids (SCFAs). Prior work by our laboratory has shown that intravenous administration of SCFAs causes acute hypotension (Pluznick, Protzko et al. 2013) and that treating vessels with SCFAs ex vivo results in vasorelaxation (Natarajan, Hori et al. 2016). To expand upon these findings, we performed IP injections of acetate in mice that were implanted with DSI telemetry transmitters to monitor mean arterial pressure (MAP) and heart rate (HR) in real time. Sodium acetate (acetate is the most abundant SCFA in the circulation) was given at a 1g/kg dose via IP, which elevates plasma acetate by 3–4 fold over baseline (Shubitowski, Poll et al. 2019). Upon sodium acetate IP injection, we observed a rapid and reproducible drop in MAP (−49.2 +/− 10.7 mmHg maximum drop, n=10 males + females, p<0.05) when compared to an IP injection of saline. Surprisingly, in addition to a significant depression of MAP, mice injected with acetate also showed a significant depression in HR (−257.6 +/− 55.8 bpm maximum drop, p<0.05). IP injections of propionate and butyrate, two other SCFA microbial metabolites, had similar depressive effects on MAP and HR, but lactate (control) had no effect. Had SCFAs been solely acting on the vasculature, we would have expected the baroreflex to increase HR. To determine if acetate was having a direct cardiac effect, we used isolated perfused Langendorff hearts from mice. During acetate infusion, Langendorff hearts showed a significant decrease in HR, suggesting a direct mechanism of action (353.8 +/− 39.5 bpm baseline vs 274.6 +/− 21.3 bpm acetate n=5, p<0.05), however the HR drop was on a much slower time scale than seen in vivo. To further probe the effects of acetate on cardiac contractility, pressure volume loops were performed on anesthetized mice and acetate was administered by IP. Inferior vena cava occlusion after acetate IP showed a significant decrease in Preload Recruitable Stroke Work (PRSW, 73.06 +/− 20.98 vs. 49.06 +/− 22.11 mmHg*μl baseline vs acetate, n=7 males + females, p<0.05) and end‐systolic elastance (Ees, 3.493 +/−1.139 vs. 1.519 +/− 0.5781 mmHg/μl baseline vs. acetate, n=7 males + females, p<0.05), two parameters of load‐independent cardiac contractility. Finally, pre‐treatment of conscious mice with cardioselective β antagonist metoprolol blocked the acetate mediated drop in HR in mice implanted with telemetry devices, but the drop in MAP remained intact. We hypothesize that acetate acts independently on the peripheral vasculature and the cardiac muscle, with direct and indirect effects on cardiac function. Both components are likely contributing to the MAP and HR effects seen in whole animals. Together these data demonstrate a previously unknown and potentially detrimental effect of short chain fatty acids on cardiac function.Support or Funding InformationF31HL144061, R01HL128512, R01DK107726