Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage

Circulation. 2019 Mar 12;139(11):1407-1421. doi: 10.1161/CIRCULATIONAHA.118.036652.


Background: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage.

Methods: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate.

Results: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent.

Conclusions: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

Keywords: T-lymphocytes, regulatory; Th17 cells; angiotensin II; apolipoproteins E; fatty acids, volatile; immunology; inflammation; microbiota.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Aortic Diseases / drug therapy*
  • Aortic Diseases / genetics
  • Aortic Diseases / immunology
  • Aortic Diseases / pathology
  • Arrhythmias, Cardiac / immunology
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Arterial Pressure / drug effects
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology
  • Atherosclerosis / pathology
  • Cardiomegaly / immunology
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control*
  • Disease Models, Animal
  • Hypertension / chemically induced
  • Hypertension / drug therapy*
  • Hypertension / immunology
  • Hypertension / physiopathology
  • Male
  • Mice, Knockout, ApoE
  • Plaque, Atherosclerotic
  • Propionates / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology


  • Anti-Inflammatory Agents
  • Propionates
  • Angiotensin II
  • propionic acid