DECEMBER 2018 – Propionic acid prevents damage from high blood pressure

Nicola Wilck is fellow of the BIH Charité Clinician Scientist Program.

Abstract

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 targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFA) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in two different mouse models of hypertensive cardiovascular damage.

Methods: To investigate the effect of SCFA on hypertensive cardiac damage and atherosclerosis, wild-type NMRI (WT) or ApoE-/- deficient mice received propionate (200mM) or control in the drinking water. To induce hypertension, WT mice were infused with Angiotensin (Ang)II (1.44mg/kg/d s.c.) for 14 days. To accelerate the development of atherosclerosis, ApoE-/- mice were infused with AngII (0.72mg/kg/d s.c.) 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 (Treg) 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 AngII-infused WT mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated ApoE-/-. 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 WT mice. Cardioprotective effects of propionate were abrogated in Treg-depleted AngII-infused mice, suggesting the effect is Treg-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 non-pharmacological preventive strategy for patients with hypertensive cardiovascular disease.

Interview

In December, Nicola Wilck and his team received the Paper of the Month award. We talked to him about the rewarded publication:

What do you research? What is the focus of your work?  

Over the last few years we have become very interested in the gut microbiome. The gut microbiome refers to the vast ecosystem of microorganisms – as well as their genes – that live in our digestive tract. The number of bacteria alone is about equal to the number of cells in our body, and the number of bacterial genes is even higher. This proportionality suggests that the gut microbiome has a big influence on our health.

We think that the gut microbiome also plays a major role in cardiovascular diseases. Hypertension and hypertension-related organ damage, such as to the heart, are a particular focus of our research. Over the last few years we have been making progress in answering the question of how gut bacteria may impact a disease such as hypertension.

What motivates you in your research?

Our motivation is to shed light on the interactions between the gut microbiome, the immune system and cardiovascular diseases in order to develop new targets for treating patients.

Important pathways here are the metabolic products (metabolites) of bacteria that are taken up by the host. We are currently studying closely a metabolite that is synthesized by the gut microbiome from nondigestible carbohydrates, also known as dietary fiber.

What is the core message of your paper, and how does your study differ from the work of other scientists in this field?

We were able to show that propionate, a short-chain fatty acid produced by bacteria, protects against hypertension-related organ damage. There has been talk for some time about this family of compounds having a protective effect in the cardiovascular system, but which mechanisms are involved and which metabolites of this family play a major role has remained largely unclear. We believe that we have made an important contribution to answering these questions. We administered propionate orally in a mouse model, which led to reduced pathological remodeling processes in the heart and reduced atherosclerosis in the blood vessels. Animals treated with propionate exhibited lower activation of immune cells, especially T helper cells. The effect of propionate on hypertension was largely mediated by anti-inflammatory regulatory T cells. Especially interesting was the fact that mice treated with propionate had less cardiac arrhythmia – a common sequela in hypertensive patients.

Who did you collaborate with on this paper? Who were the key participants?

We collaborated closely with Dr. Johannes Stegbauer and his team at Heinrich Heine University Düsseldorf. While we in Berlin were working with mice that had developed a cardiac phenotype as a result of high blood pressure, Johannes and his colleagues were analogously performing experiments on mice in which atherosclerosis was accelerated. This enabled us to test our observations in another mouse model.

What are the next steps for the project, and what are the possible implications of your findings for patients?

A big advantage of the substance we tested is that propionate was already widely used as a preservative in the last century. The EU has asserted that propionate doesn’t pose any health risks. We therefore plan to quickly translate our findings to patients. While the experimental data is promising, the focus is now on evaluating potential therapies. Possibilities include directly administering propionate but also administering precursors such as dietary fiber.