Paper of the Month
JULY 2018 – Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes
In July, BIH Professor Ulf Landmesser and his team received the Paper of the Month award.
Haghikia A, Li XS, Liman TG, Bledau N, Schmidt D, Zimmermann F, Kränkel N, Widera C, Sonnenschein K, Haghikia A, Weissenborn K, Fraccarollo D, Heimesaat MM, Bauersachs J, Wang Z, Zhu W, Bavendiek U, Hazen SL, Endres M, Landmesser U. Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. Arterioscler Thromb Vasc Biol. 2018 Jul 5. pii: ATVBAHA.118.311023. doi: 10.1161/ATVBAHA.118.311023.
Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied.
APPROACH AND RESULTS
In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes (r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×103 per mL versus ctr.: 6.5±0.5×103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+ABS: 5.4±0.7×103 per mL; P<0.001 versus choline).
The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.
In July, a research team led by Ulf Landmesser, Director of the Medical Department of Cardiology on Charité’s Campus Benjamin Franklin and Medical Director of the CharitéCenter 11 for Cardiovascular Diseases at Charité – Universitätsmedizin Berlin, received the Paper of the Month award. We talked to him about the publication, his research, and possible therapeutic approaches.
Seltmann: Professor Landmesser, your latest publication addresses the causes and prevention of heart attacks. What exactly have you found out?
Landmesser: Yes, we are taking an in-depth look at what’s known as coronary heart disease, which involves arteriosclerosis in the coronary arteries and can cause a heart attack. There are about 10,000 heart attacks in Berlin alone every year. We have observed a connection between the bacteria we have in our intestines – our microbiome – and the risk of suffering a heart attack. And we think that this connection is mediated by certain substances produced by the intestinal bacteria, which pass into the bloodstream and can then apparently increase the risk of vascular obstruction in the arteries. In the future, this finding could provide us with a completely new approach to reducing the risk of heart attacks. We are looking at ways to decrease the concentration of substances released by bacteria that are harmful to humans. And, of course, we also want to better understand why these substances are produced in the first place.
Seltmann: How could the production of these substances be reduced?
Landmesser: I would like to start by saying that our research was conducted in cooperation with the Cleveland Clinic. We have established an international, transatlantic network of research excellence. One of the objectives of this research network is to identify substances that can inhibit the formation of these metabolites in bacteria. The interesting thing about this is that when we prevent heart attacks by inhibiting substances that promote vascular obstruction, we often see an increased risk of bleeding as a side effect. In other words, substances that inhibit blood clotting reduce the risk of heart attacks, but they also increase the risk of bleeding. And the interesting thing about this new approach, we think, could be that one could influence the bacteria in such a way that reduces the risk of a heart attack without simultaneously increasing the risk of bleeding. So it could offer a particularly elegant method to reach our objective.
Seltmann: What exactly do these bacteria-produced substances do? How do they increase the risk of heart attacks?
Landmesser: This is the subject of our research, and we are continuing to investigate this in our research group. One observation we have made is that this metabolite upregulates the factors that promote blood clotting, the so-called tissue factor, in the endothelial cells that line our arteries. This means that the metabolites from the bacteria ultimately activate the formation of clots in the blood vessel. This is a mechanism we think might play a role. Through our current work we have also found out that the metabolites are associated with an increased tendency toward inflammation in patients. We still need to gain a more precise understanding of how that works. The idea that inflammation is associated with arteriosclerosis goes back to Rudolf Virchow, who, 160 years ago here in Berlin, described this process in various articles he wrote. And we are actually only now beginning to really understand the mechanisms of how this is connected.
Seltmann: The risk of suffering a heart attack depends, among other things, on how active you are, whether you smoke and whether you eat healthily. Given that the microbiome is found in the gut, one could imagine that diet has an influence on the composition of the microbiome and thus on the risk of a heart attack?
Landmesser: It is certainly conceivable that the microbiome acts as a mediator between nutrition and heart attack risk. Indeed, Dominik Mueller of the Max Delbrück Center in Berlin-Buch has been able to show that salt consumption reduces the amount of certain intestinal bacteria and increases blood pressure. It is therefore also possible to imagine that our diet could change the microbiome in such a way that more of these metabolites, which we can now identify, are released. So it is certainly conceivable that diet effects the composition of our microbiome.
Seltmann: How can the production of this harmful metabolic product be inhibited?
Landmesser: The enzyme in the bacteria that is responsible for its production can be specifically inhibited. This would give us a substance that has no effect on humans but only attacks the bacteria, which would ideally reduce the risk of a heart attack.
Seltmann: Does this enzyme-inhibiting substance already exist? Is this a drug that is available?
Landmesser: No, this substance is currently being investigated in experiments. We hope that, together with our colleagues from Cleveland, we will be able to conduct a phase I clinical trial that will allow us to investigate its effect on humans for the first time.
Seltmann: That would certainly also be interesting for the pharmaceutical industry if it were to produce results.
Landmesser: Absolutely. It is possible that a “proof of concept” study will be conducted, and, if successful, it will probably be necessary at some point to collaborate with the pharmaceutical industry – because neither BIH nor Charité have the funds to finance such a large-scale study program on their own.
Seltmann: Now, what are the next steps?
Landmesser: I hope that within the next three years we will be able to conduct trials with humans and then also test the substance on patients. But this is not the only path we are pursuing. We have found other interesting metabolites in the microbiome that influence, for example, cholesterol metabolism. This is a bacterial metabolite that can be administered orally, i.e., as a nutritional supplement. We are relatively far along in this research, and I hope that next year we can publish the data and – hopefully quickly – bring it into clinical application.
Seltmann: That would be a metabolite that has a positive effect on reducing the risk of a heart attack?
Landmesser: Yes, exactly. Our bacteria also produce beneficial metabolites.
Seltmann: Is it produced by the same bacteria?
Landmesser: No, these are probably different. Our bodies contain more bacteria than cells, and they do a lot of things that are good for us. We also want to conduct more research in this area and perhaps make use of it in preventive approaches.
Seltmann: Thank you very much for your time, Professor Landmesser.