Dr. Gary Gibbons, Director, NHLBI: I know you're a clinician scientist. Has your prescription changed to the preventive cardiology patients you see related to your studies quite yet? Dr. Stan Hazen, Cleveland Clinic: Not really. I mean, all this does, in many ways, is reinforce many of the known things: decreased amount of red meat, decreased fat, decreased cholesterol. If you do that, you have less phosphatidylcholine in the diet. I do think, though, that taking supplemental, additional choline or carnitine, these are things that are commercially available in the grocery stands. Unless there's some deficiency state of some kind or, there are conditions, like patients with inborn errors of metabolism and such, where these are essential nutrients that are provided as part of a therapy. But in a healthy individual who's trying to do something for the good of their own health, they may not be doing something good of their own health by grabbing that energy drink, or grabbing the capsule of carnitine, thinking that they're going to boost their energy. In the long run, they may be shifting their metabolism towards a more proatherogenic form. So, I'm not changing my recommendations yet, other than staying stay with the natural stuff, the fruits, the vegetables. Try not to get it in a can or in a capsule. Dr. Gibbons: Another sort of, perhaps, provocative question is what is a healthy intestinal microbiome? Dr. Hazen: Well, good luck with that one – I don't know – someone who's happy and doesn't have indigestion. I don't know the answer to that, and that is – so, the genetic complexity of the microbiome has more genetic diversity than, you know, ten to 100-fold more the genetic variance in humans, in homo sapiens. And in each one of us, Homo sapien DNA is less than 10% of all the DNA in each of us. That’s how abundant the microbes are in us. And so, it's a very complex composition. And we're very far away from being able to make a single determination or measurement to say it is a healthy one. I think instead we'll be measuring individual compounds that are made, things that we don't want to see. Dr. Gibbons: I put that question out there, because if studies like yours continue, though, as we look at different subpopulations, as you have, that we then track as low, medium risk or that we then do interventions on, are we going to be able to define a signature that starts to characterize a low or moderate, or a high risk related to that, in addition to the metabolites, as you're describing? But is there a signature that you think will evolve to, or start to have as a collection of datasets, if you will? Dr. Hazen: I think that there will be, but truthfully, I don't think it's going to be a signature in the form of a holistic pattern. I think, instead, it'll be much in the same way a diagnostic test looks for a specific thing. It will be looking for a specific character, a trait, and seeing whether in quantifying the extent of that, and we'll have some kind of clue as to a quantitative index of what seems to be good versus what seems to be bad. So, for example, the enzyme that produces this activity, this metabolite, if we know the sequence of it, you can make an RTPCR assay. You can literally quantify the number of copies of that gene over the total number of bacterial genes, and get a quantitative assay, if you wanted to be measuring things in stool. I'd much prefer to try to measure something in urine or plasma. But rather than measuring the whole thing, we could say, what's the copy number of this enzyme. So, a high level, we think, in theory, although we haven't measured this yet, would be a bad thing. And a low number would be a good thing. I think that's the direction things are going to go. Once we start to dissect and understand the biochemistry of what the microbe is doing. That's the key, is getting beyond the alphabet soup of the smorgasbord of here's all the different microbes. It's actually to work out the chemical brail, the biochemical pathways. What are they doing? And then look for and measure the mediator. I mean, that's what the blood tests are right now. And I think that that eventually is the direction where we have to go for all of these things. So, if you've got celiac disease, these are the microbes that we think may be contributing. Or if you've got an inflammatory bowel, there's a way of actually looking for a mediator or a metabolite, I think, eventually is going to be a more powerful approach than a holistic composition of a very large number of microbes. Dr. Gibbons: Now, as you know, the NIH does encourage the translation of fundamental discovery science in cases into commercialization of new diagnostic and therapeutics, and I noted that you've licensed some of your technology. Where do you see that direction taking you? Dr. Hazen: Well, on the diagnostic side, this compound TMAO, we're working towards trying to develop that and make the test more available for multiple reasons. One is, it's not the kind of thing that even if, at other institutions, someone wants to have it measured, they can't go to their hospital lab and get it done. So, we're trying to, from both a research and a clinical availability standpoint, since it seems to be a very potent and prognostic indicator. And may even be helpful in helping to tailor, for example, a person's diet and say for you, what you're doing is enough, or maybe for you, it's not enough. You need to cut back on your precursor, the things that lead to forming TMAO, to try to – those studies are so far away, but we are working on trying to make this test available as a diagnostic. But the other thing is, we're trying to work on the very question you asked before, and that is develop therapeutics to try and target and inhibit the formation of these metabolites that we think are contributing to the disease process. And all I can say is stay tuned. That's an area that's in progress and we're working on trying to see if we can have our steak and eat it, too, so to speak. Dr. Gibbons: Ahh. Dr. Hazen: Make a tablet to block the formation of the bad actor, so to speak. Dr. Gibbons and Dr. Hazen Transcript Segment 4