All about TMAO with W.H. Wilson Tang, MD


All right in today's episode we we are with Dr Tang from Cleveland Clinic. I am beyond honored to have after Tang on the podcast. He is absolutely brilliant and I cannot appreciate appreciate more tank taking the time busy busy schedule to talk with us about. Tma Island off the research is not so thank you Dr Tank for joining us. Oh thank you Danielle pleasure to be here. Thank you so I I would want free to just introduce yourself and tell everyone kind of about what do and what your work is a cardiologist researcher well. I'm actually a heart transplant cardiologist at the Cleveland Clinic and my day job I see patients with heart failure and trying into identify potential courses and trying to delay the progression and if unfortunately they get worse I try to see where what we could do with mechanical devices or transplants and then actually take care of them after wits so obviously that's very different from my research were which is trying to prevent that from happening it is too many people heading towards the same cliff and we definitely need to find ways to prevent ben from developing heart disease and more importantly heart failure absolutely and your research is is just outstanding. We'll everything you do is incredible. The heart failure and transplant is obviously very amazing aspect because so much is changing with our different not only medical therapies irby's but now with transplant and some of the mechanical circulatory support so it's really a dynamic changing an unbelievable feel. Your research is so groundbreaking and fascinating to me so I would love if you could give everyone. There's a lot of physicians scientists and Science Lovers listened to my podcast and a lot of them are interested interest in the work you did so. I'd love if you could kind of give an overview just starting kind of about what tm Ao is an and your work and how it relates to cardiovascular disease sure so I've always been fascinated by how heart how the heart interacts with other organs and in particular the kidneys and so for a long time I've been working with a different researchers to look at how the heart and the kidney interacts and my translational research has actually headed towards that direction early on where we were trying to find molecules in the blood that distinguish between those who progress develop you know kind of the events versus those who do not aw and early on I measured a lot of small molecules that we actually know to have kind of aspirations something like the adm a is symmetric saw Janine which is really an endogenous Netra. I'll say synthase inhibitor and also different small molecule metabolite so that's actually actually where I started looking at oxidative stress and nitrogen stress and how you know kind of using blood and urine we could actually detect early triggers that can can help us identify. You Know Progressive Diseases so we have this kind of. I did that potentially many unknown substances in the blood at also tell the same story and when we first started we have a mass SPEC machine that could identify different small molecule us and we have samples of patients who subsequently develop diseases that we have collected early on with a control group of those who did not develop disease so we actually try it over and over again using different incase controlled comparisons to look at a vast array of molecules small molecules usually under like a hundred Dalton and so America weight a hundred and trying to figure out you know these sma- accused whether they could distinguish patients who have events versus don't have events events and as you imagine when we keep going this case control you know comparison over and over again using different cohorts of samples we ended up saving down filtering down you know less and less number molecules until we hit about eighteen of them only after like multiple secessions off ah case controlled comparisons and so that actually seeps out from thousands of molecules through eighteen but then they all kind of in molecular weight the we actually don't know what they are art we knew one or two of them but we didn't know the rest and and so it's a hard work of a few postdoctoral fellows from Dr Stan Heathens lab that started working on literally figuring out the permutation combination of these potential compounds and then of course we have to validate date them as you can imagine many many difference. Amok you have to say molecular weight so if you think about it literally doing trial and error at that point that was it's kind of a hectic work but then we we certainly find three molecules in these eighteen that seemed to be correlating into each other and we were very perplexing what they are so we actually focus assets in looking in a band and it turns out the all having a Trimbe Isao group so three mess me sell that linked to link together and one of them seem to be a by product that is conversion version by humans but it was generated by bacteria in the literature so that's how we actually you know mentally got into the whole field of Gut microbiome grown obviously never predicted that this is going to happen but we started to be able to specifically identify the NFL which was try Michel and and Tommy fell and oxide superbeets I mean and so this is actually how we act on that and so after that we have you know obviously other samples that had long term outcomes and we started to kind of off generate and the perspective cohort of patients who we know over time had you know so a number of people have diseases and we started added to you know analyze those ampoules identify independently identify the pro value of Cameo in those cohorts which which was independent of all the traditional sectors and to demonstrate that indeed it may be a causative factor we have to turn to animal role models and conveniently the most model that we had had the bacteria and got that produces a good amount of tm that with your Mayo we learn about subsequently because some mouse actually don't have those bacteria that makes him a which becomes very very convenient for us otherwise but we the most common laboratory mouse list electric miles and in fact it does generate a lafayette meal when they were Fed with choline rolling diet chain a really comes from bacteria consumption of substrates that we the food that we eat every day so anything anything with me saw groups that they could actually use as food the bacteria used as food. ended up generating this torturing us. I protocol brought a copy emmy which it goes into the blood and through the liver and deliver. I should convert it to Tamil so the foods that are most post high in choline and carnitine which are the precursors when they go through the microbiome to go from t t mail so these you find find highest in you would say things like eggs and at red meat yeah meat liver. You know things that actually have high cholesterol electro. It's kind of some people even called it the third cholesterol and it is something that that the other thing that we as cardiologists tell patients to avoid for good balanced diet half high choline content now just be aware that choline is important some people. I feel quite strongly that in early development we do need cold into a precursor for Coleen which obviously is important for neural zero development so that's why it's actually Africa as a supplement for pregnant women and actually consumption guidelines guidelines for that and some older patients also use Coleen for that purpose thinking that they may actually help with reducing cognitive decline fine except that obviously the data there is not very strong but I think it is important to recognize this is where we found out later and improbably interesting to your audience that another compound that is common in foot- groups is commenting which is a meet and red meat in particular and that certainly has a different type of enzymes in different types of bacteria that convert the connotation into and subsequently lead to production of TM L. so I think that's where we have the the a unique opportunity to truly understand what the environment in this case that dietary intake and different food groups particularly meet and how that impact the body's response and also the metabolites produce when eating red meat. I not eating red yeah. That's fascinating and so when did you start to make the connection between TMA. Oh and Athar Genesis Platelet let aggregation atherosclerosis things like this yeah. This is actually quite early. Once we actually got the animal models going recognized at the mouth that we use indeed indeed when eating Choline fossils you're calling in particular lead to production of Cameo. Obviously we were able oh to start using the mouse model to look at after genesis so what we do is we were able to feed the mouse with without the choline content in detail and then this is the type of mouse flex most at more prone to development of Roma. This is so call eight now mice and so studies have actually shown that with like accelerated girls and and interestingly when we were well we were able to demonstrate firstly the bacteria is involved in this by giving both anybody and see whether the the cameo levels go down which they do but also for germ free mice when they don't have any gut flora where we did them choline lean diet they don't generate male or female but then when the mouse was exposed to kind of you know the the wild meaning they start doc accumulating gut bacteria `timeo production increases and the presence of this elevation leads to more through through ask the Roma and they order and when we give short-term anybody with a triple regimen something that you know stays in the bow for the four the mice we actually found that is attenuated. All these really have a direct cost-effective this now we could demonstrate you know almost like the cost postulate that we learn in in infectious disease microbiology that the presence of the bacteria is essentially making the metabolite and obviously tm AOL is also present some food particularly fish and seafood the task you I I was this is like the number one question to ask. You is in a preformed. TM In fish does this raise your humans ends and if so is a rise from that form of TMA. Oh bad for us it actually it does in fact if you actually have you you know just otherwise healthy individuals eat a wide variety of food which people have done experiments on that the the main food component that leads doue transient rise and fall and cameo is dish and particularly but not off fish half the email. You think Judy Logically Cameo. Oh is made by the muscles of the fish particularly deep sea fish because changes the melting of the the freezing point of the muscles. I was actually the muscles antifreeze so it provides a protection for the deep sea fish so that's why doesn't look like the fish in the freezer it actually make make make sufficient up freeze and so so impact people have done a lot of work in marine green biology on on this and in fact the enzymes made in fishes muscles that actually convert TMA os well alm aw generate and also eliminate because when fish you know moves from Coda to warmer waters. Actually some of this also changed so we actually actually know that not auditions created equal to not only from cameo levels but also their fish oil levels so you actually measured him. Ill level in say you know lake fish will Shallow Water Trish they actually timmy levels are quite low in back some of them. Are you know non you know very very low. Concentrations whereas deep sea fish like called and like you know a fish that we actually tuna in you know or

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