Welcome back to my YouTube channel. So we have another interesting medically themed interview today following on my previous interview about the mysterious condition called functional dyspepsia. We have here John Damianos-MD who is currently a resident in Yale Medical School, super interested in medical education, clinical educator, distinction, CED, and unlike a lot of doctors and those in the medical community, John is very active on Twitter. His Twitter hashtag is DamianosMD and that's how I came across him sharing some really interesting stuff about the gut microbiome and the gut brain axis, which is of course very relevant to FD and really something John is very interested in. So John, firstly, thank you for taking time to speak to me today. So the question I want to start with, which might be perhaps a very loaded question. But, you know, this term, the gut brain axis is thrown around. Can you explain exactly what it is this connection between, you know, our enteric nervous system and the nervous system here in our brain and how does it work exactly? Sure. I agree that that is a loaded question, but it's a very important one and understanding it, I think, opens a lot of doors. So the gut brain axis is best thought of as thinking of the nervous system as two sides of the same coin. So there's our central nervous system, there's our brain, our spinal cord, I mean, that is a peripheral nervous system like the nerves that allow us to feel, you know, when we grab something and our gut has its own nervous system as you alluded to the enteric nervous system. And this is a very extensive network of nerve cells that regulates motility of the gut, sensation in the gut contributes to digestion and has links to the immune system, the endocrine system, and many other body systems. And they're really, as I mentioned, two sides of the same coin, and they come from the same both evolutionary and embryologic precursors. And so in human development, in the womb, the central and the peripheral nervous system really come from the same progenitor tissues. And so people who have dysfunction in the central nervous system are more likely to have some sort of dysfunction in the peripheral nervous system, including the enteric nervous system, and vice versa for this reason that they're really two sides of the same coin. And this is relevant to many disorders, but particularly the disorders of gut brain interaction that whose pathophysiology is involved dysfunction along that relationship between the central nervous system and the enteric nervous system. And again, this encompasses many different aspects, including a gut motility, the gut microbiota, systemic and local inflammation and the entrainment of the immune system, and the endocrine system as well. I think most gastrointestinal conditions can be thought of in light of the gut brain axis. And GERD is an excellent example, because the underlying pathophysiology of GERD is transient weakness of the lower esophageal sphincter that allows reflux of contents from the stomach, mostly acid from the stomach, into the esophagus, leading to irritation and eventually erosion of the esophagus. Now, over time, that can cause irritation of the nerves in the enteric nervous system that cause sensation, that allow us to sense what's happening in the esophagus. And like any other nerve, let's say nerves on the skin, if you get a sunburn, as the sunburn is healing, your skin is very sensitive there. And so the same thing can happen. Your esophagus can become hypersensitive to any stimuli at all. And because you're having pain, you tend to focus on areas where you're having pain. And so people tend to have what's called esophageal hypervigilance, and they begin to have this hypersensitivity of the esophagus due to chronic irritation of the nerves. And even after the reflux is gone sometimes, they can still have this abnormal sensation, basically oversensitive nerve. So you're saying that's almost like it sounds like a sort of phantom condition where the actual acid is no longer there, but you still can feel it as if it's happening right now. That's a very good analogy. Another one that I use is PTSD of the gut. And this is relevant to functional dyspepsia, IBS as well. Sometimes you can have an insult where you have inflammation or trauma within the GI tract. And then after you leave that, you can have lasting changes to the local environment, including to the nerves that causes this hypersensitivity. So PTSD of the gut is another way to think about that type of phenomenon. Amazing. That is super, super interesting and something that actually makes me think about all of this and a whole new light, this idea of there being some kind of trauma and lasting response. I mean, and is there any way for, you know, for a patient to, you know, I presume when we're saying it's kind of a phantom sensation, whether it's that kind of, you know, FD like problems with bloating and motility or GERD, is there any way for me to know whether there's actual acid or this is just a sensation of acid or from a patient's perspective, does it feel pretty much the same? It can be very difficult to tease apart on just a symptom basis alone. The GI tract, it's my favorite organ system and it's a very complex organ system. At the same time, I often say that it has a limited symptom repertoire because the GI tract can only signal to us that something is wrong in a few ways. It can have pain. It can have altered bowel habits. It can have nausea, vomiting. There are really only a limited number of symptoms that the GI tract can produce. And because of that, many GI conditions will present with similar symptoms. And so if you look up, for instance, bloating. Well, there are literally hundreds of conditions that can cause bloating, gastrointestinal and non-gastrointestinal. And so symptoms alone are usually not the best way to distinguish what the underlying pathophysiology is. And this is where specialized testing can be helpful. And in the context of GERD and esophageal symptoms, for instance, there are many types of tests that we can use to measure the acid load in the esophagus to really track how much reflux is happening, how many reflux events are occurring throughout the day. And then with motility as well, there are many people who are diagnosed with GERD sort of empirically based on symptoms, but actually have esophageal dysmotility. And so people with, for instance, achalasia, it takes them about on average 10 years to actually get their diagnosis, which is usually done by high-resolution esophageal monometry that looks at the motility of the esophagus because you're actually using a test that finds the underlying pathophysiology instead of just going on symptoms alone. So let me ask you a question because your average patient who comes to their doctor and says, I'm getting horrible heartburn, so they're going to kind of lead the diagnostic process. They're not presenting to a tertiary center of excellence with esophageal mammometry. I'm sorry that I'm getting the name wrong. Does that mean that there's probably a lot of overdiagnosis of what everything looks like GERD and these more common, these more rare maybe conditions that actually have a more complex pathology are not going to get diagnosed because most people don't make it to those specialized tests and treatment centers? That's definitely true. One of the key phrases that we have in internal medicine is that common things are common. And we know that GERD is an extremely common condition within the population. It's one of the main complaints that comes to primary care. It's one of the main reasons for gastroenterology referral as well. And so if you have 100 people who are presenting with heartburn, the vast majority of them are actually going to have GERD. And so a lot of those people will respond to empiric therapy of GERD. We don't even need to necessarily put them through invasive testing of their acid levels. If they respond to GERD therapies like acid suppression, then job well done. Now we all need to have in the back of our minds of what happens when patients don't respond. And so that's where I think we can probably do a little bit better in the medical system is recognizing patients who are not responding to our GERD therapies and getting them to a gastroenterologist to work up their refractory GERD to see if it truly is refractory GERD, or if maybe we're dealing with something else like esophageal dysmotility. Very, very interesting. I think there's an expression that when you hear hooves think horses not zebras, right? Yes. Another common internal medicine phrase. So I know you are super interested in the microbiome, which is, from my perspective, kind of the superstar of medicine lately. It's all over the news. How does this complex world of bugs in our guss, does that affect the gut brain interactions, guss brain access? And what's the kind of interplay between these two things that affect our digestive health so much? Sure. That's a great question. So our gut microbiota comprises really trillions of microorganisms, bacteria, viruses, fungi, and archaea that live symbiotically with us. And they really comprise their own organ system. We really should think about the gut microbiome as its own organ system that exerts local and systemic effects. And so it does contribute to digestion via breaking down food into nutrients that we're ingesting. And another very important role of the gut microbiota is the creation of metabolic byproducts. And so a classic example is short chain fatty acids. So when we eat fiber, which we can think of as prebiotics, fiber is fertilizer for the good bacteria, I always like to say. And so when we eat fiber, our gut bacteria digest, ferment it, and create as a metabolic byproduct these short chain fatty acids like butyric acid and acetic acid that exert effects locally in the gut, protecting the gut epithelial barrier, exhibiting anti-inflammatory effects. And these are also absorbed systemically and have systemic anti-inflammatory effects and have been shown to be protective against many different types of disease states, including metabolic and immune mediated disorders. And so related to short chain fatty acids and other metabolites produced by the gut microbiota, these are things that are absorbed into the bloodstream and distributed throughout organ systems. And one of those organ systems is the brain. And so this is another link that underlies the gut brain axis is the metabolites that the gut microbiota are producing. And so you can think if your microbiota is healthy and enriched with healthy species, with diversity, functional connectivity, you have an abundance of these healthy metabolites that preserve neurologic and psychiatric functioning. And on the flip side, if you have dysbiosis or low diversity and overabundance of pro-inflammatory bacteria, they're going to produce more toxic metabolites that can have adverse consequences systemically. So it sounds like in the kind of classic chicken and egg analogy here, the chicken is the gut microbiome and dysbiosis, and then the egg is that that's going to sort of break or impair the operation of this gut brain axis. Does it work the other way around as well?  No. One of the most important components of the gut brain axis is that it is bi-directional.  And really the classic sort of first study that truly identified that the brain can affect the gut is there was a study where young healthy medical students were told that were put under endoscopy, colonoscopy specifically, and told that they had rectal cancer. And immediately they saw contractions of the GI tract. Their motility increased. There was a lot of spasm in the GI tract. And this demonstrates for the first time that the brain can impact through a top-down processing the functioning of the GI tract. And we've seen that from a motility standpoint, but also from the gut microbiome standpoint. This is relevant to disorders of gut brain interaction where early life trauma is an important risk factor.  And the mechanism of this is that chronic stress can lead to dysregulation of the autonomic nervous system and can impact the abundance of pro-inflammatory cytokines. And we have found that this does happen on the level of the microbiota as well. And there's some fascinating research of looking at top-down therapies such as cognitive behavioral therapy. And there's a suggestion that even cognitive behavioral therapy for disorders of gut brain interaction can improve the gut microbiota. So it is clear that top-down effects also impact our gut microbiota. That's crazy. So medical students who were told they had colon cancer, developed contractions, characteristic of actually having it. And people who received therapy and therefore lessen their burden of mental health had better microbiomes. So that is really, really fascinating. So it's real. It's real guys. I want to move on to a couple of super, slightly more random and specific questions. And this is not an attempt to get a free medical consultation, John. I'll send the bill. Yeah. After the interview, I saw you tweet a couple of things about bile. And that kind of caught my attention because my sort of introduction to the world of the FD club came about through gallbladder and that changes. I know the bile stuff. So you said that's like a longstanding association between dyspepsia and the bile acid pool being dysregulated or messed up is how I kind of translate that. Can you explain that? Do you understand why and what is that about basically? Sure. So it's very common for people to develop new onset gastrointestinal symptoms after having their gallbladder removed. And there are many reasons for this. Oftentimes this is bile acid malabsorption. Other times it's related to local pain in the area from surgery. And sometimes it really is a disorder of gut brain interaction like functional dyspepsia or irritable bowel syndrome related to either antibiotics, the sort of trauma and inflammation of surgery or antibiotics that were given with surgery as well. Antibiotics are certainly an important risk factor for dysbiosis and the development of disorders of gut brain interaction. Now one of the other important functions of the gut microbiota is to regulate bile acid metabolism. And in disorders of gut brain interaction has been shown that patients do, that certain patients have altered bile acid metabolism that may be attributed to their particular composition of the gut microbiota. Now in functional dyspepsia specifically there is a suggestion that some patients may have bile acid reflux after their colostectomy. And so colostectomy in general can lead to more bile acid reflux through changes of the hepatobiliary motility. And in patients who sort of are predisposed to this sort of visceral hypersensitivity over the oversensitive nerves in the upper GI tract may have more symptoms after colostectomy due to this bile acid reflux. And so there are several studies actually that have shown that some patients with functional dyspepsia have this abnormal physiology. They just have more bile that's sitting around in their stomach and really we shouldn't have that and that can be irritating. To the nerves. Got it. Interesting. And speaking of nerves my second very specific question is something that I know a lot of patients are really interested in is the various antidepressants. And the fact that it seems that for FD and also for IBS that the older tricyclics amitriptyline nor triptyline are used in these low dosages and not the newer SSRIs and SNRIs. And I've tried through my very limited ability as someone with Google to understand that's intriguing. Why is it that the older drugs are used? Does anyone actually know or is it all kind of just trial and error at this point? No, there actually is a good path of physiological explanation for that. And before I go into that I want to emphasize that in the GI world we refer to these medications as neuromodulators. We prefer not to use the term antidepressants even though they were developed as antidepressants. And the reason for that is we're not using them to treat depression. That's often a favorable side effect that we use them for and certainly when we treat disorders of gut-brain interaction we want to treat the comorbid psychiatric disorders that are very, very common in disorders of gut-brain interaction or really we're using them as neuromodulators to impact either the central nervous system or the enteric nervous system because again, two sides of the same coin. 95% of our serotonin is made and stored in the gut, not the brain. And so medications that affect serotonin like SSRIs and SNRIs are going to affect the gut just as much as they're affecting the brain. Now as to why the older medications tend to have more favorable effects in disorders of gut-brain interaction I actually have a diagram here that I think is going to be very helpful for you. Yeah, and so this comes from mainly Dr. Drosman who is behind the Rome Foundation for disorders of gut-brain interactions and he's published a lot on central neuromodulators for disorders of gut-brain interaction. And the diagrams here specifically come from the psychopharmacology literature that looks at the receptor targets that each of these compounds is targeting. And so as you can see here, if you look at the TCA to start, you can see that it's filled with all these different receptors that it targets. So it targets serotonin receptors, norepinephrine receptors, autonomic receptors, histominic receptors, muscarinic receptors. So it just targets a lot of different receptors. I want to jump in with one really, really quick explanation because my intention is to share this with a similarly layman audience to me. So TCA's are those drugs also called tricyclics, right? It's the same class of, sorry, I was going to say antidepressant neuromodulators. Yep, exactly. And you can see at the top there, at the top left that it gives some examples of TCA's like amitriptyline, nortriptyline, amipramine, disipramine. And so as you can see, these exert many physiologic effects due to the many receptor targets that it has. Now sort of the potential downside of this is that can lead to more side effects. And that was one of the reasons that SSRIs and SNRIs were developed because they're more targeted in their receptor selectivity. So if you look at SSRIs in that second column, and that includes things like peroxitine, fluoxitine, like sertraline and lexapro, for instance. These, and I also, if there are any psychiatrists or psychopharmacologists watching this, I want to emphasize that this is somewhat of an oversimplification. But in general, the SSRIs tend to have greater selectivity for the serotonin pathway, and they lack a lot of the other receptor targets. And this is great if you're treating anxiety and depression and want to reduce the side effect profile of the medication. Similarly, SNRIs target the serotonin pathway and the norepinephrine pathway. And then there are other classes like the tetracyclics, which again have more receptor targets. And so because of this, we, for neuromodulators, tend to use things like TCAs and the so-called atypical antidepressants because of these other receptors that they're targeting. Remember that gut motility involves some of these other receptors like the autonomic receptors that the TCAs are targeting. And so for that reason, there's better data for these than for the SSRIs and SNRIs, and particularly for painful conditions. And so a second figure here from Dr. Drossman, again, helps us determine what types of symptoms are going to respond better to what types of medications. And so again, SSRIs tend to be for kind of when anxiety and depression are really prevalent in the patient's presentation, whereas TCAs are more favorable for pain. And then the second half, the bottom half of this slide talks about augmentation when we can use other types of neuromodulators based on their receptor profiles and their side effect profiles to help patients with, again, particular symptoms. So that's kind of how I think about using neuromodulators in patients is what type of symptom are they actually experiencing? What types of symptoms are they experiencing? And in my arsenal of many different potential agents of neuromodulators, what receptor profile is best going to help their unique presentation? Super interesting. So I guess the really sort of summary version I'm going to give is because these earlier antidepressants were less selective, that made them ironically less good for psychiatric disorders. But you actually want that kind of broad array of the histamine receptor and all the other ones they kind of bounce off. Exactly. We're targeting pain. We're targeting motility. So there's just more that's beneficial for disorders of gut brain interaction there. I'm so excited to finally have an answer. I've been wondering that for like a year and I know there's lots of people doing it. So I'm sure that'll be very much appreciated. Because I think as patients, you know, often, personally, my family doctor is really on top of the research. And, you know, he wasn't surprised to see amitriptyline being used for stomach. But I do think that a lot of older doctors kind of say, oh, we don't use those drugs, the tricyclics anymore.  And I've seen through, again, my own Googling that there is really good research for their use. I mean, I think it's also I think there's an economic advantage in the sense that these drugs are all on generic now. So in the developing world, I understand that they're actually still very much the kind of first line, even for psychiatric stuff. So that's awesome as well. I want to close with one question. I know you are you're clearly usually interested in gastroenterology and you tell me that's what you're going into. You know, you're interested in functional all these functional disorders. What's your feeling? Are you kind of optimistic regarding what's coming down the pipeline for treatment based on what you've seen about our understanding? Or how do you kind of feel the treatment of these is going to evolve over the coming couple of decades? I'm very optimistic about about the future of disorders that got brain interaction. And I think we've seen a major shift even within my own lifetime of people's attitudes and research efforts to understanding these conditions. I think in the past, there was this mistaken dismissal of these conditions as essentially manifestations of psychiatric disease. And just so just sort of very little interest from the side of primary care and gastroenterology to manage these conditions. But through more and more emerging evidence, it's very clear that this sort of organic functional dichotomy is very superficial and misses so much of the nuance of the brain-body connection. And even with the terminology change with the Rome IV consensus from functional GI disorders to disorder of gut brain interaction, that better describes the underlying pathophysiology. And granted, there's a long way to go. There's so much that we don't understand about these disorders. But there's so much encouraging research of trying to figure out where these symptoms come from, the basic mechanisms from kind of a cellular and molecular level, and then trying to identify unique pathophysiologic contributors in each patient. I think that my personal opinion is that things like irritable bowel syndrome and functional dyspepsia are really umbrella terms for symptoms. Again, the GI tract has a very limited symptomatology that it can use to tell us that something is going wrong. And so a lot of things are going to present similarly. And so I think to use again the bile acid reflux example, I think some people with FD have bile acid reflux. Some people have small intestinal bacterial overgrowth. Some people have more dysmotility. And there's going to be a lot of overlap. But I think the future is really going to be nailing down pathophysiologic abnormalities in each patient to figure out the best treatment for them. And that's one of the challenges now is that we do have good medications for functional dyspepsia, IBS, et cetera, that work really well for some patients and not at all for other patients. And why is that? Well, it's probably because you're targeting different aspects of the pathophysiology. And so I think the future is really going to be how do we distinguish what's actually causing this patient's unique presentation of IBS, FD, et cetera, so that we can better target our treatment. Essentially, personalized medicine. That is good. I always like to end on an optimistic note. And I also caught that you're saying functional is on the way out is terminal. I know the Rome Foundation does amazing work in this regard. So if we have any consolation, at least that because it always strikes me as kind of a ironic terminology when often it's actually the fact that the system seems to have stopped functioning when you get one of these functional disorders, but that's good to know as well. So John, if people want to keep on top of your output and interest and research and get it, I'm guessing Twitter is the best place to do that. But anywhere else that might be of interest. Yes, I think GI Twitter is a wonderful place to keep up with the latest in GI knowledge. I'm at John underscore Damianos MD, and there are many, many other folks out there who are doing phenomenal work and publishing great research. I think that's a great place to start. The Rome Foundation has excellent resources for disorders of gut brain interaction. And there are many other advocacy groups that also create great patient facing content in the space with GI Twitter to their organizations like Tuesday night IBS that has that links patients and providers to have discussions about. Relevant topics and disorders like that brain interaction. And so there's just kind of more and more excitement and activity in this space. And so I'd say start with Twitter and the Rome Foundation and there are a lot of doors that will open up from there. Cool. And I want to say for anyone else who's watching this video, at my level, I find John's Twitter is super interesting because of the fact that he shares these crazy complicated medical papers, so you actually break it down in a way that I think a lot of interested people, probably mostly people who have these things because if you don't have IBS or FD, you probably have other things on your mind than the gut microbiome. But if you are engaged in the space, I think your your Twitter, your Twitter feed strikes are really great balance. And I definitely really recommend it. John, thank you very much for talking with me and best of luck with all your research, learning and of course also medical Twitter. Well, thank you very much. I truly appreciate it. It's been a real pleasure.