All right, good morning. Everybody take their seat, we'll get started. I'm Dr. Hines. I'm a psychiatrist at Walter Reed National Military Medical Center, and I'm also on the faculty of the National Capital Consortium Residency. We'll be presenting today with Dr. Landon Sorensen and Dr. Matt Rusling, two of our outstanding residents. We've organized this. I'm going to start off with a functional medicine societal overview of some of the problems we have with our current food supply, and the way we eat, and the effects it has on the microbiome. And then some basics about the microbiome. And then we're gonna really take a 180 degree turn, and Dr. Rusling is gonna talk at the microbiome level and the cellular level about some of the ways that the microbiome affects particularly tryptophan and short chain fatty acids. And then Dr. Sorensen's gonna sort of center us back on clinical psychiatry and talk a little bit about some of the things that we can actually do now. And some of the things that will be coming along in the future in terms of better helping our patients with better treatment of their disease. All right, I don't have anything to disclose and all these opinions are my own. So what is the microbiome? The gut micro, I like the quote from Rosenberg, the gut microbiota is a complex community that helps maintain dynamic balance and ecological balance. It actually, the microbiome contains a gene set that's about 150 times greater than the human microbiome, and there's about 100 trillion bacteria on an average person, about 80% of which are in the gut, and about 5,000 strains of microbiome, microbes, and about 1,000 kinds of microflora. And we really only understand or have identified about half of them. In fact, I was actually reading a recent study of one of those scientific accidents where they knew just by the genetic material that there should be another microbe around, but they were not able to grow it. And then they accidentally contaminated it with some other microbes and they figured out that it had to grow commensally with other, with a different type of microbe in order for us to even grow it. And so that's come, I think that speaks a little bit to part of the problem we have with identifying all these, is some of them are very specialized. And then sort of the whole idea is that we have this symbiotic evolution and a lot of people like to talk now about the holobiome, meaning all of us and all of our things that are carried with us as the total part of the human. All right, important to remember, we are taught in medical school that microbes are bad, and actually only 1% of microbes are pathologic. I can say that a significantly higher percent can cause dysbiosis, and so they're not particularly good for us, but they're not pathologic. And we'll talk a little bit more about that as we go along. So what's the problem? I think we all kind of know these numbers, but I think we'll just restate a little bit. Obesity is a huge problem, 32% of men and 35% of women, and 18% of children, 2 to 19, are obese. About 50% of the world population, if we continue in our same trend that we have now, are gonna be obese by 2035. It costs a lot of money, obesity does, and it also takes up a lot of medical resources. So people who are moderately obese are twice as likely as healthy weight individuals to be prescribed a medicine. And 10% of adults, actually more than that now, have diabetes. And as we all know, diabetes is pre, at least a decade earlier, mostly, people have insulin resistance. And a lot of the damage is occurring from that insulin resistance well before you're actually diagnosed with diabetes. And so we should probably be looking at that at a little bit earlier time frame. As an example of part of the problem, I think it's partly how we eat. And this is actually an excellent study that was done at the NIH. And the reason I call it an excellent study is because diet studies are hard because we can't get people to give us true accounting of what they eat, right? So in this group, all of these patients were brought in and kept in the hospital for the entire two weeks. So we had 100% accounting of what they ate and how they ate. And the groups were divided into two parts. One group got a highly processed diet typical to the American diet. And the other group got an unprocessed diet. And the diets were actually matched for sugar, fat, fiber, and all the macronutrients. But as you can see from the slide, the people in the ultra-processed group ate about 500 kilocalories more per day. And in just the short 14 days, the group that ate the ultra-processed diet started gaining weight, whereas the group that ate the unprocessed diet was losing weight. And so I think we can sort of extrapolate from there that our current diets are not great for us. All right, a couple of the problems. We don't eat enough fiber, and we ate way too much high fructose corn syrup. And so the guys at University of Iowa who initially figured out that you could extract high fructose corn syrup from corn products didn't do us a great service. And now that it's in everything, it's really driving a lot of our insulin resistance and inflammation. And then I won't name the company, but we're all familiar with Chicken Nuggets. And it's a good example of some of our problems. Chicken McNuggets in the United States have about 40 ingredients. And interestingly, in Europe, they only have about 25 ingredients. And why is that? Because the other 15 ingredients that we have aren't allowed in Europe, and to be in food in Europe. And there's a bunch of bad actors. I particularly like to point out tertiary butyl hydroquinone. That's what they put on the McNugget to make it shiny. But interestingly, it's also what they use to make clear coat paint have depth. And so you're basically eating the paint off your car. And then you would think that the number one ingredient in a chicken nugget would be chicken, but it's not. It's actually corn and corn products. And most of the calories come from fat. I'm not actually opposed to fat. It's really the types and kinds of fats that we eat that are the problem. And in general, fats can be good for us. All right, I'm not going to go through the whole thing. And actually, my two colleagues are going to speak more about some of the specifics of the gut mucosal immune system. But what I will say is I like this particular picture because it reminds us that the gut isn't just a tube that sucks nutrients out. It has a lot of other things. And they're actually compartmentalized in different parts of the gut in entirety. And so when we eat super highly processed foods that get absorbed very early in the digestive tract, we're essentially starving the rest of our gut. And a lot of that leads to some of our extra hunger and cravings and also hurts our immune function. Oh, by the way, I cut this or culled this out of a much larger lecture. And so hopefully it's not too disjointed and schizophrenic. But we're going to just touch on a bunch, a little hodgepodge of a number of different studies that sort of prove the point. And then I'll leave it to my colleagues to do some more of the specifics. I think this is important. As we all know, these are sort of bad actors. And then down here, we generally think of lacto species and bifido species to be good for our microbiome or our gut. And so you can see when you ferment food, all the bad bacteria die off. And in fact, it's actually helpful to the lactobacillus species to be fermented. They actually thrive in that environment. So I would also say that sort of that ancient wisdom is there and that eating a little kimchi after your meal is actually very good for your microbiome. This is actually really fascinating to me. This is a study where they actually looked at a group of hunter-gatherers and their nearby industrial counterparts in, I believe this was in South America. And they compared them to remote farmers and their industrialized counterparts in, it was either Tibet or Nepal, but it was basically halfway across the world. And what they found was the environment you lived in, as opposed to where you lived in the world, was much more, you had a much more common microbiome than compared to other people who lived nearby you. And so, and in general, as you can imagine, the industrialized communities had a little bit worse microbiota than the farmers. And that speaks a little bit, again, to another big issue is how we farm right now. And there's a difference between soil and dirt. And we basically farm in dirt now. And so our soil is not rich in microbiome anymore because we've killed it all off. And so, that being said, you know, we've talked for years about how being in the country is restorative and healing. And that's probably more than just the bucolic nature of being in the country. It probably has a lot to do with picking up soil and environmental bacteria. All right. So here are a couple of important studies. There's a partial restoration of microbiota in cesarean-born infants when you actually swab them with vaginal secretions. And so I think that's a great study because it's really, I often wonder about how they got through the IRB to do this. But Dominguez-Bello did a good job in terms of actually getting this done. And they showed that actually doing that improved the microbiota of those infants. And then, in another study, they looked at the microbiome in the first 100 days of an infant. And they found that dysbiosis had a correlation with ATOP and other problems. All right. So this is actually, on your left, is an excellent study that they actually took a standard daycare. And they dug up the asphalt and the gravel. And they actually planted gardens and grass and other things. And then they compared that to the microbiota And then they compared that to kids who were in standard daycares. And, of course, as you know, our topic we're talking about, the group that were allowed to play and put their hands in the dirt and do other things did much better than the other group. And so biodiversity enhances immunoregulatory pathways. And then, on the right, is another interesting study, basically, that looked at autopsy data in Wayne County, which is Detroit, and really looking at whether having green spaces affected the microbiome. And so they took swabs from these autopsy patients. And then they compared them to geocaching data on where there was a problem. And then they compared them to geocaching data on where there was green space versus where there wasn't. And, of course, they found that there was significantly better, a positively correlated microbiome with people who had green space. All right, so what do we know? We know for sure that microbiota abundance and diversity is health and wellness. And that can cause some disease. What we don't know is how or why the specific microbes that we need and how we make that be the best it can be. We're going to talk about that we do have some ideas now about how that is, but we don't know for sure. I'm not going to talk a lot about this because Matt and Landon are going to talk more about it. But suffice it to say that our gut does a lot of important things for us. And the bacteria in our gut are incredibly important in that. Particularly, I think we're going to have some discussion of short chain fatty acids and also some of the other things that come from our gut. All right, back to this hodgepodge of some studies that we know about. If you take a germ-free mouse and you put it in a hostile environment, so basically aggressive mice that have been bred to be aggressive, it actually comes out with a pretty poor microbiome in its gut. So it's lower in beneficial bacteria and diversity, and it's higher in harmful bacteria. And then they end up having infection and inflammation in their guts. But if you transplant a good microbiome back into them, then they lose those infection and gut inflammation that they had. And then if you actually take the transplant from the mouse after it had been exposed to the aggressive other mice and put it in some other germ-free mice, they'll experience the equivalent of anxiety and depression and cognitive dysfunction. There's another study that looked at 7 million patients who were admitted for infections and treated with a course of antibiotic. And although this is obviously kind of a stretch to immediately say it's your microbiome, they definitely had a higher risk of suicide throughout the rest of their life if they were admitted in the hospital for an infection. Another way to look at it, don't kill the messenger. I did not personally do this monkey experiment. But they actually exposed pregnant monkeys to random noxious stimuli. So mainly it was like banging a large pot next to their cage at random times. And then their children were born with poor microbiome. And so you can actually pass along a problematic microbiome to your children, and stress definitely affects that. We've also looked at college kids. And in college kids, when they're normally having a good time, they take their microbiome. And then they wait till after finals week. And they test it again. And they find out that they have less beneficial bacteria. So stress definitely affects your microbiome. All right, so I want to talk just briefly about something that I was involved with. I lived in Augusta, Georgia for 15 years. And my wife ran a nonprofit that basically worked with farmers, local farmers, and helped get wholesome food to populations that were at risk. And Harrisburg is a neighborhood that's a known food desert in Augusta. And we started a fruit and vegetable prescription program. And sorry, I'm having a little panic attack. Happens to me all the time. Anyway, we started the fruit and vegetable prescription program, where we brought people in. We gave them some diet advice. And then we allowed them to use their SNAP benefits to buy local fruits and vegetables. And I agreed to be a part of this only if we could collect some data and look at it. And I think we're the only group that's actually collect wellness data in addition to the standard health data that they usually collect. And here's what we found. So at baseline, 22% said they couldn't afford a balanced meal. 44% said they would cut meals. And 30% said they were often hungry because there wasn't enough food. Post-intervention, that number went down to 4%, 11%, and 3%. But importantly for us as psychiatrists, we took the SF-36, which is your standard wellness screener. And in almost all of the scales, they improved. And then particularly, not only did they statistically improve, but they met the reliable change index, which means they clinically improved as well. All right. So what do we need to do? So prebiotics are important. In the low-carb arena, they talk about slow carbs. And slow carbs are basically carbs that are attached to fiber. And if you eat an apple, it's much better for you than you squeeze the juice out of the apple and eat that, right? And then whole grains, again, things that take a little bit to digest. And then they have a lot of good secondary metabolites that you should be eating. And then probiotics or symbiotics are important. The question is whether you get them from your food or do you take a probiotic. And we'll talk a little bit more about that later. And then so here's some takeaways. You are what you eat. Your gut microbiota is complex. And it's got a bidirectional flow of information from the brain. And it's rather fragile and can be easily manipulated. Current state of science is correlational. But there's a lot of research going on. And so we hope that soon we're going to have a better idea of exactly what we need to do. And then lastly, I love Michael Pollan. If you haven't read his books, he's great. And I believe in all of these. I do understand there's some equity issues with some of the statements. There's lots of people who don't have access to not eat at a convenience store at a gas station. And that's something we should be working hard on. But in general, this is good stuff. All right, thanks for listening to me. And I'll turn it over to Matt. Thank you. Hey, thanks, Dr. Hines. And welcome, y'all. My name is Matt Rusling. And I'm a captain in the United States Army and a second-year resident at Walter Reed National Military Medical Center and involved as a collaborator in some really interesting microbiome research going on in the DoD. I have no disclosures to make. And this is just me talking, not as someone who's talking for the United States government. So I am really interested in pursuing a career in non-clinical opportunities, specifically microbiome research. I have, at this point, been involved in microbiome quantitative research for about eight years. And I have skills in 16S and metabolic pathway analysis using QIIME 2, R, and PICRUST. And I'm starting to apply machine learning to microbiome data sets. So my civilian email is up there. And if anyone is interested in collaborating and looking for someone with some technical background and performing microbiome research, please reach out to me. I would absolutely love to hear from you and collaborate on anything, especially PTSD, TBI, and suicidality. Because I think there's a lot that we can do to help our patients who we have really struggled to meet their needs historically. So the way that I conceptualize what the microbiome metabolically does kind of breaks down this really hand-wavy huge topic into two parts. The first one is the monoamine building blocks. So I think in psychiatry, we're really familiar with the idea that serotonin, dopamine, and norepinephrine are some of the most important predictors of psychiatric illness. And most of our drugs are acting on these pathways. So I want to first talk about a topic that we're all pretty familiar with and how the microbiome acts as a modulator of where our neurotransmitters come from, how they enter the brain, and what affects their biochemical ability. Oh, my goodness. So then the second part is going to talk about the non-monoamine microbiome actors. So this is going to go a little bit deep into biochemistry, and I'm going to use my psychiatry skills to really pay attention to the, you know, relationship with the audience, and if I see too many eyes glazing over, I will, like, you know, bring it down a couple notches. So, please use expressive body language. So, we're going to go back to the, like, first semester of med school, biochem. So, close your eyes, remember being in the lecture hall and learning that there are these amino acids, and they turn into neurotransmitters. We're going to use tryptophan as a metabolic kind of example, because it's so complex and interrelated with the microbiome, so it should be simple, right? If tryptophan gives us serotonin, and more serotonin makes us happier, we should just be able to eat more protein, and everything is good, right? But it turns out that there is a, like, nonlinear relationship with these things, because, like, everything in psychiatry, it is super complicated. So, starting at ground zero, so we have these amino acids that are our precursors for our critical neurotransmitters, and kind of focusing in on tryptophan. Tryptophan actually turns into both serotonin and melatonin, and these two things that you might have never heard before, because we didn't learn about them in medical school. So, keenorhenic acid and keenolytic acid are both tryptophan metabolites, but kind of so what, right? Because anything metabolized from tryptophan should act on the serotonin pathway. But it turns out that that's not exactly the case. So the NMDA receptors, we all are pretty familiar, is involved in neurotoxicity, and the modulation of the NMDA receptor is strongly associated with the benefits that we see in ketamine, NMDA, all this stuff, and also in neurotoxicity of catatonia. So the fact that tryptophan can be metabolized into both the serotonergic stuff, as well as this NMDA actor, kind of emphasizes how important the metabolic state in both our brain and our microbiome is on kind of determining the pathway that these things go. So we've reinforced that our amino acids are our neurotransmitter precursors. We're going to take a little journey about how they go from your sandwich into your brain. So you're sitting there, you're eating a sandwich, and you swallow it. That starts the metabolism of your food by our organs. So our pancreas shoots out a bunch of peptidases, and that liberates our proteins into free amino acids and these oligopeptides. And what we learned in medical school was that these amino acids, the oligopeptides, directly hit our intestines, and then from there, immediately are transported into our blood. What we've learned since we were in medical school, because this is actually a very new science, is that there is actually this metabolically active bacterial biolayer. So I conceptualized this as a Petri dish. So there is a Petri dish overlying our intestines, and conceptualized like back in microbiology lab when we were looking at colony forming units on plates, we could actually see the bacteria growing on the plate a couple days later when you throw some kind of stimulus like food at it. Turns out the same thing is happening in our gut, and it's at a metabolic level of activity that we can actually quantify the products that are being produced, and we're going to go over how some of these are psychoactive metabolites that are of clinical significance. So cool. The bacteria metabolizes our food before it hits our intestine. A big question is, in all these preclinical science-y, hand-wavy things, is always emphasizing, is this clinically important? So for tryptophan, tryptophan can enter into a number of different pathways. On the right-hand side, we have a figure just kind of showing you that tryptophan can turn into these things that are not serotonin and are not melatonin. So this is considered the catabolism of tryptophan into other non-serotonergic metabolites. So the state in which our gut is balancing where tryptophan goes directly regulates the quantity of tryptophan that is bioavailable to cross the enterocyte layer and enter our bloodstream. This is super important, as we know that tryptophan and serotonin deficiency is associated with depression and other illnesses, including psychosis. So the metabolites are also psychoactive because they are acting on the NMDA receptor, especially the bottom metabolite, kinelinic acid, which is one of the most potent endogenous and exogenous NMDA agonists that we are aware of. And this catabolism is also balanced by the fact that our bacteria can even synthesize tryptophan from other metabolites, from other amino acids, and can directly increase the amount of tryptophan that's available to cross the blood-brain barrier. So these things are made, they act on the NMDA receptor in these preclinical studies. Is this important? It doesn't matter. So emphasizing the NMDA-active metabolites of tryptophan, we can look at kinerinic acid in the middle with the red box and kinelinic acid in the green box. These are modulating our NMDA receptors and kind of affecting broadly our depressive symptoms. And pretty consistently, kinelinic acid has become a biomarker of significant interest because it has been shown in numerous studies to be increased in patients who have completed suicide, making this a potential biomarker to better understand, you know, a population that we can only estimate who's going to kill themselves about 50% of the time. And if only 50% of those patients are presenting to psychiatry, then we need to start developing new mechanisms by which we can identify these patients in a primary care and other setting so we can really help our colleagues and better take care of these patients who, for one reason or another, might not be presenting to us. So once we have tryptophan and that tryptophan has been synthesized into the other stuff, how does it get into the brain? So there is this really intricate system by which tryptophan does not just freely flow across the blood-brain barrier. It crosses largely through the LAT1 transporter and competes against other large amino acids and branched-chain amino acids. The big takeaway is that our central concentration of tryptophan is not just regulated by tryptophan serum quantity, but also by the quantities of branched amino acids, which are de novo synthesized within the microbiome and catabolically removed. So the metabolic state of the microbiome, super important in regulating central tryptophan bioavailability. So we've talked about these psychoactive things, we've established that tryptophan itself does cross the blood-brain barrier, but do these psychoactive metabolites cross into our brain from the gut? And it turns out that they do. So serotonin itself does not cross the blood-brain barrier. There is some questionable evidence that it might at very small quantities, but functionally it doesn't appear to do so. However, quinolinic acid and quinarinic acid both do cross the blood-brain barrier and appearing to do so at clinically relevant quantities. So four big takeaways. One, bacteria synthesize and degrade amino acids, which affects precursor bioavailability. The metabolome produces these potent psychoactives, which do cross the blood-brain barrier. And these metabolic microbiome products affect how and how frequently our precursors are entering the brain. So because most of our medications act on this monoamine pathway, maybe the microbial regulation of this should be of some interest for psychiatrists to better understand what we can do right now with the knowledge that we have. So moving on to the second part of my talk, which is going to be about the metabolomic psychoactives that are non-amino acid, non-monoamine. So I just want everyone to take a breath and acknowledge that this was super biochem heavy, and I really appreciate that I'm not seeing too many freaked out faces. So I appreciate everyone here. So endotoxins. We've all probably heard of leaky gut. And it turns out it's very much a thing that is implicated in a lot of disorders. So what is leaky gut? So gram-negative bacteria are coated with this stuff called lipopolysaccharide, summarized as LPS. Normally we have very low quantities of LPS because it's a toxin, our body looks out for it, and when we get too much of it in our blood we become septic. And when we have a healthy gut, the barriers between our enterocytes are really intact because short-chain fatty acids are like, hey, stay tight and don't let this poison in. But when dysbiotic events happen or there's a change in host physiology, those junctions weaken and the bacterial byproducts, including LPS, are actually able to enter into the bloodstream. And this relationship has been shown to increase depressive symptoms, be associated with metabolic syndrome such as obesity, as well as depression. So we have said this kind of hand-wavy thing, that LPS enters the blood, but kind of so what, from a biochemical perspective? So once in our blood, LPS exerts these profound effects on the host physiology. Going back to immunology, our body is highly primed to look out for the things that can kill us. One of the things that can kill us is the proliferation of gram-negative bacteria throughout our body. So we have these specialized receptors called TLR4 receptors, which are really on the lookout for these potentially lethal byproducts. When LPS binds to this TLR4 receptor, it triggers this really long immunologic cascade that I don't remember. But the big takeaway is that NF-kappa-beta goes into the nucleus and kicks out a whole bunch of cytokines. So when we see these studies that show that we have an increase in cytokine production, that can almost be seen as analogous to how much NF-kappa-beta is in the nucleus and kicking out this stuff that is causing inflammation. Notably, for psychiatry in particular, these TLR4 receptors are highly, highly expressed on the vagus nerve. And going into not just the immunologic regulation of the entire host, how does this affect the brain from a structural perspective? And the high expression of the TLR4 receptor on the vagus nerve means that when endotoxins are released into the blood, they hit the TLR4 in the vagus nerve and decrease parasympathetic tone. Why this is important is that the duration of this innervation can be very, very, very, very long, especially in conditions such as obesity or other metabolic disease. So when we have this decreased vagal tone induced by microbiome dysfunction, that hits into the nucleus tractus solitarius, which has projections throughout the thalamus, the hypothalamus, and importantly, the locus coeruleus, which we know is the producer of our norepinephrine. So not only is the microbiome playing in the tryptophan world, it's also playing in these other neurotransmitters and broadly affecting our autonomic loops that lead to potentially decreasing the tone of the frontal cortex and our patient's ability to apply executive function at this long-term level because of this changing in the circuitry of the brain caused by LPS stimulation of TLR4 on the vagus nerve. That's the stretch, but that's really where the science is heading, that the innervation of this immunomodulatory mechanism has strong implications for psychiatry. So thank you for bearing with me on that kind of hand-wavy jump of logic. But this kind of isn't. So they were like, hey, we have this hypothetical relationship. Does it actually have clinical implications that are significant and measurable? So this was a Dutch or New Zealand study that recruited between 2,000 and 3,000 patients from one of their enormous databanks of human research in one of their depression datasets. And they asked the question that averaged over nine years, are individual symptoms of depression increased or related to lipopolysaccharide levels? And what they found is in the red bars at the top, which were the behaviors, and the blue bars at the bottom, which are the cognitions, that there was this conserved pattern of what behaviors and what cognitions were increased with increases in lipopolysaccharide. So this hand-wavy hypothetical stuff that we mentioned earlier appears to be clinically relevant. So I'm going to finally bring it all together and connect the non-monoamine actors with the monoamine hypothesis and then hand it over to Dr. Sorensen. So a lot of stuff has happened in the last 15 minutes. So we're going to go back to tryptophan. So remember that tryptophan can be taken into other stuff. That other stuff can be neurotoxic. So the enzyme that commits tryptophan to the neurotoxic pathway is called IDO or TDO. IDO is the inducible version. So we have lipopolysaccharide. Lipopolysaccharide kicks off into an immune cell, which releases TNF-alpha as kind of a help signal. The TNF-alpha hits cells which are expressive of IDO or TDO and triggers the translocation of NF-kappa-beta from that TNF-alpha relationship. In cells expressing IDO, this binding of NF-kappa-beta in the nucleus increases the translation of IDO. And remember that the increase of kinelinic acid is associated with suicide. So this is a relationship by which LPS has a really strong theoretical mechanism behind which endotoxemia can lead to suicide in a potential mechanistic way. So I want to hit on two things as a primer for Dr. Sorensen's talk. So short-chain fatty acids. Short-chain fatty acids broadly are formed from indigestible starches, and they have been shown to reduce leukocyte invasion or white blood cell invasion into the gut and broadly attenuate the immune system. So short-chain fatty acids found to be decreased in patients with autoimmune disorders, gut dysbiosis, and all this stuff. So the metabolic production of these things is super important. And this, I think, is going to become one of the future cutting edges, which is the production of gases and increased aqueous solutions of acids. So H2S, at high levels, when the microbiome is producing H2S, it accumulates in sufficient quantity at the enterocyte border and causes inflammation and direct chemical irritation and has been shown to be increased in patients who have what had been deemed a functional GI disorder. So creating an opportunity for us to identify a biologic subtype of these functional patients that have a treatable pathway for their illness. And then nitric oxide. So we found that nitric oxide produced by CGMP to dilate blood vessels to get blood where it needs to go, also made by the microbiome. At high quantities, nitric oxide production has been shown to be increased in patients with neurodevelopmental disorders. It nitrosylates enzymes in the brain and reduces the scavenging of plaques from the brain, which is the likely mechanism by which it worsens these disorders. And then finally, H2 gas. So it reduces autophagy in the brain, potentially neuroprotective and acting as a electron sink. So some really great mechanistic stuff is in the pipeline. I truly believe that we're at the edge of being able to apply these interventions broadly. We just need the right push in the right direction to make these insights actionable in a clinical setting. So with that, I want to introduce Dr. Sorensen. All right. Thank you. My name is Brandon Sorensen. I'm a psychiatry resident from Walter Reed in Bethesda, Maryland. And I'm here with a simple small task of taking all the information we just heard, repeating some important pieces, bringing it all together, and discussing clinically how many of us are already acting on some of these mechanisms with the medications we're prescribing, as well as areas of future things we should consider to expand to. And of course, all representations and views expressed are my own, exclusively, and I report no conflicts of interest. So what are the possible options and targets for manipulation of the microbiome? What clinically can we use? Listed here, I've got specific objectives and things I want to discover and discuss for the remainder of the presentation today. I'll provide overviews of current research and provide recommendations on how psychiatrists can continue to manipulate the microbiome of your patients. Additionally, because as Dr. Ruslan just noted, this is a lot of information, there's also a lot of references. So for my sections, slides with five or more references will have the numbers listed at the bottom. So if there's a particular area of interest, you have the option to review that at a later time. I don't expect you to remember every single piece today, but have the option to review as appropriate later. So let's begin with some of these different things that we were just discussing. Recall from our last section that some of the different substrates and metabolism actors that could be potential targets for manipulation of the microbiota. Several of these are used as second messengers, carrying different messages or to inform cells about the presence of absence of stimuli, say the food we're eating, for example. Some of the most common of which include G-protein-coupled receptors. Others are metabolites of the receptors, such as the short-chain fatty acids that Dr. Ruslan was just discussing, which I want to clarify. Short-chain fatty acids in majority are produced via anaerobic fermentation of things we're already ingesting, like fiber and starch. We already know that these likely influence brain communication via several different potential mechanisms, whether it be directly via vagal nerve stimulation, such as what we were just discussing, or indirectly via follow-on metabolites, systemic circulation, or other second messenger systems. Additionally, nitric oxide, as we were just discussing, which is another byproduct of metabolism and digestion, has been found in increased levels systemically, leading to yet incompletely understood alterations of the brain. As we just described, multiple enzymes that are nitric oxide-dependent have shown differences, but recall even further back to basic anatomy and physiology, nitric oxide's effects on the vessels systemically. We know that it affects smooth muscles and vasculature. It's very well studied, and overall, it's likely the increased nitric oxide levels are decreasing vascular tone to vessels that are also supplying our central nervous system of the brain. Additionally, in this list, we see different actors of the tryptophan pathway that you just became familiar with. I highlighted my key favorites, pertinent carotenoic acid, penicillinic acid, quinolinic acid, as we just discussed. And as Dr. Rusling said, they have been noted to be found in the systemic circulation of individuals at time of death by suicide. There's also other research listed in major depressive disorder, other different psychiatric illnesses of increased and specific levels. And we will come back to all of these soon. So it was initially postulated at the start of this research that there was likely specific bacteria that lead to specific disease, similar to the Clostridium difficile mechanism of disease. And in some cases, that is still being found to be true. And we'll discuss a few of those later, as we have already discussed a few of those today. It's also becoming more and more apparent that we should likely be focusing on defying and supporting a healthy microbiome, specifically, rather than focusing on specific actors or that 1% as Dr. Hines had on one of his first slides. There was an article written in the Journal of Gastroenterology in 2015 that specifically postulated the first three things I've listed on the slide here as defining a healthy microbiome. So they defined it as factors such as distinct members, increased diversity. You want to have different richness and evenness in how they interact with each other. They focused as well as coining effectively a term called dysbiosis, which we've used a few times today. But I want to clarify, it refers to the microbiome associated with the disease state. And the last but not least piece that I've added after my review of literature for this presentation includes the interaction of all of the above, as well as the interaction of that microbiome with you, the host, via those second messenger systems we just reviewed, via your central nervous system, et cetera. And this concept, as we've alluded to, can be thought of as the hollow biome. We should focus on providing our microbiota the best foundations we can to overall lead to improvement of the hollow biome, and we're finding decrease in psychiatric illness and disease when we do so. So what research supports clinical evidence and how do we actually modify the microbiome and therefore the hollow biome? One of the most obvious ways would be alteration to diet, which I'm going to rehash some of the key points. I agree with everything Dr. Heinz said before. Now I'm going to show you some additional information and maybe change some of the things we're eating in the near future. Most of the studies in dietary modification of psychiatric disease use elimination diets, which is a simple concept. You take some of those foods your grandmother would not recognize as food, you remove them from your diet, and you monitor for changes clinically. Significant evidence in particular with respect to ADHD has already found near or even complete remission of symptoms in children diagnosed with ADHD when placed on a few foods diet. Healthy fruits and vegetables, none of those things that are contributing to likely dysbiosis included in their diet, and then just monitor clinically. And we see progress, and we see improvement. This appears to lead to a reduction in not just symptoms of ADHD, but also symptoms of other psychiatric illnesses as well, specifically growing evidence for major depressive disorder, as well as schizophrenia and other psychiatric illnesses. And I expect we'll find more of these types of correlational studies and papers being published in the next few years noticing improvements after certain modifications. Improvements, but not necessarily remission, of course. I expect that the additional evidence will also come with the graphic that I've listed here at the bottom of the slide, which I'm summarizing a very specific section of the inflammatory hypothesis of depression for us. Sources of activation of the inflammatory response in major depressive disorder are immense. It's becoming increasingly evident that the gastrointestinal tract with the gut-associated lymphatic tissue, or GALT, is leading to increased intestinal permeability, like Dr. Ressling was discussing, and increases of bacterial lipopolysaccharides, or LPS, like we were just discussing, systemically. This is leading to a low-grade inflammatory state in the gut linings and the areas where a microbiome flourishes, as well as systemic increases in inflammation. And as I said, this concept is one specific section of contributing to the inflammatory hypothesis behind depression. While research will continue to attempt to further elucidate the reasons why these effects are noted, it is likely either via the second messenger systems we've been discussing, or perhaps directly via the vagal nerve changes in tone, as Dr. Ressling was just so pertinently discussing. It's interesting to me that a change at my gut level is directly traveling through a cranial nerve to the central nervous system. And then there's also secondary and tertiary messengers being transmitted from the microbiome through the holobiome to that same central nervous system, the brain. I expect we'll continue to see more information related to this in the near future, as well. So one of the things, because I am a scientist and I present both the positives and I'm not just hand-waving, I expected that we've got countries in this world that have already removed these things. We would likely be able to find prevalence changes, as well. So in preparation for this talk today, I reviewed several of the population-based studies, looking for further evidence to support or perhaps discredit elimination diets or healthy food changes. Since the original Lancet study in 1993, highlighting trans fatty acids and their contribution to cardiovascular disease, several countries, especially in the European Union, as listed here, have removed these different things that we're suggesting we not consume. They did then also notice clinically significant changes in cardiovascular disease at a population level. Interestingly, when I did my review now, in 2019 being the last major section of this population review data, there was not yet any sort of prevalence decreases from illness. Another interesting piece was nearly every country that was polled in these population-based studies was finding increased incidence and prevalence of nearly all psychiatric illness. So obviously, some attempts for confounding and assessing whether or not how much of this is from the diet change will continue to go. But it's interesting to me that overall of this research, every single one is noting we're finding more psychiatric illness. And I will defer to your interpretation as far as is that because we're finding more or we're diagnosing more or what. But unfortunately, I don't have a good solid, it worked and we fixed everyone's depression across all of Europe yet. So let's talk about other things we can change. Like Dr. Hines was highlighting, fermented foods in particular or other different things can be added to our diet. And I want to highlight when my clinical recommendations that I give at the end of this slide, I highlight focusing on safe without risk and the level of benefit based off of the clinical research to support. So there is a lot of research to support fermented foods in particular, which is why it's listed first. They have significant benefit likely mediated through alterations of the microbiota and its byproducts. And some of these benefits have been noted in different fields of study, not just psychiatry as being anti-diabetic, anti-obesity, anti-inflammatory, which may or may not be the direct time to psychiatric illness. Whether there are direct factors or indirect factors of our microbiota leading to the clinically seen decrease in psychiatric illness with interpretation, I still just recommend adding it in because it's a safe, easy change, something we can encourage. Fiber, I think there's a lot of colleagues and other specialties, especially gastroenterologists who would also agree we should be eating more fiber. I think my mom told me that since I was a child as well, so it makes sense. But of course, fiber is effectively a prebiotic, which is something I'll talk about here in another slide is prebiotics and supplementations. While it's not necessarily promoting specific microbiota, remember, tie in to that, I don't want certain things to grow. It's more of a providing an opportunity for the microbiome to grow and flourish overall. That Petri dish that Dr. Rusling was talking about provided the prebiotic things it needs to grow. Additionally, one of the healthiest ways to improve our diet is to eat fresh, fresh foods, vegetables, et cetera. Fresh fruits and vegetables provide the healthiest source of polyphenols, which recall, they tend to promote further healthy digestion, they tend to improve blood sugar control, and even appear to improve cognitive benefits. One of the studies recently looking at increasing polyphenols in Alzheimer's disease. Overall, notably, polyphenols do not get digested by us directly. Our holobiome digests them via the microbiota. Nearly 95% of all polyphenols that we ingest stay in the gut. Only about 5% get absorbed. They're getting modified via that microbiome and leading through second messenger or other direct pathways are altering our holobiome and likely that's the mechanism that we're seeing these changes when you ingest polyphenols, for example. In addition to what we eat, we should also pay attention to what we drink. Specific evidence for water being safest, sure. But also tea in particular and caffeinated beverages appear to have positive benefits for our microbiome as well as being safe. In fact, one of the teas that's listed on the slide here attempts to take advantage both of fermented foods as well as the benefits noted in tea via polyphenols or caffeine. And in fact, even when controlled for removing the admittedly high caffeine content of the specific tea, they still found benefits both with weight loss and psychiatric likely manifestations although it was not directly assessed for psychiatric improvement in these studies. The short and sweet answer with respect to sugary beverages is no. Does not benefit our microbiome. It does simply tend to, while maybe growth, perhaps not the best type of growth. And then there are also other health concerns we should be aware of with respect to the holobiome because keep in mind that includes us, the human, and we know overall sugary beverages are not good. In fact, it does seem to promote overgrowth of flora's and to some degree, flora's that we typically do not want to be overgrown. I would also like to note some interesting evidence that I discovered during this talk with respect to things we should not be regularly consuming, specifically alcoholic beverages, sugary beverages, and kombucha. Red wine, I will concede, does have a significant amount of polyphenols. Unfortunately, the benefits we're getting from consumption of red wine via alcohol is likely outweighing those benefits pretty quickly. Instead, we should consider fresh fruits and vegetables or other sources of polyphenols where appropriate. Some studies that looked into the effects of alcohol in particular looked at chronic ethanol administration in animal models and found it does induce a gut dysbiosis, which as we described earlier is the microbiome of a disease state. It's also not surprising given that almost every day when I go to the hospital, I use an alcohol-based sanitizer to kill so-called germs on my hands and then we drink that same product and wonder what it does to our microbiome. So for these reasons as well as others that we won't discuss today, I recommend against alcohol being consumed by patients with psychiatric illness and disease. One beverage that I've also seen listed as a health food is called kombucha. I found evidence that not only does it not seem to manifest any form of clinical benefit, it also has been associated with harm to patients. So for me, with my guidance of focusing on helping without harm, even if the research isn't fully done yet, we can say these things are not harming, go ahead and start eating healthy, right? Kombucha on the other hand has been tied to a patient who drank kombucha for approximately two years leading to a case of toxic hepatitis. He was admittedly drinking a lot of this sugary tea. But interestingly, the kombucha on the store shelf has a lot of those different sugars that we all just agreed we probably shouldn't be consuming. So you could build it at home, right? You could make kombucha at home. Unfortunately, there've also been other cases of acute renal failure from patients making their own kombucha at home, as well as symptomatic lead poisoning being tied directly or indirectly to this. So for these reasons, as well as the likely not yet found or likely non-existent clinical benefit of drinking kombucha, I also recommend against kombucha, other sugary beverages, and alcohol. So we provided several dietary recommendations, and I know Dr. Hines already mentioned the concept of food deserts, but I want to assess our limitations because before we all leave here and say, here's what you should eat and here's what you shouldn't eat, we have to realize what's actually available for each of us as well as each of our patients. One of the biggest concerns I had would be making these recommendations and then having them walk out and only thing being available would be those different stores selling some of these foods and some of these foods to patients. And then the only thing available would be those different stores selling significantly high levels of omega-3 based products that have been sitting on a shelf for who knows how long and won't decay apparently. So we must balance this with consideration based off of your local level and the patient population you serve. Do they have access before you recommend these fresh fruits and vegetables? Do they have the time and skills to prepare these meals? There have been some studies in particular looking at New York as an area where there's much less individuals who cook. They were going out to restaurants every day and they did do studies finding certain restaurants are still making food in a way that we can consider healthy. Overall, it's gonna have to rely on some judgment of frankly fresh being the better choice whenever possible. We must balance this also with the consideration of do your patients expect the psychiatrist to start talking about diet? Over the last year, I've been expanding into a lot of these different concepts and frankly, I've met very little resistance because I'm already discussing sleep and sleep hygiene and then I discussed diet in addition to medications and obtaining form consent and the reasons why I'm trying to treat their illness. Treating the whole person is akin to treating the whole bio. In addition to making recommendations to our patients, we should also consider other options and something I had success with in medical school and actually somewhat accidentally had a positive turnaround was changing the food that was in the cafeteria. Keep in mind, if you're working in an inpatient setting, there's a limited amount of things that can be ordered for your patients. In an outpatient setting, if you work in a hospital facility, many of those patients go to the cafeteria and many of us and our staff eat there as well. My recommendation at this point is if any of you are in a position where you could make changes at your local level, I just wanted to put that consideration out there and I'll briefly, since we're a little early on time, share a short story where I accidentally made this change while in medical school. Admittedly, I was in line, focusing on my diet, trying to eat healthier and I couldn't find a single fresh thing. That day, the salad bar had been closed. Admittedly, it was pandemic type restrictions, potentially that contributed. But I also couldn't find lean proteins. I couldn't find the other healthy things I'd been used to eating during my time in the military as frankly, my main source of foods. And while buying some over-the-counter something that had been in a bag for probably a week, I was discussing with one of the other medical students how I noticed this and coincidentally in front of me ended up being someone who was effectively in charge of the food contracting, not just for that hospital, but for the entire local region. An accidental comment, admittedly, I'll be honest, a complaint, immediately led to, here's some contact info. You should, we should talk more about what could be included. And it took three weeks for this hospital system to implement Fit Meals. And I mean that as a short turnaround. Could you imagine making a thing on accident leading to an email, leading to three weeks later, they brought these things, they called them Fit Meals, F-I-T, no trademark as far as I'm aware. But either way, they started implementing them and for $5 I could buy a healthy meal in my cafeteria for the rest of my medical school time. So I wanted to provide those considerations and limitations before we continue. But now we've talked a lot about diet and I'm gonna transition to the key pieces of my talk, which will be modifying the things we were just discussing via supplements and medications. So after reviewing the evidence for pre and postbiotics, overall there does seem evidence to support the use of these supplements, regardless of the source of the supplements with very little concern or cause for harm. Overall, it is likely also that probiotics in particular do tend to lead to more consistently being beneficial. Omega-3 I would like to discuss for a little bit has been researched significantly, specifically originally mostly related to the cardiovascular benefits. And along with those research, there's been some shifting in the last several years in as far as the fields of cardiovascular benefits, as far as the effect of does supplementation work and is it safe? Interestingly overall, that body of research has found it's consistently safe in high dose supplementation up to five grams a day, which is significantly higher than anything I've ever recommended or used in my own practice or with my friends and family. But some other interesting research I found is in populations that may or may not be exposed to traumatic brain injury, there is currently ongoing and recent research looking at animal models and its effects of recovery after traumatic brain injury. Interestingly, high dose supplementation specifically of Omega-3s does seem to decrease the long-term effects and improve recovery after traumatic brain injury. So for those of you who are treating patients who may or may not be exposed to these types of dangers, I wanted to bring that up. Also, there is other research into which of the Omega systems is appropriate. Colloquially, while not listed on the slide, the reason why Omega-3 is there is because it can be thought of as decreasing inflammation in particular, whereas Omega-6 tends to be pro-inflammatory or increasing inflammation. Some anthropological studies that I also did not list, admittedly, in this reference, I'm just thinking of now, when I was back in, frankly, undergrad, reviewed details of what were the ratios in early man, in Homo sapiens, in societies. For those who don't know, it was probably closer to 1 to 1. Today, if you walk out of this, sorry, if you walk out of this seminar and go to lunch, which I presume many of us will, and you go to a restaurant, there's a good chance, depending upon where you go, it's gonna be closer to 16 to 1. 16 specifically being for Omega-6s for every Omega-3 in the food that's being preserved and being provided to you. So additional food for thought after we leave here. Also, in addition to Omega-3 research, some things that we should discuss would be eicosapentatonic acid, or EPA, as well as DHA. I won't bother saying the full name of the second one. DHA, in particular, compared to EPA, but both do have positive benefits cognitively, as well as in patients with mood disorders. It appears DHA is providing some significant decreases in symptoms via correlational studies. Where possible, it appears that increasing these vitamins via diet will likely be the easiest and most bang-for-your-buck type of mechanism of making these improvements, but eating five grams of Omega-3 without supplements, I fear, would be potentially impossible, maybe. So I looked a lot at do vitamins provide benefit, and the answer is yes, we are still finding benefits. I recall, and I included at the bottom here, one of the most famous psychiatric examples of vitamin supplementation when combined with selective serotonin reuptake inhibitors does appear to be beneficial in patients with major depressive disorder. And then I further posit that with research showing them being safe for supplements, there's no reason why we couldn't recommend the supplements, especially Omega-3 DHA, EPA, sorry, DHA, EPA. So let's move now to something that perhaps many of us might be more comfortable discussing, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and medications. I'd like to highlight how some of these medications we're already prescribing are likely affecting our microbiota and translating to the hollow biome. SSRIs, I'm sure as many of you have read, retained some significant attention in the last year, specifically related to the mechanism of treating patients for major depressive disorder, specifically related to the monoamine hypothesis. Proposed alteration of levels of serotonin in specific regions of the brain is one of many hypotheses into how these medications are treating the disease process. And I'll jump ahead, I'm still recommending we use SSRIs and SNRIs. Specifically, I found more information related to microbiome research supporting this use. They both seem to decrease inflammation, both at that gastric-associated lymphatic tissue level, as well as systemic changes to inflammation, whether this specifically is being mediated by platelet inhibition or otherwise. Either way, it's decreasing inflammation, as well as likely decreasing inflammation in the central nervous system, which we won't talk as much about today, but those are the things that Dr. Rustling was highlighting with some of those different enzymes and things in the central nervous system. Interestingly, these medications, whether via decreased inflammation or an alternative yet elucidated mechanism, are being found to regularly alter in vivo microbiomes. Looking at studies and samples of people on these medications, we're seeing changes before and after initiation, we're seeing changes months later. As such, I still recommend and further support both the use of these medications in patients with appropriate psychiatric disease, as well as monitoring for ongoing research, further looking into some of these mechanisms, as we've hinted at, as these medicines in their role in relating to microbiome, tryptophan synthesis, or other mechanisms. Earlier this year, one of these studies that I'm recommending you watch for came out, and some of you might have read it, some of you might have missed it, but specifically, it was about lithium. Recall Dr. Rustling was discussing an enzyme called IDO, indolamine 2,3-dioxygenase. It's been shown here on this pathway as the rate-limiting step of conversion for tryptophan into a pathway that, if you look at, ends with kynurenic acid, quinolinic acid, picolinic acid. And as mentioned by Dr. Rustling, picolinic acid is one of the most potent endogenously produced neurotoxic and MDA effectors. As we've also just started at the start of this talk, levels of picolinic acid is being found in increased systemic circulation in those who die by suicide. It's further found in research related to patients with chronic or treatment-resistant depression, and there's other research ongoing about these different levels and their ratios. So it's interesting to me that we found that lithium inhibits IDO. Imagine inhibiting that enzyme and where it would shift in this pathway in particular. Lithium, of course, as you know, is one of our excellent choices for decreasing suicidality in patients. It's not escaped my notice that we just discussed multiple depression-suicide finders with these particular enzymes, and perhaps this is a contributor, or even the mechanism of lithium decreasing suicidality, and perhaps it contributes to its treatment in mood disorders. So that's why we review the biochem, is for when things like this come up and how they make sense. So let's talk about some other medications. Perhaps some of you are prescribing, perhaps not. Diabetes medications, as they're traditionally thought of, such as metformin, pioglitazone, citagliptin. Interestingly, I'll also revert back to medical school again. I was told then that, I think someone asked me, what's the mechanism of metformin, and the answer was that it's not yet to be elucidated. Similar to polyphenols, metformin appears to stay significantly in the gut, not really being absorbed or transmitting systemically. We're also finding that it inhibits branched-chain amino acids and promotes a more metabolic homeostasis in elements of our microbiome. Overall, it is possibly or even likely that this is contributing to metformin's mechanism of action both for diabetes and blood sugar control, as well as the things that have been noticed in multiple studies where it's causing clinically significant decreases in depressive symptoms. Imagine being an endocrinologist and providing scales to your patients after you're starting these different diabetes meds because you notice that they come back and they don't seem as depressed, and that's effectively how a lot of this research started. So with this in mind, given its well-researched topics and relatively safe profiles, I recommend specifically increasing our awareness and monitoring for metabolic side effects of our patients. We're starting them on medications that can contribute to these metabolic syndromes. We should make sure we're using the best methods to detect where appropriate, screening for where appropriate, considering other mechanisms such as HOMA-IR, another mechanism I recently learned in another one of these talks that could be used to screen and catch more of these metabolic syndromes, and where appropriate, initiating these medications or referring to appropriate specialists to manage them if it was above our comfort level, as well as using it basically in treatment of disease in appropriate patient populations based off of the indications at your discretion. So one of the things I also listed at the bottom here was I brought us back to C. diff. I'm sure you remember oral vancomycin. You may have gotten five test questions in your life, correct, because you clicked oral vancomycin, sure. I had thoughts that perhaps antibiotics would be working in a similar way and, you know, remove the bad, right? Overall, I think that while you could reset the microbiome via aggressive antibiotics, Dr. Ressling, and I apologize, it might have been Dr. Hines, discussed increases in suicidality, depressive symptoms after patients were admitted for infection and treated with these broad-spectrum antibiotics. Furthermore, I like to just conceptually think of it as attempting to remove weeds from a garden with a flamethrower. You're killing everything and removing all of that and not providing any of those prebiotics or postbiotics. However, it is an interesting idea of if a microbiome were so off the rails as it were, perhaps we would use specific antibiotics to help cull and maybe reset. As far as ways we could particularly reset, I would like to target, we'll actually jump to the end of the slide first, then we'll come back to bacteriophages because I think they're so cool, we should end with those. Bacteriophages, fecal transplantation would be an option if we needed to rebuild a microbiome. And as we're finding, like Dr. Hines mentions, where he performed a study where he started giving fresh fruits and vegetables and monitored for improvement of symptoms, we would also likely see microbiota changes and potentially be able to reset or improve or just help where appropriate. The thing I said I wanted to discuss in particular would be bacteriophages and their ability to precisely edit the microbiome. Well, by and large, we can start now saying, go to the store, eat these things, take these supplements, here's the medications I'm prescribing and realize it can benefit the holobiome. We also have the option in research clinically where they are using bacteriophages to target a specific culprit of a disease. One of the most interesting studies I read about this was in animal models, they had identified an endotoxin called cytolysin that likely contributes to alcohol-induced liver disease and in this case was being bolstered for the purpose of creating liver disease in animal studies. This particular cytolysin is produced almost exclusively by a bacterium E. fasciculus as listed on the slide and what they simply did was took a bacteriophage as a vector, they found a way to remove that particular bacterium and then monitored for levels of cytolysin and it was really interesting to see that over the clinical course, not only did those levels go down but it allowed the liver to recover in what would otherwise have likely been a terminal piece of disease. So while perhaps you don't have bacteriophage as an option for clinical treatment now, I'm interested to see these areas of further research and how they can potentially change the way we're practicing over the future. For now, I recommend not delaying using medications and diet modifications as we've spent our time discussing at length today to support improvement in our patient's microbiome and monitor for improvement in the holobiome, including the severity or even recovery of their psychiatric illness. That is actually the end of my time. Thank you very much for your time and I'd like to open it up to further discussion before lunch. Okay, so I know that ran a little bit long but if you have any questions, just throw your hand up and... We got 15 minutes. Oh wow, we got 15 minutes. We do have 15 minutes. Hi, thank you. This is just so exciting. I really appreciate the excellent presentations. And I'm wondering, I had two questions. One is, do you recommend to your patients to eat fish? And the other question was, you noted the benefits of green tea and Pu-erh tea, but I'm wondering if black tea also has benefits. Thank you. So for those who are interested in those ratios, fish is four to one, significantly better than 16 to one in particular. Overall, it's also a relatively fresh option and relatively healthy option. So yes, of course, why not eat fish as appropriate? And then as far as the tea, yes, the research does tend to be green tea, just more plentiful, but overall there were no negatives and there was promising data with black tea as well. And for Pu-erh, so it is unique because basically you take some black tea and you put it out in the sun in a big pile, it ferments. So the phenols that are in the Pu-erh have historically been used by Eastern medicine for weight loss and hepatoprotection. And as we've kind of applied a biochemical perspective, we've learned that there's something about that biotransformation from black tea to this Pu-erh, which is just modified black tea phenols. There's something in that modification that makes Pu-erh especially beneficial, but thank you, ma'am. Thank you, I have some in my cabinet that I haven't had, but now I will. It's also really tasty. I have become a huge fan of it personally. I would just take a moment to speak to where we get our oils from. Of course, the biggest problem we have right now is the introduction of seed oils into our food. Basically anything that makes a seed, you can actually get the oil out of it, but it typically takes very high heat, 1,200 degrees or more, and very high pressure, as well as solvents like hexane to get it out. And if you can avoid seed oils, so basically, again, I understand the equity issues here, but coconut oil, avocado oil, and olive oil, which olive oil is obviously a key in the Mediterranean diet, which we know has probably the most data to support its healthfulness. And avoiding seed oils, which is nearly impossible, I challenge all of you to go to the grocery store and find anything that's actually in a package and see that it doesn't have some form of cotton seed oil, linseed oil, corn oil, you know, all the other seed oils. It's basically ubiquitous, so that's why Michael Pollan and myself, I reckon, and my patients, you stay away from the center of the store. Everything you need to eat is actually on the periphery of the store, and if you never go into the middle, you're probably better off. Yes, ma'am. You mentioned metabolic syndrome and metformin, which is information I've heard before, and I'm so glad you put it together for me today. There's a huge, right now, I think there's a drug shortage because it's so popular, with semaglutide, and I wondered if you could comment on whether that's good, bad, ugly, or what. Yeah, so I think it's important to note that, because we're discussing a non-FDA-approved use of a medication, so it's off-label, so we're strictly describing what we do in our practice, but I personally do use metformin as an SSRI adjunct because of its regulatory role in changing microbiome composition and reducing that branched-chain amino acid composition because the glutides are subcutaneous injections, and in shortage, I think that considering alternatives that are plentiful, very, very cheap, more often approved by insurance, and even if they're not, a patient has to pay cash, they're affordable, makes it a good consideration for all of the challenges that our patients face. Can you speak to what dose of metformin? I'm not used to augmentation doses, only diabetic doses. Yeah, so studies that have been published that look at the use of metformin for the reduction of depression have looked at subtherapeutic for diabetes doses of 500 to 1,000 milligrams, but if you're interested in this topic, there's a lot of published literature to help guide your own practice uses, but it's typically in that 500 to 1,000 range, but most often, that 500. Thank you so much. Yeah, thank you. I would also just mention, as we all know, not all depression is the same. The right patient selection's important as well. People who have insulin resistance and have other inflammatory telltale signs are people who I would potentially recommend metformin for, as opposed to just saying, everybody who's depressed should get on metformin too, because some of the studies have shown that that isn't effective. I'm wondering if you are aware of the Public Health Collaborative, PHC-UK, and their efforts, Heidi Giffner, David Unwin, and Jen Unwin, and their efforts to get this information out to the public with pictures, infographics, and the negatives that they incurred earlier from trying to do this, but how positive the effects have been and how reduced the expenses have been in general medical. How can we implement those kinds of things here in the United States? So one of the biggest differences we have as far as legalities, and again, these views are my own exclusively, those regulatory bodies tend to pull things and then see what happens across the UK. The US has a somewhat different strategy. We tend to publish warnings, such as the different things you might see, and that's mostly the extent. So unfortunately, that was a non-answer for you. I would challenge each of you to find ways, the appropriate avenues to make those changes, and I think the thing that will help is the more we see the positives and the decrease in cost in particular, the easier that advocacy will be. And I think Dr. Sorensen is very modest and has an interest in that field, so if you're interested in collaborating, I'm sure he would love a connection on the APA app. Thank you. I'd also just mention, of course, everyone knows that the agrochemical industry is significantly opposed to a lot of these efforts, and so it's gonna take a lot to overcome the dollars that they're putting towards continuing our ultra-process diets. Food Junkies podcast with Dr. Vera Tarman is one of the resources that's easily accessible to people, so there are over 100 and some interviews easily accessible. Thank you so much. Thank you, ma'am. I was wondering, I know it's a little outside the scope of this talk, but if you could comment anything about the microbiota in people with autism spectrum disorders, if you've read anything about that, because there's some fairly good evidence that their microbiota has changed, even just the double the rate in women that have had C-sections versus vaginal births. So I was wondering if you had any, what's on that? I actually have that in my longer talk, but definitely there's good data for, in fact, they actually did microbiota transplantation in some autistic kids, and even seven years later, they had improved outcomes. And then, sir, who's been waiting at the second microphone? Thank you. I just wanted to commend you for an excellent presentation. I wish I had heard this in medical school or during my residency. One quick comment, in one of your slides, you, of course, touted the benefits of fresh foods, but in that same slide, you also touted the benefits of fermented foods. Could you comment about that? Sure. I think in the terms of fresh food, we're talking about non-processed foods. The benefits of fermented foods is, of course, they start with fresh foods, and then we let the bacteria do their thing. And we end up, as I noted in my slide, we end up with primarily positive bacteria in fermented foods, and with that, you're inundating your microbiome with the good stuff, which is likely helpful. Thank you. Hi. In terms of improve or to make it more strong, for how many years do you recommend breastfeeding to children? In Mexico City, the new recommendation are five years, but how many time you recommend it? That's a fantastic question that I do not know the answer to. That's a great question. Thank you. So from a research perspective, there is no answer to that. We don't have the data to support it, but we tend to take a strategy of fed as best overall. So we want to encourage breastfeeding where appropriate without specifically removing, but it is akin to eating fresh versus eating processed in a way. So we'll see if that changes. My answer offhand is two years. That's the international recommendation, two years for now. In Mexico, Ricardo Garcia Cavazos told us recently that five years is the best recommendation to improve my microbiome. That population level change could pose some interesting research opportunities would be my comment. And then, ma'am. Thank you. Yes, thanks for the great presentation, first of all. Second of all, I have two questions. One is about metformin and one is about the Dutch study you mentioned. First of all, with metformin, I was curious and wanted to know more about patient selection, but also given that metformin depletes B12 and the SSRIs need the B vitamins as cofactors, do you recommend a B complex vitamin in conjunction with that cocktail? And as far as the Dutch study goes, you had mentioned LPS and depression and I was just hoping for clarification of what the clinical question was in that study and what the conclusion was. So I'll address the LPS study. So the clinical question was, they have this huge data set and it was kind of a data mining approach where they focus in on a single biomarker and the clinical question was, does this biomarker over this population size of 3,000 patients over nine years have a consistent effect on worsening single components of the depressive experience and behavior to look for the conserved physiologic changes that could be changing the phenotypic output? Thank you. So for, in my practice, I've started doing a number of patients who seem to have some of the inflammatory telltale signs. I get insulin levels and CRP and some other markers and then sort of decide from there where to go. But we're also proposing a study looking for biomarkers for suicide that includes some of the ones that Dr. Rusling mentioned and also some pupillometry and heart rate variability data. And so it would be nice if we could get a cocktail or a toolbox of actual reproducible markers that we would use to make these decisions, but we really don't have that yet. I'm hopeful, certainly in these guys' clinical lifetime, we're gonna get there, but we've been ignoring this for a long time and again, not to sort of harp on industry, but pharma's goal is really a pill a day forever and they're not looking so much for these types of things and so it's really up to us in academia to do those studies because certainly pharma's not gonna do that. Thank you all. Money rules the world. Are any of you familiar with the writings of Dr. Stephen Gundry? He's sort of out in the pop culture. He wrote a book called The Plant Paradox. He talks about things called lectins and leaky gut and a healthy biome, increasing longevity and mental health and all of that. He's particularly fond of olive oil and avocados. He's a little bit on the extreme side, but you know, that may be needed. Anyway, Stephen Gundry, it's kind of cool. Thanks. Cool, I'll add it to the reading list. As long as we're recommending pop culture, guys, I really like Mark Hyman, so if you don't listen to his podcast and Jason Fung, they're both good podcasts to listen to for functional medicine type things. Jason Fung is great. Then I really also like Ben Bickman's book, Why We Get Sick. If you want to think about insulin resistance, that's a great book to read. Then we have time for one more question, sir. Well, I have a comment and two questions and that was related to what I was gonna say that 20 years ago and all these folks were talking about leaky gut syndromes and this was fringe science and so it's so refreshing to see you guys bringing science into the conversation and legitimizing this conversation, which is truly important. First question is, can you comment on the role of exercise in the microbiome? That's one. The second question is, there's plenty of us who are replenishing and working on our microbiome. Can you comment on the life cycle of the shern in terms of how long these bacteria live, how much are we replenishing, just at a volume time scale? Yeah, so I think that is one of the most fascinating parts of the microbiome is the time scale. Our genetic makeup is largely fixed over our lifetime, especially in our non-gamete cells, right? So of course there can be some epigenetic modification and then the epigenetic modification sticks around and our histones can be acetylated and deacetylated, but the time course of that stuff is like hours to weeks. The speed at which a bacteria turnover can happen can occur in a doubling life cycle in as few as like two to three hours. So the lifespan of these bugs is gonna be on the course of days to weeks. So there's this huge adaptive turnover. So I kind of think of the microbiome as this hyper-adaptive metabolic powerhouse that lives in our guts that we are on the edge of understanding to be able to kind of optimize as a new frontier of human health. And for exercise, so there was recently this awesome nature paper that was published that looked at voluntary running behavior in I believe it was rat models and found some pretty conserved predictors of running behavior. So like spontaneous exercise behavior could be related to the microbiome. When it comes to exercise, there's a difference between aerobic and anaerobic exercise and how it remodels microbiome because the aerobic stuff, your gut gets a bunch of blood, the anaerobic stuff, your gut actually begins to favor anaerobic metabolism to further support your adaptation to tolerate anaerobic exercise. So there's a lot of co-adaptation that's happening. It's really complicated, but I think optimizing that, especially in our high-end athletes, could be the next frontier of human performance. And for sure, the data's there that, we didn't talk as much about it, but it's much a bidirectional system, right? And so our own stress levels, our sleep consistency, our exercise all factor into our microbiome diversity. I would say that there was a study a decade or more ago looking at eating lactobacillus-containing yogurt, and you had to eat it every day. If you skipped even one day, your microbiome started slipping back to a worse condition. So that's one of the reasons why in my longer talk, we talk about whether you get it from your food or whether you get it from probiotics, but it's really hard for people to get, to maintain the diet every day. And so probably a probiotic supplement is a reasonable addition, as long as you get it from a reputable source. That probably is helpful, but you can't, if you can eat enough fermented food, you probably don't need the probiotic. Right, since I'm the last one, I'm gonna add, what about pets in the household and microbiomes? Can you, you wanna? So there's data for, the more animals you're exposed to in the first two years of life, the better off your microbiome is, and also the less likely you are to have ATP and other allergic symptoms. Thank you guys, excellent. And then I guess like one more. Yeah, yeah, everybody can go, we'll answer your question, yeah. Quick question, this might not be completely relevant, but a lot of my patients have gastric bypass surgeries. What's the effect on that, if you know of any, and where are the microbiota, where are we looking at in the gut specifically? Yes, that's a really good question. A lot of the absorption and metabolite. So think of the different conditions in the gut, right? So coming straight out of the stomach, we are talking about a extremely acidic, inhospitable environment that quickly gets a ton of bicarb dumped into it from the pancreas, which is another inhospitable environment. So it's kind of once those things mix, and you get more into the distal small intestine and the large intestine that the metabolism becomes a little bit more relevant, just because there aren't so many chemical poisons that are reducing the microbiome metabolic functioning. I would also point to the fact that the surgeons are on board now, right? So post colon surgery, they recommend three months of probiotics. And so that's actually a standard for them now. So even they have realized that that improves their outcomes. And there's other mood benefits to losing weight, I've noticed. Absolutely. Yeah. Jerry. How many colony forming units are you recommending to your patients per day? I've read previously 20,000 is the minimum to achieve a sustained change. Yes. So the data that I haven't looked at in a while, but the most recent data I looked at was you have to have at least three billion colony forming units in whatever supplement you're taking. And the one I personally take has 15. So that's, you know, I think that's obviously data that really still needs to be studied. And so we just have to figure that out. Thanks so much. Yeah. Thanks guys.

functional medicine

microbiome

gut health

mental health

diet

processed foods

tryptophan metabolism

neurotransmitters

mood disorders

dietary adjustments

fiber

fermented foods

mental wellness