GutBrain. Okay, doctor, I'm going to pass the controls over to you. Okay, here's my screen, perfect. Wonderful, let me get my presentation out, okay.

Transcription

1 Ron: Vreeland: Ron: Vreeland: Ron: Vreeland: Okay, doctor, I'm going to pass the controls over to you. Sounds good to me. Okay, here's my screen, perfect. Wonderful, let me get my presentation out, okay. Good, ready to go. Ready to go. All right. So thank you Dr. Grisanti, you know this is a really important topic and I think in functional medicine if you are kind of well into functional medicine or if this is your first module, it's good place to start and good place to investigate. This connection between the gut and the brain is very, very, it's very well connected and it's very important for overall health and we are starting to see that not only for brain health but for you know if the gut isn't healthy the entire body is not healthy and it is connected to the brain. A lot of doctors like to look at the brain as maybe an isolated environment, when it's really not. I'm going to show you why it's not today. So let's get started because we probably have too many slides to try and get through. So what are we going to talk about? Well, this is kind of the summary of the entire lecture. We will talk about the Microbiota and why it's important. And then we'll look at stress and the importance of secretory IgA, talk about Barrier Function, we'll talk about that good old fashioned, standard American diet, high end fructose, high end calories. We'll look at lipopolysaccharides and a phenomenon called endotoxemia. We'll tie it all to brain function because that's what we are here to do. We'll talk about some therapeutic options and then we will look at a case study because I think if you are learning about functional medicine it's helpful to look at it in a format that you can see that it does work clinically okay. So we do know that there's this huge body of evidence now that exists that shows that there's healthy, the healthy gut function is very important for not only function of the entire body but healthy function of the entire body but for the central nervous system. And when we look at the microbiota that's present, right the entire balance of the bacteria, we should look at it as an inner organ, just as we would look at your heart or your liver or your spleen, etc., just as disruptions in those organs can cause dysfunction in the central nervous system, dysfunctions in this Page 1

2 inner organ of the microbiota can cause dysfunctions in the central nervous system. Now the human gut is sterile at birth, I may, should, maybe amend this slide a little bit because we are doing the research for the book chapter that I have actually finally completed now, actually just completed it. We are starting to show that actually there is evidence of bacterial DNA in the placenta, there's bacterial DNA in the meconium, there's bacterial DNA in the amniotic fluid so we might need to change this slide a bit and that's how fast it's changing. You know I wrote this presentation less than a year ago and we are finding that evidence changes that fast. Now, by the age of one year that profile looks very similar to an adult, the bacterial profile. But everybody has their own unique profile, no two are the same. The total load is enormous. You guys can read the numbers there but a 100 trillion in number, that's a big number and you know that's kind of almost an incomprehensible number. So to give you an idea if you are born and someone gave you $100 trillion, you can immediately start spending that money at $42,000 a second. And let's say you live to be 75 or you stop spending it at 75, whatever the reason was, you could spend that $42,000 a second and by the age of 75, you would have $661.5 billion, billion with a B left of that $100 trillion, so that's how much 100 trillion is, it's a lot. And we want it to be in balanced okay because if it gets unbalanced that's when we start to run into trouble. So the gut brain axis, what does it involve? It involves pretty much every system you can think of. It's the central nervous system. It's the endocrine, the endocrine system, the neuroimmune, sympathetic and parasympathetic, it's the enteric nervous system and it's of course the intestinal microbiota. It's bidirectional okay. The brain influences the gut and the gut influences the brain, two-way street and I'll show you a good study. As a side note, many of the references that I have in here are open access journal. So if you do happen to have a copy of this or you like a copy you can certainly me and I'd be happy to give it to you, if it's not provided to you. And you want to go through that. Most of these journals are open access okay. So let's look at the microbiota, just a little bit closely, you know I'll close it for a second here. So what does, what do we know, what do we know for fact the microbiota do? Well, it regulates the mucosal immune system, it helps gastrointestinal motility, helps Page 2

3 regulate that, that's why somebody can take if they are constipated, giving them a probiotic may help them with their constipation, it's really important for epithelial barrier function, it's really important for digestive and host metabolism and it's critically important for the prevention of colonization by pathogens and if you are in practice and you are looking at these things and you are looking at stool profiles and you start to see pathogens you almost always see that when there's a pathogen present the counts and the balance of the good bacteria is often off or low. Now, the effects of the bacteria on the central nervous system begin really early in life and here's the way this works. They take germ-free mice and they expose them to mild stress okay. When they expose them to mild stress the germ-free mice have an exaggerated HPA axis response as measured by high corticosterone, high ACTH okay. This is corrected when they colonize those germ-free mice by pathogen-free bacteria from controls and what's been shown is that there's a window for this. So when these germ-free mice, if they go longer than they, longer than a certain set of time, the colonization by these pathogen-free controls doesn't correct the abnormal stress response and that's a major problem because if this is happening to human beings where they create this abnormal stress response because perhaps the bacteria are unbalanced this may persist for their entire lives and what does that mean for psychiatric disease down the road, what does that mean for the one-third of births in this country that are cesarean section? C-sections are sterile births and it's becoming very clear that if a baby is not exposed to the bacteria of the birth canal that can create or set the stage for disease down the road. Now they haven't looked so closely at psychiatric disease but they've looked very closely at autoimmune disease and things like asthma. And kids that are born in C-section happen to have experienced much higher rates of those types of disorders maybe because they are not exposed to the bacteria in the right order, they are born sterile, maybe they are handed to the mother, maybe they are not, but if they are handed to the mother, the first exposure is the bacteria on the skin, that's not the correct order or maybe they are not handed to the mother and their first exposure is the bacteria on a pacifier or bacteria on the bottle. So it's a little bit of a problem and we need to look at those things. And we are starting to see that the evidence is really supporting that we need to really be very vigil of this bacterial, these bacterial balance issues because it can create permanent long-lasting issues. Now, what they found is that, so where is this, how do we connect these microbiota with the central nervous system? Well, in patients Page 3

4 with hepatic encephalopathy okay, when patients go into liver failure, they can develop impaired cognition, tremors, dementia, coma and death. The treatment is in non-absorbed, oral antibiotic so people take the antibiotic by mouth, it's not absorbed okay and what it does is it works to reduce the ammonia producing bacteria in the gut and people maybe, these were studies done in the 60s, and they said well jeez if we can give someone an antibiotic and we know it's not absorbed and we are inhibiting bacteria that are producing a certain chemical that must be getting out of the gut what other connections might there be. And just as a side note when I wrote my book chapter I found that there's a lot of research at the turn of the 20 th century so early 1900s looking at these things. But it became, it fell out of favor because other things came into favor like the theories of Freud and how the mind can control people s symptoms and so people were looking at depression and anxiety as related to the gut but then it kind of disappeared. And there's a little blip in the 60s and people started to study these things again but then it didn't get looked at again until maybe the 1990s even the early 2000s. So we know that this has been looked at for a long time. This isn't necessarily a totally new subject. So here is a great slide. Try to commit this to memory if you can. If you can't, I can certainly send you some information about this, but I would like to start in the upper left and this is the whole cycle, this is it right here, this is the entire presentation on one slide. Stress, dietary and environmental triggers lead to changes in microbiota. Those microbiota changes lead to gut epithelial breakdown or leaky gut okay; that leaky gut causes immune activation by endotoxemia or lipopolysaccharide stimulation and I'll tell you what that is in a moment. That immune activation is inflammatory through cytokine production. Those inflammatory cytokines break down the blood brain barrier; that barrier breakdown causes alterations in neurotransmitter levels; neurotransmitter levels that are altered cause changes in synaptic plasticity or the connections of the neurons. The changes in the plasticity eventually result in neural, behavioral and mood changes and then the neural, behavioral and mood changes lead right back to your stress, dietary or environmental triggers because if you have neural changes or behavioral changes or mood changes you maybe, you may perceive more stress or you may make worse dietary decisions or you may need more medications that we know can, in some instance break down the gut barrier so it's a vicious cycle. We are going to tell you I'm going to tell you how to fix that and how to interrupt that cycle okay. Page 4

5 So a couple of definitions. What are lipopolysaccharides? I'm going to talk about them all night here. These are molecules present on the surface of gram-negative bacteria and they elicit a very strong response. So when the bacteria are alive, they are attached to the bacteria. When the bacteria die, they are free to try or attempt to get through the gut barrier. The gut should keep them inside the gut. If they get out, they stimulate a very potent immune response which is inflammatory okay and the inflammatory response is through cytokines. What are cytokines? Well cytokines are messengers used by the immune system to communicate with itself, makes sense, and other parts of the body including the central nervous system. Now, the cytokines might be inflammatory, they might be anti-inflammatory, they might be regulatory. The ones we are going to focus on tonight are inflammatory. Barrier Function: the gastrointestinal track is essentially an exterior organ system right. There's a hole in the top, there's a hole in the bottom and it's just a big long tube in between okay. We put the outside world in. We got to have a selectively permeable, selectively, if it becomes overly permeable and we lose that selectivity, we start to have, that's the phenomenon of leaky gut and we start to run into trouble, that's where we start to increase inflammation. So the epithelial barrier s huge, 2100 square feet, I mean that's enormous, that's bigger than my house okay, so it's big. It's got a lot of square footage. We have a lot to protect. And tight junctions play a very important role in keeping stuff in the gut, that should be in and letting things through that should be let through. So let's talk a little bit about tight junctions. You know it's kind of a summary slide of what they are: composed of 50 different membranes associated proteins and located between the cells, I've got a slide here to show you what that looks like. Some actually extend into the intercellular space and function is like a gate. They also function as structural protein so they hold together the cell and they make it rigid. Here's what it looks like essentially. And you can see here if you can see my cursor the tight junctions are here at the apical membrane, apical and lateral membrane. And when it goes we have, it prevents paracellular flow which you can see here. Now there's also a transcellular flow but that requires selective binding of proteins and nucleic acids and fats and all kinds of things to the cell surface. This paracellular flow can be a bit of a problem especially if tight junctions break down. Then things can get into the bloodstream or the surrounding Page 5

6 immune tissue I should say or the portal circulation without regulation and that's a major problem. So what are some of the triggers for gut dysbiosis and gut dysfunction? Well, we've got physical stress okay, well, we've got stress in general and we've got physical things like lack of exercise, believe it or not. Lack of exercise will cause gut dysbiosis and gut breakdown. Too much exercise will also do the same thing. Infection will do it. Mental stress, your body views physical and mental stress the exact same way, it responds the exact same way. Environmental triggers, chemicals like medications like NSAIDs, I mean the most commonly used medications in this country are NSAIDs and they are available over the counter and people pop them like they re sugar pills but they really break down the gut barrier and very quickly inflammation from an NSAID, the inflammation that an NSAID will cause will rise you know within three days of taking an NSAID okay. So it's a major issue. And then there's dietary factors. Now it may be different for others from person to person but some it's gluten, some it's dairy, some it's some other food sensitivity, alcohol is a really big one or generally poor diet. We are going to go through a lot of those things tonight. Essentially what happens is all of this break downs the gut barrier, it changes the balance of the bacteria in there, we get translocation of those endotoxins so when I talk about translocation tonight I mean that there's these endotoxins are getting from inside the gut to outside the gut and endotoxins is just another name for LPS. And then when that happens we get an inflammatory response. Now, stress, that's a big one, everybody s got it right or everybody thinks they've got it right and I say everybody thinks they got it, it did air quotes, not that you guys can see me but everybody thinks they've got it because stress is a perception okay, at least mental stress is a perception. But here's what happens. It activates the autonomic nervous system and interestingly enough the sympathetics which are primarily activated by stress are mildly anti-inflammatory and the parasympathetics are powerfully antiinflammatory. And this won't just make any sense. Well, it does if you think about it. When the body activates the sympathetics especially from stress, powerfully activates them, we turn up the volume, essentially on the mildly anti-inflammatory system and we turn the volume way down on the powerfully anti-inflammatory parasympathetic so the net result is inflammation, it favors inflammation with stress and that's the confusing part because a lot of people have talked to me and they say, well, I thought the sympathetics were actually pro-inflammatory. They are not but by Page 6

7 activating them the net result is inflammation. So I hope that makes sense. And here's just some evidence that shows that the parasympathetic is potently, parasympathetic system is potently anti-inflammatory. The vagus, the research is pretty clear that the vagus regulates the intestinal immune system and when they stimulate the vagus they can actually prevent LPS induced shock or endotoxin induced shock by reducing pro-inflammatory cytokine production. And we know that the vagus is the primary parasympathetic nerve of the body. Additionally, cytokines and endotoxins stimulate vagal afferents and the brain stem in a structure called nucleus tractus solitarius or the NTS. In return that NTS generates this vagal outflow that modulates this immune response and when they do a vagotomy, okay selective vagotomy, in animals, they cut the vagus nerve usually below the diaphragm or maybe on just one side and they find that there's a total loss of inflammatory control in the gut. So we know that that's a really important piece and we don't want to inhibit parasympathetic function so much that we generate this inflammatory response but lots of people are doing it day in and day out with their stress. Now, secretory IgA, this is, here's what I want you to take out of this: it's the first line of defense okay. Anywhere where there's a mucus membrane you are producing the secretory IgA and this immunoglobulin A binds to toxins, to bacteria, to viruses, to fungal spores and to fungal forms and prevents them from gaining access to the epithelial barrier okay. And so it's really important that we have that in the correct amounts okay because if these antigens are not bound and then excreted they have this ability to break down the gut barrier and generate this inflammatory response okay. We know that secretory IgA is naturally anti-inflammatory because it neutralizes pro-inflammatory antigens so that's really important. And when you combine this complex interaction with the microbiota that are present in the gut, this symbiotic relationship maintains the intestinal inflammatory response within physiological limits because we want to have an inflammatory response in there and we need it. If we have an infection we need an inflammatory response. We just don't want it to get out of control. Now, what happens with secretory IgA is that we get with acute stress, we usually generally get increased secretory IgA in the short Page 7

8 term with chronic stress we down regulate it and we produce less and less and less and less of secretory IgA so not only have we decreased our parasympathetic function and increased our sympathetic function, now we've taken our protective, our first line of defense from in terms of immune function out of the equation with chronic stress. All right so it leads to increased adhesion of the pathogens to the intestinal epithelium. We get altered balance of inflammation leading to greater intestinal permeability, aka leaky gut. So, we just talked about this. This slide is looking at the difference between acute stress and chronic stress. We kind of move on from that. This is a kind of neat thing. When we see stress and we know it becomes chronic stress becomes immunosuppressive over time, we can mediate those effects on secretory IgA by activating a system called the PPAR system or the peroxisome proliferator activated receptors. When you look at all of the research on how to activate the PPAR it's just kind of a little clinical nugget for you guys. You can do that by supplementing it with polyunsaturated fatty acids, the omegas and exercise. So we can activate that system to modulate the effects. So when these patients come in they are in a lot of stress, what are you going to give them? Fish oil and you are going to tell them to exercise, pretty simple. And so it's a really good connection there. So here's a summary slide of how secretory IgA works and this is a, I don't have the actual reference on here but one of the references that I have is I probably don't have it on here, but one of the this is an open access journal that you can get and I think to be honest with you if you Google secretory IgA it's one of the first studies that comes up out of Nature. And you can do it just right on Google, you only have to go to pubmed. All right, so here is how it works. Secretory IgA interacts with the good bacteria which reinforce the tight junctions and reduce the inflammation from NF- Kappa B nuclear factored Kappa B. It binds with pathogens and allows them to be destroyed by the local immune cells thereby down regulating inflammation. And it binds with pathogens and allows them to be caught in that mucous that coats the gut and the biofilm rendering them harmless and more easily excreted okay so that's secretory IgA for you. Now, let's look at the dietary considerations, really important. High fructose diet, the western diet, nutrient deficiencies. Now we can certainly combine them all into one because usually the western diet is very commonly associated with the high fructose diet, etc. Page 8

9 We kind of separate them for these purposes because there's some research that looks at it a little differently. Now, we know that fructose, high fructose corn syrup, maybe potentially consuming too much fructose from fruit, I don't know if anybody has looked at that, but it might be the same way. It's implicated in insulin resistance, fatty liver, metabolic syndrome. And studies have shown that fructose but not glucose can induce liver damage you know fatty liver eventually cirrhosis if it kept going directly through increasing intestinal lipopolysaccharide translocation and endotoxemia okay. So what they do, what they found is that when you take fructose and you combine that meal, high fructose meal with antibiotics, you get reduced fatty liver and you get reduced endotoxemia, isn't that interesting? So there seems to be this interaction with fructose, the bacteria, the immune system and inflammation but if you knock out the bacterial piece fructose is not so much of a problem. Now, I'm not advocating that everybody consumes an antibiotic with their soda but there is this definitely this connection. If you look at mice who have been genetically modified not to have this very specific immune receptor and this is the receptor for endotoxins and the receptor is called a toll-like receptor because these mice don't have this receptor on their white cells, they can't generate an inflammatory response. They don't get fatty liver or insulin resistance when they consume fructose. They can consume as much as they like. So that means that this response to fructose may not totally be well, we just absorbed fructose and we you know it gets shoved right into the liver and it's get converted right into fat etc. that might be a part of it, that might be a mechanism but also there's an inflammatory component to this and there's an immune-mediated response to this. And you know this is important because when I start to tie this to brain function you are going to see well, what do we need to eliminate from our patient s diets to reduce their inflammation so that they can feel better in terms of mood. Well, big surprise, it's going to be high-fructose corn syrup. But I'm making the case for it here all right. So for you visual people, here it is, all right, little diagram, little motion here, so here we got fructose in the top left. We consume some fructose, yummy that soda was wonderful, these lipopolysaccharides or endotoxins as labeled by these red little colored things here, they are more easily absorbed through the gut barrier, these endotoxins because that's what fructose does okay. And they bind to the local immune cells okay. And these local immune cells don't like lipopolysaccharides. They generate a very Page 9

10 potent immune response remember okay so there's your immune response. Now, it's inflammatory. Over time if that happens day in and day out over a number of years, over and over and over again, chronic, low grade inflammation which we are all focusing on in functional medicine, that begins to increase systemic inflammatory excuse me, systemic inflammatory load because now it doesn't stay local anymore, it gets to the rest of the body and starts to create more and more inflammation everywhere. And now your patient has heart disease or depression or anxiety or cancer or autoimmune disease or you name it, name disease X, Y and Z, it all comes back to this inflammation. It's maybe because they spent the whole last 25 years consuming nothing but high fructose corn syrup and there's a lot of mechanisms there that might be interfering with their metabolism but this is probably one of them. When we look at patients who have depression, we start to tie this a little bit to the brain, we look at patients who have depression, they have abnormal hydrogen breath profile after they consume fructose okay and other sugars as well. When they eliminate fructose guess what their depression gets better, big surprise. Other studies have shown that when people have fructose malabsorption okay it's associated with a reduction in plasma tryptophan. Why is that a problem? Because the level of tryptophan that's in the plasma is directly related to the amount of serotonin you can produce in your brain. Low tryptophan equals low serotonin. Higher tryptophan equals higher serotonin. So yes, that means if you supplement it with tryptophan you can increase serotonin levels in someone s brain okay. And fructose malabsorption also provides a substrate for bacterial fermentation that can alter GI motility, mucosal biofilm, and the profile of microbiota. So all in all fructose is a terrible thing which I guess you guys aren't surprised to hear but here's a little bit more icing on that cake if you needed it. Now, the western diet, generally when at least in this study that I was looking at for this presentation, they consider the western diet, they labeled the western diet, a diet that's very high in calories and what they are showing is that a diet high in calories is associated with higher levels of plasma LPS. Now what's high in calories, well, what's high for one person is not high for the next. So you kind of have to look at basal metabolic rate, activity level, what are they consuming and I also believe the type of calorie is important too. But you know if you are out and you are exercising and you can burn 3500 calories a day, 3500 is not so high, but if you are a Page 10

11 110 pounds and you sit on the couch and do nothing else, 3500 calories is going to be way too much okay. So it varies but you have to know that for your patients. Excessive fat and excessive carbohydrate intake increases the transport of lipopolysaccharide from the gut into the blood stream, fat seems to be more efficient with saturated fat being the biggest offender. Am I an anti-fat guy? Absolutely not. Am I an anti-saturated fat guy? Absolutely not. I'm just telling you what the research is showing right now. I think as this gets ferreted out a little bit more we are going to see that it really comes down to like everything else, it's the refined carbohydrates and it's not necessarily kind of the fat piece. This is just what the research says now. The western diet has been shown to affect host GI tract metabolism and immune homeostasis, not a good thing. It shifts things towards inflammation. The western diet also leads to the over-growth of bacteria of a class of bacteria called firmicutes and a reduction in bacteroides. Why is that a problem? Well, that change is associated with obesity and increased inflammatory load and that change is also associated with an increase in extraction of calories so when you start to shift that you start to actually over-extract calories from your food okay. Diets high in omega-6 I hope you've been exposed to these things. The 6s are, they are potentially anti-inflammatory but generally they serve as the source of inflammation for the entire body. So usually the western diet is high in 6s, considerably higher in 6s than the 3s and so it reduces that bacteroides class while increasing the firmicutes again leading to more inflammation and what's been shown is that that type of diet leads to a more mobile bacteria, a more mobile bacteria is something that can work its way to the cell surface and all of its toxins and metabolites now can have greater access to that epithelial barrier. We don't really want it to have access to that barrier. All right, nutrient deficiencies. Really important, just like four that you can look at, calcium is also an important one, but we consider vitamin A, magnesium, zinc and vitamin D and all four of those are really important for managing and maintaining those structure, the structural integrity of those tight junctions. And I did a webinar just for the public maybe 2-3, you know I came across a great study which I think I would like to include in this slide in here and people say well, I probably get enough nutrients, right, I'm not deficient. The study from 2012 found that 70% of people were deficient in vitamin D, that's not a big surprise. But somewhere around 40% of the people were deficient in magnesium and zinc Page 11

12 and vitamin A I think was about not quite as much. I think that was right around 10%. So you know your patients, it's very likely that they are deficient in most of these and can benefit from taking these to repair gut integrity. It's really, it's likely that they need them. So vitamin A and magnesium, we know the retinoic acid is really important for it plays a major role in the expression of genes related to epithelial barrier function that vitamin A status regulates the cellular availability of that retinoic acid and if we take vitamin A and we reduce it, it's been shown that there's an adverse effect on barrier function and tight junction expression and then magnesium deficiency has also been reported to reduce tight junction expression and reduce bifidobacteria content in the gut. Also a problem, because it promotes inflammation. Zinc is a biggie okay. It's really important for tight junction health and when people are low in zinc they are more sensitive to other external stressors like alcohol that would break down the gut. So not only is that person not consuming enough zinc perhaps, they are also consuming a six-pack every night which breaks down the gut barrier, that's a problem. When they do, when they look at some studies they find that when they supplement with zinc in children who have subclinical enteropathy that they actually get better and that enteropathy goes away and their intestinal permeability gets much improved okay so we know zinc s a major player there. And good old vitamin D. You can't get away from vitamin D these days. It's really important. The vitamin D receptor is present throughout the entire body. We know it's hugely prominent in the brain. Also very prominent in the gut. It's really important for the preservation of the junctional complexes and it stimulates epithelial cell renewal, modulates immune function associated with the mucosal barriers, it prevents under action but it also prevents over reaction so that you are not getting an over inflammatory response when you don't need one and then when they do administer vitamin D to experimental animals they find that they get an increase in chronic epithelial cell resistance to any kind of injury mechanical or chemical. So here's what it looks like okay. We have our Dysbiosis on the left there. We have a dietary pattern high fat, high fructose. I also think that eventually it's going to be more about high carb. I don't think the high fat is necessarily a major, major issue but that's what the research is saying now. We also look at our nutrient Page 12

13 deficiencies. We get all of that eventually results in increased intestinal permeability, increase in plasma endotoxins okay or lipopolysaccharides. And then of course it eventually results in activation of the systemic immune, systemic inflammation which if you look here, you follow my arrow, follows itself back okay, eventually resulting in increased intestinal permeability. So it's a vicious cycle but once we've activated the systemic inflammatory system we end up with alterations from that very first, one of the very first slides I showed you. We end up with changes in blood brain barrier integrity. We alter it. We end up with changes in neurochemistry. We all end up in with changes in neuroplasticity and then once that starts happening people start feeling different and once they feel different then they start altering their behavior and that leads to the back to vicious cycle of poor dietary choices, I need more drugs, blah, blah, blah and it's just a big cycle. We know if we can, we are going to start to connect this now to the central nervous system. Almost all of the mental health disorders that have been studied are associated with low grade inflammation, oxidative stress and an elevation of inflammatory cytokines. Now, nobody has been able to say, pinpoint exactly where this has come from but I can tell you from looking at the research that the most likely source is a leaky gut with lipopolysaccharide stimulation so the lipopolysaccharides you get coming from inside the gut to outside the gut generating this low grade chronic inflammatory response. Interestingly enough, if we take lipopolysaccharides, these toxins on the surfaces of those bacteria and I inject them into you, you are going to get a mood disturbance. You are going to feel low mood and you are going to be very tired okay. So we know and that's generally from the immune response that occurs okay. Now, in general, in a healthy person, it's very small amounts of lipopolysaccharides in the blood stream, very, very small amounts. So it suggests that the gut does a pretty good job keeping these things from getting out or should do a pretty good job. It's when it break downs that there's a problem. Now, other disorders in which we are positive there is a known inflammatory connection. These things, things like obesity, high insulin, high triglycerides, poor cholesterol profile, diabetes, they are also connected with depression and anxiety and they've all been shown to be associated with higher circulating levels of lipopolysaccharides and people say well, of course you are depressed, you are sick. Or what if it's not necessarily that way? What if you are, there's an underlying inflammatory disorder causing the illness, the physical illness but Page 13

14 also causing the symptoms of depression and or anxiety or whatever the presentation is. I want you to remember that all of this is in a genetically susceptible person, not everybody is going to get to have the same presentation of course and that's the beautiful thing about functional medicine is we don't look at it that way, everybody is very their own unique person, there's no cookie cutter approach to this. So we need to make sure that we remember that. So if we look at probiotics quickly just there's new information out there that is talking about probiotics as psychobiotics right. You can give these things to people and they feel better cognitively but there's evidence that oral probiotics impact favorably systemic cytokine levels, oxidative stress, inflammatory markers, mental outlook and cognition. So once we start to fix that that bacterial balance in there which starts to alter the gut, permeability which starts to keep those lipopolysaccharides inside the gut, we reduce inflammation systemically and all of a sudden we start to feel a little bit better. So systemic inflammatory cytokines can induce the production of inflammatory cytokines in the central nervous system via glial activation so it's important that we make this connection between what's happening in the peripheral circulation and what's happening in the central nervous system. So these cytokines that are inflammatory are produced peripherally. They generate a central nervous system inflammatory response through glial activation. Now, what are glial cells, microglial cells? Glial cells are accessory cells that are in the brain. They are not neural tissue but they are important, they are very important. They are very important. They don't generate any kind of thoughts or anything for us but they are kind of the immune system of the brain and they clean up debris and they fight and you know if there's infection in there which is very rare of course but they keep things from becoming a major problem in there. And they need to be active, they need to be activated to do those things. The problem is you don't want overactive glial cells and they are very easily activated because chronic activation compromises neural function through inflammation and through oxidative stress and the end result is abnormal intracellular and extracellular communication, abnormal function, probably neurodegeneration as well. So what activates glial cells, well, we just said one thing, systemic inflammatory cytokine production, possibly brought on by lipopolysaccharides but also we can see low exercise activates them, head trauma activates them, high blood sugar activates them, gosh, toxic exposure activates them, all the things that we know are adverse Page 14

15 for human health. So if we can avoid all those things and get our gut in a better place then we should be able to see great results with our patients. We are seeing that the research is showing that systemic inflammation is likely brought on by lipopolysaccharide stimulation coming from inside the gut through a leaky gut. Again, if I inject you with even small amounts of lipopolysaccharides your immune system will respond because lipopolysaccharides are potently immunostimulatory okay. If I do that we show people get acute anxiety, they get depression, they get cognitive deficits, they get brain fog, okay they get decreased visceral pain tolerance and they get pain syndrome. So it's a very powerful, powerful connection we are looking at here and it's one I don't think many physicians consider in their practice often enough, in my experience anyway. We also see there's been study that lipopolysaccharides can induce, so lipopolysaccharides induce peripheral cytokines to change that peripheral cytokine increase inflammatory can cause altered neuronal activity in the amygdala, excitotoxicity in neurons and increase in the activity of indoleamine 2, 3-dioxygenase okay. We are going to look at that and pull this together for particularly depression but also beginning to look at how this alters neurotransmission. So there's two enzymes we need to consider when we are looking at this pathway. There's IDO, you can see that up top there and TDO or Tryptophan-2, 3-dioxygenase. And when we look at Tryptophan the, really the vast majority of Tryptophan is metabolized primarily using TDO but also IDO. And in a healthy person, less than 1% of circulating Tryptophan is available to be converted to serotonin in the brain. We just don't need a lot of it but we do need some of it. We need about 1 percentish okay. TDO is usually dominant but IDO can become active. And when does IDO become active? Well, guess what, it becomes active when the immune system is stimulated, perhaps from lipopolysaccharides coming from inside the gut and translocating out and generating an immune response, that is, that are cytokines that is inflammatory and we know that IDO is activated by inflammation. So now we've got through with leaky gut, we've got TDO, we've also got IDO and its active on one substrate Tryptophan, what we see is serum Tryptophan, maybe reduced by as much as 25 to 50%. And what did I say about 10 minutes ago? The level of Tryptophan in the serum directly determines the amount of serotonin present in the brain. If we begin to reduce it by 25 to 50% it stands to reason that Page 15

16 we would get a 25 to 50% reduction of serotonin in the brain. Now, nobody has tested that specifically but we do know that the amount of Tryptophan in the serum is directly related to the amount of serotonin we produce. So here's the pathway okay, so follow me along here. Here's our Tryptophan okay, here's the serotonin pathway. Tryptophan has converted to 5-HTP on to 5-HT which is serotonin and then in the pineal gland into melatonin. Most of it goes in this direction and is converted by TDO and then IDO under some circumstances to Kynurenine and on to Kynurenic acid and eventually down the bottom right there to NAD which is Niacin okay. So if you see at the bottom there Christmas et al. Neuropsychiatric Disease and Treatment 2011, that's a great study, it's open access, go download it, it's fantastic, that's where I got this slide okay. So we know that IDO can create this activity, this further activity and drag in Tryptophan away from this, away from this serotonin pathway and into this other pathway and it's induced by cytokines which are induced by LPS. So now we've got because of the lipopolysaccharides we are getting out, we are generating inflammatory response and now therefore less serotonin is available. So to look at it in a different way, we have our gut barrier, we have on the top here where my cursor is here, is a leaky gut. We've got an intact gut barrier. Here we've got bacteria with lipopolysaccharides on them okay, so here's how it works. You have a leak gun, those lipopolysaccharides get out okay. You generated inflammatory response. You get increased IDO activity which reduces Tryptophan metabolism, decreased serotonin production in the brain. If however your gut barrier s intact guess what although lipopolysaccharides stay where they are supposed to stay in the gut, ends up with normal serotonin production in the brain okay. So quick review, altered cytokines can be brought on by stress, high fructose diet, western diet, all culminating in endotoxemia or lipopolysaccharide stimulation. All of this is complicated by the changes to the intestinal barrier from those above mechanisms certainly but also some documented nutrient deficiencies. Here's what it looks like as a picture okay so we have our high fructose diet and a western diet, stress and lipopolysaccharides on the left, complicated by nutrient deficiencies, all breaking down the intestinal barrier resulting in altered cytokines levels which alters neuro-chemistry and alters mood behavior complicated by blood brain barrier breakdown okay so that's what it looks like. Page 16

17 Now, altered cytokines equals altered neuro-chemistry so we know that when we alter our cytokines we get altered neuro-chemistry. And here's an experiment that they did. They compared these cytokines here as you can see to the flu virus, influenza and you can see that most of them actually go up in response. There's some that don't change. And this is just one comparison and one study but it did prove the concept that these things do change that these cytokines do actually change neuro-transmitter levels okay. So how does this occur? Well, cytokines may act on central sites where the blood brain barrier is weak or cause breakdown in the blood brain barrier themselves. So let me just summarize here because I'm feeling I might have gone a little quick over that. So we've made the case that fructose and western diet and nutrient deficiencies and stress and all those things can breakdown the gut barrier leading to lipopolysaccharide translocation out of the gut. That response is inflammatory through cytokines. Now we are trying to make the, I'm going to show you that this cytokines can alter the neuro-chemistry. So the cytokines may also be transported in by selective transporters bypassing the blood brain barrier. They can act on peripheral nerves that send information to the central nervous system. They can affect the secretion of molecules who are not limited by the blood brain barrier but themselves can affect neuro-chemistry okay. And then cytokines can be synthesized by immune cells that have infiltrated the central nervous system through a compromise blood brain barrier. So these are the mechanisms through which this can occur. So eventually that altered neuro-chemistry changes behavior. It changes mood, changes cognition and then that's what it looks like when they walk into your office okay. They are not telling you hey guess what happened, I have been having, I have had a poor diet for the last 20 years, I think I have altered my microbiota, I think there are lipopolysaccharides getting out into the local immune system, I'm pretty sure that's inflammatory, I think those cytokines are circulating now in a systemic level that are too high and it's altering my blood brain barrier and therefore it's altering my neurochemistry and here I am with depression. So they are not going to tell you that. Of course they are not going to tell you that. But now you know that and you can fix that okay. So we've got to control leaky gut, we've got to restore cytokine levels and to be clear too, you can run a high sensitivity CRP or general CRP or homocysteine or sedimentation rate or any of the particular inflammatory markers that we know we can run. They may not be high unless you specifically check cytokines and you Page 17

18 can't do that but it's kind of pricy and you can kind of safely assume that if you do either a stool test or you do some blood work that suggests that there's leaky gut, you can safely assume those cytokines are going to be high too. So what do we want to do? How do we work? How do we fix this? We reduce small intestinal bacteria overgrowth SIBO, we reduce endotoxemia, we want to reduce inflammatory cytokine production, improve intestinal barrier function and improve blood brain barrier. So here's how this, here's that slide again, just a quick summary, so the microbiota changes are brought on by high fructose diet, the western diet, stress that is complicated by nutrient deficiencies and dysbiosis or SIBO so our gut has broken down. Because our gut has broken down we get immune activation by endotoxemia, SIBO increases that potential. Now we have inflammatory cytokine production and blood brain barrier breakdown so we've had endotoxemia increasing the inflammation and accelerating blood brain barrier breakdown, eventually infiltration of cytokines through that leaky blood brain barrier or some of the other mechanisms that I mentioned alters neurotransmitters, mood, behavior, plasticity. There you go, that's how it works. Okay, so the basics, how do we work here. Well, exercise, everybody s got to exercise, it's so, so important and it's very, very, very effective. So how does it work? Well, it causes weight loss which we know is inherently anti-inflammatory. It reduces inflammation through other mechanisms. It increases fuel delivery and waste removal from the brain. It increases neural feedback, regulatory neural feedback. I usually recommend 30 to 60 minutes at least four times per week. If you are on the 30 minutes side be fairly intense. If you are on the 60 minutes side it can be moderate. Very, very important, really important. Food allergy testing: I think it's really important. I know it says ALCAT testing here. I have moved on from using the ALCAT test a little bit and I'm using another test called the FIT test and I find that to be a little bit more reproducible, little bit more reliable. But do what you would like, do what you're comfortable with and what I usually recommend is for moving all moderate and severe allergies. You can rotate the milds and if you can't do the test, either the patient is financially not viable or for whatever reason, start with the biggies you know remove casein, remove gluten, remove soy, you might consider eggs in there. So you got to get those things out of the diet because we know that those types of Page 18

19 things left in the diet can trigger increased gut permeability, can trigger leaky gut. Again, remember its bidirectional okay. So just look at the bottom here, on the bottom of the diagram, healthy status, physiological levels of inflammatory cells/mediators normal gut okay, normal gut microbiota. In stress and disease we get increased levels of inflammatory cells and mediators and intestinal dysbiosis and it goes both ways. The gut causes problems in the brain and the brain causes problems in the gut okay. So we want to optimize the bacterial profile okay here's where you've got to use your stool test, so if you are looking at these patients and you have no idea where to start, a stool profile is probably the best place to start. I like using the Genova/ Metametrix. I use the GI Effects It looks at DNA testing for the bacteria. It looks for parasites. It looks for yeast. It looks at bacterial biodiversity. It looks at digestive and absorptive markers. It looks at inflammation. It looks at immune response. It's really exceptionally beneficial. It gives you a ton of information and tells you exactly where you need to go. So I like, I do think that's an important step. Now, what are some of the supplements you might consider using. Now I'm going to tell you about the supplements that I use. I'm going to tell you exactly what I'm using and how much I'm using because I often find that if you are just starting in functional medicine or sometimes even if you've been in the long time you don't necessarily, it's sometimes very difficult to know what's effective and so I'm going to tell you exactly what it is. People sometimes don't use enough or they don't know what product to use. I use Oregano. It is a potent anti-microbial. It kills lots of stuff. You can read that there. Make sure you get it an emulsified, time-released product okay. If you don't, you are just going to treat the proximal small intestine that doesn't help anybody because if you leave you know the mid to distal small intestine untreated you run into trouble. In this study 600 milligrams daily for six weeks was used and it worked very well. I use something from Biotics called, Biotics Research here called ADP. It's emulsified and sustained release. Four tablets, three times per day with meals for 20 to 40 days depending on the overdose. Again very important is taking with meals because it will help kind of avoid some gastrointestinal side effects for some people. So very important products. It works great. If there's a need for an adjunct either you think there's Page 19