The Microbiome Mind and Brain Interactions

this program is presented by university of california television like what you learn visit our website or follow us on Facebook and Twitter to keep up with the latest UC TV programs you dr. Maier is an MD PhD and I believe that the the symposium today entitled gut feelings was coined with him and mind because he is one of the major pioneers in how your gut controls your brain as opposed to the other way around there's very clearly a crosstalk between what's going on intra-abdominal E and also in the brain now we always think of this in one direction brain to gut but apparently it goes both directions and dr. Maier has been one of the leaders in this field he is the head of the Oppenheimer family center of neurobiology and stress at UCLA has been there for several years is an MD though trained in Munich and also in bank at Vancouver General Hospital so is very well equipped to explain not just the medical but also the psychological and psychiatric aspects of what's going on in your gut dr. Meyer thanks for the invitation to be here talk about a subject that I've spent the brain gut interaction pretty much most of my career and thanks for the kind introduction I adopt elastic the the topic is kind of difficult because it ranges a wide range from neurological diseases to psychiatric diseases and normal emotional states so I've tried to pack a lot of information into this talk and organized in the following way just going to give a few introductory words to they got to microbiome brain axis I personally have studied this all my career from the top down actually just been recently a convert that there's a lot of important stuff going on the other direction will show some information about the perturbation of gut microbes and effects on brain and behavior this data comes mainly from animal studies so for our I put in a section about the development of gut microbiome brain interactions because I think in in brain based diseases that is a crucial part and that's probably why we have a certain discrepancy between the wealth of animal data and the lack of human data which have been mainly done in in adults and then showed a little bit of information about the merging role of altergott microbiome brain interactions in IBS the long focus of long interest of mine and he city and food addiction particularly so the brain cortex is the way we conceptualize a day is really an interaction between between two very complex systems which reproduce the gut connect on not a single cell under God not a single microbe that even the microbes by itself but the interaction of the hundred trillion microbes with a set of cells specialized cells during the enteric nervous system in 50 million neurons but the largest immune system of the gut and enter endocrine cells the largest endocrine system it's the interaction of all these cells with each other that I think generates an output that has an influence on the brain by multiple pathways which I will show you and then we have at the brain level we have we now understand there's not a couple of regions but there's complex networks the brain connectome that generates an output in response to what it receives from the guard so it's a very complex system but it has been an alteration this has been implicated in regulation of emotions pain sensitivity ingested behavior relevant for this symposium stress responsiveness and social interactions did not make the list of psychiatric and neurological diseases that have been implicated because in many of them we don't really there are speculations we don't hear the evidence yet so why would there be a interaction between the gut microbes and the nervous system so so like to think about this in the way if you look at in evolutionary terms the the microbes in the oceans have been around for a long time some several billion years before before this first symbiosis between microbes and intestinal tract happened and very primitive marine animals these are interesting creatures because they have a basically a digestive tube with a nerve network around it and when the first time the microbes decided to settle in that in that GI tract they had the ability to close to communicate and transfer genes to the door to the enteric nervous system added organ and then later over evolution the SPN evolution from the enteric nervous system to move the main control centers into the brain so we have actually very logical evolutionary history why there would be this close connection that we all refer to in the term God feelings but until recently not really understood the the biology so there have been a lot of studies and this is really triggered they've been a few pioneers in Ireland and Canada that has really triggered the excitement in this field just to give one example so transplant ate the fecal transplantation of from a mouse trained it is more to MIT had to use these anthropomorphic terms but that's that sort of mean that makes it easier understandable the less exploratory various behavioral tests into an an more outgoing Mouse train which then changes the behavior of that animal into the same timid animals so this has been some of the first studies kind of really a lot of people skeptical at the beginning but in the mean time quite a few similar studies have been published this is kind of summarized here with largely with germ-free animals so that is important to realize that these this is kind of a developmental model so these animals had been without the input to the brain of the microbes from early on I think that it's a key thing to put this into perspective in the adult animals they have been changes in those deceptive reflexes emotional behaviors social behavior and ingested behavior some of these experiments have also used the the fecal transplantation and if you have used probiotic interventions it's not just being the behavior of these animals but also biological readouts such as brain or chemistry HPA axis responsiveness which was actually one of the first demonstrations some some 10 years ago and at a gut level a stress and used microbial gene expression change so let me just go proving go to some of the data what are the communication channels and I would like to start this with how the brain talks to the gut even though this is not been emphasized as much today as the other way around the earlier studies really came from that and I think it's very relevant to keep this in mind so the brain through many through yarn or me nervous system can influence various cell types in the gut from the immune cells the and enter endocrine cells and the neurons and one particularly intriguing example is the studies on open Efrain so it's been shown in vitro that i think it was close to ten different pathogens NOPA nephron addition to the culture changes the gene expression of virulence genes of these organisms and indeed any vivo it's been shown that for example in pigs that stress changes microbial behavior and increases the risk of prolonged and often deadly infections in these animals so this is because with increased stress not just an increased norepinephrine in the blood but it's also an increase in the luminal content of free norepinephrine and there are receptors analogous on microbes of to the adrenergic receptors that mediate this effect and the side issue is also intriguing and this kind of confirms as long symbiosis of the microbes with the human host these cells the microbes can also produce an open area like molecule they can act on our own mucosal adrenergic receptors now there's other examples so serotonin levels go up in the brain in the in the guttering stress and there's most likely most of these endocrine cells that are they contain about 20 different gut or moans have this bi-directional signaling so with stress and emotional reactions we get an increase in these transmitters we don't really know other than for no canarian what they do so the other way around from how the gut talks to the brain so there's multiple mechanisms that have been implicated in many review articles few data but neuro active metabolites tryptophan gaba glutamate bile acid metabolites secondary bile acids short chain fatty acids and cytokines to just name a few there was a mention about the short chain fatty acids before that this is intriguing because we have there are short chain fatty acids and bile acid receptors on many of these transducer cells in the gut so these are not just things that are good for the epithelial cells but there are signaling mechanism that can transduce an increase in the short term fatty acids into signals that go back to the brain I want to focus on one aspect which I personally think after sort of thinking a lot about this field the immune signaling for you plays particularly important role in this gut to brain communication shown here the example of the dendritic cells that can even without a breach or increased from a gut permeability can sample signals from the microbes with toll-like receptors and other sensors including the short chain fatty-acids and then lead to a release within the basolateral side within the lamina propria of cytokines now what happens to these cytokines and how do they get to the brain one is it's clearly been demonstrated there can on cytokine receptors on vagal afferents so the sickness syndrome has been described within the Watkins many years ago it's one example but there's also other pathways that have been emphasized so cytokine release into the circulation even at low levels and also other inflammatory marker searches lipopolysaccharide getting to the brain passing the blood-brain barrier changing the permeability of the blood-brain barrier in activating microglia in the central nervous system to in turn produce regional increases in cytokines and affect neurons this neuro inflammation has been implicated in a range of CNS disorders depression neurodegenerative diseases chronic pain but also in obesity and possibly food addiction I won't get much into that but the serotonin signal signaling is another very very prominent way of how the microbes can signal to the brain didn't implicate it quite a bit in studies were a in animal studies where they cut the vagus nerve and basically no longer saw the effect of microbial changes as I'll show in a minute the vagus nerve has an intimate relationship with these cells the cells by themselves are intriguing because they contain more than 95% of the body's serotonin and there's a couple of things we have learned recently about them that makes them more intriguing so one is study by elaine chao recently published has shown that microbial metabolites can stimulate the synthesis of serotonin in these cells and the second one is that the vagus nerve doesn't just isn't just sitting around there the terminals but it actually forms troops and active connections so these sounds are really almost like part of the nervous system that sample that opposition to sample because on the gut and have a significant input from the microbe metabolites so if you put this together the microbes obviously a major influence is what we eat and this gives a pathway by which chronic changes I think acute changes are probably not as important as chronic changes the chronic changes in our dietary habits can have an effect on on background emotion and behavior so there's a lot of this animal science I think as opposed to some of the other areas that people have talked about today it's been harder to really get the clues what happens with this in humans so one is we don't with the exception of autism we don't see these dramatic increases like in obesity or autoimmune diseases so that is something you have to think of it is clearly different we haven't seen a dramatic rise in depression anxiety and the other one is so let me get to this can be we several years ago asked the question can we alter signaling from the gut microbiome to brain networks in healthy humans this was really approved for principle study we did we selected carefully selected healthy young women without any evidence for any pain chronic pain psychiatric even baseline training xiety elevations were were eliminated and we want to know can be influenced the system shown here the signaling from the gut microbiota to the brain to brain networks and use the intervention with a mix of probiotics in a in a yogurt drink that individuals consumed for four weeks twice a day there were a couple of control groups one we did not do any intervention and one was a non flamenco product and we used we want to see because we base this on the animal data that was available does the emotional reactivity of these individuals change to that intervention we use sort of a standard emotional face recognition task where basically the individual is asked you to match the face on at the emotional expression depicted by the face on top with of Wanda two below what we found was so really against different from our hypothesis we did not see primarily the modulation of the emotional arousal Network that we had hypothesized with amygdala and the anterior insulin D at the anterior cingulate cortex the anterior region but we saw an extensive network of brain regions that was differed dis differed from the beginning of the study to the four-week at the end of the study this networking included sensory both visceral sensory and somatosensory regions as as well as pain modular regions and what was most interesting that the intervention and showed a change in the connectivity of this network so the individuals that consumed the probiotic mix had a decrease in this network so they showed a decreased response to the these negative emotional recognition tasks - these are all negative emotions not positive ones as opposed to the control group they got a non fermented milk product that did not show change or the the group that had no intervention at all which showed a slight increase during that time there's several other studies going on at the moment but unfortunately they are much slower than the then the animal studies so and there will be a delay but it will be exciting to see some of these confirmative studies also in disease populations so let me say a few things about gut microbes and brain development we've heard a lot about that it's important what happens early in life I think that applies probably equally to the central nervous system I give you a few examples and why I think that way so one is clearly does the early gut microbial environment affect brain development and one the earlier studies one the best studies that was published in this by Sven Patterson's group they showed that in term freeze mice Humphrey mice as opposed to their the control animals there was a reduced anxiety-like behavior when these animals grew up so indicating that somehow the microbes growing up with intact microbiome has a stimulatory effect on emotional reactivity they they also found that there was at the brain level there was an increased turnover of several neurotransmitters in emotional areas to the hippocampus and the stratum open efferent dopamine and serotonin and also there were changes in gene expression of several anxiety and synaptic plasticity related genes in these animals so some impetus himself thinks that in personal conversations with him that this has to do with the metabolism the ultimate have ilysm early on in life and that this is intention to this response it is interesting that this goes contrary if you take two army animals they have an increased responsiveness of the HPA axis which may really be in response to the metabolic stress but a decreased anxiety so this is a combination that we rarely see in human anxiety disorders so why would development be so important so there's obviously multiple factors that have been characterized that influenced the development of the gut microbiome in the first three years starting prenatal leaders there's maternal effects this effects during delivery and there's postnatal effects and I was going to show you I'm going to show you just a couple of examples of what we have some evidence that the the interaction of the mother with the with with the fetus also with a newborn may play an important role in shaping the gut microbial brain interaction so one is something that we've had the lungs interesting long before we thought about that I got microbes is the quality of the the infant primary caregiver many mother interaction early in life and what effect this has it's been a wealth of studies in the last 15 years so starting with Michael Meany Paul Trotsky and others which in animal models have shown that this maternal care plays a major role in the development of many emotional brain systems and including the HPA axis responsiveness anxiety-like behavior so until recently this was thought to be completely explainable by mechanisms excluding gut microbes there wasn't even any talk about that well we know from a very recent studies just come out that it appears that two components of this response are mediated by different mechanisms or the aah HPA axis response being independent of the gut microbial composition being equal in term free animals and animals with a normal microbiota but the emotional response the increased anxiety like behavior was dependent on the gut microbiota so this is a I think an interesting study we really dissect out mechanisms that before we explain purely by neurobiological terms and now we have a microbial aspect to it another study that I find particularly interesting is the recent study on the effect of maternal stress so this was interaction infant mother now it's maternal stress before birth by Tracy Dale's group and where they found that stress or the mother during pregnancy in mice changed the vaginal microbiome may need a decrease in the lactobacilli in in the maternal vagina that this was associated with a change in the gut microbiome of the offspring not too surprising because we know that this is the main mechanism of inoculation was it also decrease in lactobacilli now getting into the details this was sex specific so it was different a male and female offspring and most interesting this was associated with a difference in the amino acid profile at the brain level of the newborn so the stress of the mother change of the national microbiome change the infant's gut microbiome and then change in brain levels of neurotransmitters and is a sort of an intriguing example to how these things are connected we have several data sets where we start to look at is there a correlation between the gut microbial organization associate with brain architecture my personal feeling is if you look at architectures where is something that developed early in during development it's unlikely that a change in your microbes will change the rewiring or rewire your your brain and I'll show you one study that we've recently completed where we looked at the Guttmacher IDs is one of the areas that we were pursuing in our research and it's been a recent study from the court group that showed that if it based on 16s data there seem to be at least two subgroups of IBS patients one that looks indistinguishable from from healthy people and another one that is distinct we confirm the same thing we had a healthy control like IBS group in terms of this is a very tight taxonomic classification based in Firmicutes abundance of Firmicutes impact or adidas but then there was a group that had higher levels of the Firmicutes and angries i'm showing this to you because if you looked at their brains we found that these two IBS groups differed in their brain structure in the gray matter volume so smaller volumes in the abnormal IPS found in the frontal and insula regions and larger volumes who have found in these sensory motor regions so in a very large group of data that we've published in the past we have always found that that the the changes in the sensory motor area in IBS patients or so the most consistent so we think it's one indication that might from cross-sectional data that allow you to speculate this is something that may develop early in life and give you basically a a brain system that has an increased sensitivity to sensory stimuli as we know from IBS patients are not only more sensitive for god´s stimuli but also for a variety of other somatosensory stimuli so I have five minutes I go through this topic of dude the gut microbes play a role in relationship between obesity in alter brain networks and one area of interest that we have this area is in chess CP havior particularly food addiction rather already mentioned that study role eat just to emphasize there are mouse models that are supportive of this concept that gut microbes can play a role in regulating chestie behavior in this particular study in this teal are 5 knockouts it was clearly related to the hyper fate show these animals a trophy the obesity there's a lot of evidence and obviously I'm talking to the experts here and this in his audience that the brain plays a very important role in obese subjects the even before ingest you know the food there's abnormalities and this has been summarized many of these features have been summarized in this concept of food addiction by Nora Volkow based on elegant studies implicating the the dopamine systems so we were interested or are interested in have ongoing studies on this is there a change in brain networks that relates that is seen in individuals with food addiction and is there relationship between gut microbial profiles and metabolites and these dis alteration these are ongoing studies I just want to show one aspect of this so just looking at the white matter connectivity so using diffusion tensor imaging of obese completely healthy people we could classify them simply based on a limited number of brain parameters that separate these groups completely without knowing any other zone rob said you can profile obvious people to send the microbes we can profile them based on their white matter connectivity obviously nobody is going to do that because you know we know if somebody's is obese but what what is interesting was going to be the most interesting question is there relationship between these two alterations and microbes in the gut and these parents and brain the connectivity affected primarily the central reward system so the the nucleus accumbens is a ganglia so regions of the extended reward network how would these changes do a plastic changes occur would this be early on in life or during a lifetime the one we talked earlier about this immune to brain signaling i person that is still a very good candidate for what we see in the in the brain of people with food addiction that that alter microbial compositions based on dietary patterns for example high fat intake has been associated an increase in gram-negative bacteria increase the LPS leading ultimately and there's obviously a lot of steps in there that still has to be confirmed to a state of metabolic toxemia low-grade increase in cytokines LPS circulation and ultimately to neuro inflammation so showed you earlier I'll come back to this what this new information would do at the brain level and which region they might affect one model that we've been pursuing is very a trick surgery not that I think this is a solution for the obesity epidemic but because it gives us a good model of something a very effective intervention that hopefully will give us answers about mechanisms they can be then addressed with what non-surgical means so won't talk about the various bariatric surgeries that have been used but from animal studies we know that bariatric surgery in rodents leads to significant changes in the gut microbial composition a reversal a partial version of this increase from acute to vector-a due to this ratio that seems to be some concept that I think goes consistently through various studies and we think that this this change in the Indus in the in the gut microbiota is responsible for not just for the fairly rapid changes that occur in ingested behavior components such as the prevalence for for food items so the decrease in the craving for fat and and sugar content but that also it's responsible for the for these changes that have been described at the brain level so decrease sensitivity of the hypothalamus for example to to satiety signals which were inflammation nor inflammation of the hypothalamus has been implicated and we also would speculate that some of the neuroplastic changes we see in individuals we have been obese for for many years at within the reward system so i hypothesis at the moment but some come to the last slide so like just like what i talked to you earlier about the maternal stress and the model said we had until about five years ago so he's interesting to me to see this we thought we had a completely figure out then the microbiome came and then we had to greatly expand these models same thing has really been happening I think in food addiction that so this model where you have the hypothalamus is the main regulator of the homeostatic brain intake and II the extended reward system with this transmitter dopamine is the main regulator of the and the motivational aspects and ultimately to food addiction then a major role in the regulation of these systems may come be coming from the gut microbiota my personal feeling is an important component of this mechanism maybe it is low-grade neuro inflammation in regional parts of the brain so to take home message I think the brain even though we don't have the same stunning data epidemiologically as we have in other areas I'm strongly believe that the brain can influence that got microbes I very strong evidence for that in animals and humans and they've got microbial signaling molecules can affect the brain these interactions play a prominent role in brain development and lifelong brain modulation I perceive a most enthusiastic about the brain development part rather than these acute effects that are easy to demonstrate in animals early life got microbial programming is influenced by many factors including the mode of delivery quantity and quality of early nutrition medications and perinatal stress both prenatally and postnatally and diet induced gut microbial modulation is likely to play a role in neuromodulation this regulation of intestacy behavior I think we'll see in the next few years many studies that are ongoing that will either prove or disprove this hypothesis so I'd like to thank the people in our group particularly Jen leavers Kirsten Tillich Lisa kill Panther again Gupta for involved in these studies I showed you and the NH support and thank you for your attention thank you thank you dr. Maier we have a time for two questions anything burning I see lots of psychiatrists in the room there's got to be at least one question from South quietest come on Owen a bit all right well then Allah yeah so when when you do salute them as lights I had a lot more about autism and Parkinson's which I took out because it really talks in themselves what's what's fascinating about Parkinson there is this concept that the earliest degenerative lesions really occur at the in the enteric nervous system these Lewy bodies and there's a hypothesis that they can gradually be traced from the enteric nervous system to the nuclear tractus solitarius before they reach the classical dopamine containing brain regions in the brain there's also as a recent study that is one study so far they've shown also it's got microbial composition in patients with parkinson's the problem like with all human studies is Parkinson probably because of this enteric nervous system involvement very typical they have severe constipation which of the changes the environment for the microbes so we don't know what's the chicken and the egg are these so but I think the potential as Rob said in the beginning to be able to diagnose people at high risk of Parkinson's early on based on their gut microbes I think is it's probably better than from any other brain diseases I would say based on the data that we have Lord Oh about a Furius or indirect relationship going on here so you could have a person with poor diet who develops dopamine down-regulation in the brain and the range is going on leptin resistance and so forth and then that would account for a not very healthy gut bacteria situation and so are you thinking about both indirect relationships and also spurious associations here but this is probably multiple mechanisms I mean there's factors because of this integrated circuit that we have between the gut and the brain could gut connectome and in the brain it's clearly interaction of for example mind based factors and diet based factors and often you probably won't be able to I mean olicity huge human studies where we can identify subtypes with with high and low trading side for example low in high stress we're pretty difficult to show that but I think that the main concept understand this is it's this is a nonlinear system you cannot say diet alone will for example change the microbes if Parkinson is is a good example to maybe dietary factors but there also may be central factors and then there's you have these changes in transit rates of the GI tract that makes it particularly challenging gratitudes come up with any simple linear relationship between these various factors that play a role I think can be very difficult

Channel: University of California Television (UCTV)

Views: 86,863

Rating: 4.7877669 out of 5

Keywords: gut-brain axis, microbiome, neurobiological

Id: c-1WgYFB8VE

Length: 37min 45sec (2265 seconds)

Published: Thu Jan 28 2016