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Are Probiotics Ready for Practice?

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The gut microbiome influences the brain in numerous ways, but can building a better microbiome treat depression? Dr. Ted Dinan walks us through the science in this interview.

Published On: 1/17/21

Duration: 27 minutes, 50 seconds

Article Referenced:Probiotics in Psychiatry,” The Carlat Psychiatry Report, January 2021

Transcript:

Today, an interview with Dr. Ted Dinan (Dee-nan) on probiotics and the mind-gut connection.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie Newsome: The mind-gut connection is a term that’s being tossed around a lot these days, from Fitness Magazine to the National Academy of Sciences. But is this hard science or is it some fuzzy new age concept? And what does it mean for your patients? To get some answers we spoke with Ted Dinan, a psychiatrist whose research has helped pioneer this field over the past 20 years. Dr. Dinan spoke to from Ireland where he works as a professor of psychiatry at University College in the seaside town of Cork.

Dr. Dinan: Right. My involvement goes back quite a while. My first faculty position when I was in my early 30s was in Trinity College in Dublin; I had come back from London at the time. And there was a gastroenterologist there, Matt Kealing who is a very good friend of mine. He persuaded me that the brain-gut axis was relevant in to psychiatric illness. At that time nobody really considered microbes within the gut to be relevant in relation to the brain-gut axis. And when I came back to Cork 17 or 18 years ago a group of microbiologists and a gastroenterologist decided that they were going to set up a new brain-gut institute which we set up, so I was involved in setting it up. And at that stage, people thought microbes might be important in relation to the brain, but it wasn’t at all clear. So we began research in the area and I’ve been working in that area now for the past 17 or 18 years.

I’m a psychiatrist and I decided in the very beginning that if we were going to engage in this research that we were going to publish in the best journals out there because it’s an emerging discipline; as you rightly point out, there’s a certain degree of skepticism about it. So our initial publications would have been journals like PNAS, and we’ve had several papers in Molecular Psychiatry; we’ve had reviews in Science.

Dr. Aiken: In the 1990’s the general sense I got was that the brain is protected from the rest of the body by a tight web called the blood-brain barrier. Other than stroke, endocrine disorders, and a few infections there wasn’t much that affected the brain. Back then psychopharmacology was all about synaptic vesicles and neurotransmitters, but things have changed. One landmark that stands out to me was 2013. That was when Charles Raison’s group at Emory published the first randomized controlled trial of a mediation that treats depression without even crossing the blood brain barrier.

Kellie Newsome: Without getting into the brain? How did that work?

Dr. Aiken: It was the tumor necrosis factor antagonist infliximab, and it worked for treatment-resistant depression, but only in those who had elevated markers of inflammation like CRP. You probably won’t be using infliximab in everyday practice because it has to be given IV, but in this journal we’ve featured a few articles on ways to treat depression by reducing inflammation, and Dr. Dinan’s work on probiotics and the mind-gut connection is one of them. But first let’s hear from Dr. Dinan about what the gut microbiome is.

The Microbiome

Dr. Dinan: The gut microbiome is essentially the collection of microorganisms within the intestine. Now the majority of them are in the large intestine, and the biggest volume is clearly bacteria. Now, there are obviously viruses as well and there are fungi; there are a variety of microbes, but we’ve largely focused on bacteria. 

Recently, we’ve worked a bit on phage viruses as well, but mainly we’ve worked on bacteria. And the gut microbiota of the average adult, like you or I, is at least a kilogram in weight, so it’s quite a large weight. It’s pretty much the same weight as the human brain really; the average human brain is a little over a kilogram in weight as well. So it is the collection of microbes within the gut. 

Now traditionally, we’ve I suppose, taken the view that they are commensal; they don’t do us any harm; they’re there; we feed them because we eat and we feed these bacteria as well. 

But it really is only within the last 15 years that people have begun to realize that in fact there really is a synergistic relationship between these microbes and us, and whilst we might feed them that they in turn produce chemicals that our brain and other organs in our body absolutely require.

Mind-Gut Mechamisms

Dr. Aiken: How do these gut bacteria influence the brain?

Dr. Dinan: Well I think they influence the brain in a variety of ways. That has been one of our kind of I suppose, big areas of research over the years is trying to, and I think we haven’t come to the bottom of the problem. I mean think there are lots of unknown questions. 

But the vagus nerve is clearly very important. I mean clearly it’s a long meandering nerve. It sends signals from brain to gut. It sends signals from gut to brain. We show it in a paper in PNAS about 12 years ago that certain microbes could only communicate with the brain if the vagus nerve was intact. So in other words if we did a vagotomy in an animal the microbe couldn’t communicate with the brain. So the vagus nerve is very important.

Other important communication routes would be short-chain fatty acids. Now we don’t produce short-chain fatty acids, but certain microbes within the gut by metabolizing fiber can produce short-chain fatty acids like butyrate, propionate, acetate, and they get into the blood stream and they may also signal through the vagus nerve, but certainly their production is important and they are important signaling molecules to the brain.

Other important signaling molecules to the brain which maybe we would have ignored 10 to 20 years ago, and that is, almost everyone will be familiar with tryptophan because it’s the building block of serotonin, and the general view has been that all of the tryptophan that goes to the brain and we need a constant supply of tryptophan crossing the blood-brain barrier because the human brain does not store tryptophan in any great quantity so we need this constant supply. 

And the view 20 years ago certainly was that all the tryptophan came from the diet. Now I do think the diet is an important source of tryptophan, but it’s become clear in recent years that certain microbes like bifidobacteria have the machinery to synthesize tryptophan. So tryptophan is coming not just from the diet, but from the microbiota as well and getting into the blood stream and then, of course, traveling to the brain and crossing the blood-brain barrier, and as I said it’s the building block of serotonin. I mean there are other routes of communication as well. 

You know how important they are under normal circumstances is debatable, but certainly you know Covid is the big issue at the moment clearly, and cytokines and their impact on the brain are very relevant in their impact to viruses like Covid. And it does seem that in certain circumstances that the gut can produce cytokines which will travel in the blood stream to the brain and signal across the blood-brain barrier. So those are some of the ways; there are probably some other mechanisms as well, but they are the most widely studied mechanisms of gut to brain communication.

Convincing Research

Dr. Aiken: The idea that bacteria in our gut influences our behavior may seem a bit far fetched for some. How would you convince the skeptics?

Dr. Dinan: Well, one has to start off by saying that because it’s a new field most of the research that’s come from our lab and from other labs is preclinical. So we’ve learned a lot from studying mice and rats, but we’ve translated some of it to humans obviously as well. 

There are so many studies out there now with either single probiotic bacteria or multiple probiotic bacteria, many of them placebo controlled suggesting that levels of arousal and the activation of the hypothalamic-pituitary-adrenal axis is certainly regulated by gut microbes. We have shown, and I think we were one of the first groups to show, that patients who were attending my clinic at Cork University Hospital when we looked at their microbiota they did have a very different microbiota to age- and sex-matched healthy controls. You might ask, “Well what are the differences?”

Well, there’s a decreased richness in diversity of microbes in the intestine of patients with major depressive illness. Now these were quite markedly depressed people. They weren’t in primary care; they were attending my clinic at the University Hospital. 

Interestingly enough, when we transplanted the microbiota from depressed patients into rodents, and in a parallel study we did a transplant from health subjects into rodents; well, if you transplant the microbiome from a health subject into a rodent, you get no changes in behavior; you get no changes in physiology or immunology. But if you transplant the microbiota from of a depressed patient you get major changes in behavior which you can monitor in a variety of ways. And this was done blind; the people doing the assessments didn’t know whether the animal had a transplant from a depressed patient or a healthy subject, so I think the findings are pretty robust. The animal’sbehavior does alter; it develops more of a depressive type phenotype, but as well as that it also has an alteration in its tryptophan metabolism, which I think is very relevant in relation to the biology of depression. And also, interestingly, acute phase proteins like CRP are elevated. Now as I say when the animals had a transplant from a healthy subject this most definitely did not happen. 

So you’re really getting many of the features of depression. I mean depression we all accept at this stage, when in a severe form, is pro-inflammatory, that there’s an increase in pro-inflammatory markers that tryptophan metabolism probably is altered. So I think that’s another piece of evidence that the gut microbiota can change the way the brain works and can change behavior. I mean there are other pieces.

Kellie Newsome: Dr. Dinan found that CRP (C-Reactive Protein) levels were elevated after unhealthy or depressogenic microbiota were transplanted into an animal’s GI tract. C-Reactive Protein is a marker of inflammation, and inflammation is thought to contribute to 50% of cases of treatment resistant depression. In our January 2020 interview Andrew Miller describes how to measure CRP and use it to guide antidepressant selection and lifestyle change in depressed patients.

Microbiome and Mental Illness

Dr. Aiken: Which psychiatric disorders are most associated with poor microbiome health?

Dr. Dinan: Depression is clearly the one that’s been most extensively studied. 

There’s been quite a lot written recently about autism, but I’m quite skeptical of the autism literature because you know people say the microbiota in autism is changed; it’s altered, and I think that seems to be true. I’m convinced by the data. But the question is why? And, of course, I don’t profess to be any expert on autism, I’m not. Any patients with autism that I’ve seen at my clinic over the years, sometimes they’re quite obsessional and they have rigid dietary patterns. So I’m not really sure and I certainly haven’t seen a paper describing a study where they truly controlled for that. In other words, is the change in the gut microbiota due to the fact that the autistic patient has a rigid diet that has changed the gut microbiota or is the gut microbiota fundamental to the pathophysiology?

Now we can say with depression that even if you have depressed patients whose diet hasn’t changed during the depressive episode that they’re microbiota is still altered, but we can say that in my opinion we can say that with autism. 

Dr. Aiken: Have they done that with mice though – like you did with depression – have they transplanted microbiota from autistic patients into mice to see if the mouse develops autistic behaviors?

Dr. Dinan: Well, we’ve published, we had a paper in Molecular Psychiatry there quite a few years ago. We have a germ-free facility here in Cork so we can breed rodents in a germ-free environment so they have no microbiota, and I think we were the first group to show that animals that are bred germ free have very autistic patterns of behavior. And you might say, “Well, how do you know that in a germ-free animal?”

You know if you have an ordinary mouse and you give that ordinary mouse the opportunity to either socialize with another ordinary mouse or interact with a pen or some inanimate object; mice are like ourselves; they are sociable, they will go to the other mouse.If you take a germ-free mouse as we’ve shown in that Molecular Psychiatry paper they are as likely to be fiddling with the pen as they are to interact with another animal. So their patterns of behavior are very abnormal. And we’ve demonstrated that these animals that don’t have a microbiota their serotonergic system is very abnormal; it doesn’t develop normally. 

And you know brain-derived neurotropic factor (BDNF) is very important obviously for establishing new synaptic connections and sustaining them particularly in regions of the brain like the hippocampus, but BDNF levels are significantly altered in animals that are germ free. So germ-free animals tell us quite a bit about brain development and behavior in the absence of microbiota, and what they tell us is really in the absence of a microbiota is that the brain does not develop normally and behavior patterns are abnormal as a result.

Dr. Aiken: So the research on autism is suggestive but not as definitive as what we know about depression and the microbiome. What other psychiatric disorders have a strong relationship to the gut microbiome?

Dr. Dinan: Recently there have been a number of papers that have come out in relation to schizophrenia. I remember about six years ago what was a rather speculative paper, but Molecular Psychiatry took it, and it was a paper in which I suggested that really looking at the genes purely in our human cells was an inadequate analysis of schizophrenia and that we should consider not just the genes in our human cells but in our microbial cells as well. And the paper you know it got a certain buzz at the time, but I hadn’t done any studies of schizophrenia and neither had anyone else. But over the last year or two there have been a number of papers that have come out suggesting that the microbiota in schizophrenia is definitely different structurally to that in the healthy controls.

Dr. Aiken: And bipolar disorder?

Dr. Dinan: Yes, there’s been some data in bipolar disorder as well from the U.S. A lot of it is using throat swabs and looking at the microbes there rather than actual fecal samples. I’m a bit skeptical of looking at microbes there because you know I view the microbiota as essentially like our liver. It’s almost like an extra organ that we have really ignored up until relatively recently. It’s big. It’s biochemically complex. So I think that you know for me this complex organ produces molecules. 

Now, I’m not sure what we learn by looking at the microbiome in the mouse in patients with schizophrenia. There are some people who do that and they say, “Oh, it’s valid” and whatever. I don’t see what relationship you know microbes in our mouth could have with brain function. Whereas I think one can definitely, no matter how skeptical one is of this area, one could build a good complex case for how the gut microbiota produces molecules, and if those molecules weren’t produced brain function would alter.

Dr. Aiken: And how about addictions?

Dr. Dinan: There’s been quite a bit recently. We had a paper on alcoholism and there’s an interesting study published in the last fortnight looking at a microbiota transplant in people with alcoholism and suggesting that a transplant from a healthy subject can actually reduce the addiction type behavior of an alcoholic. So that is certainly you know very interesting if it’s true. I mean how long the effect is sustained is debatable and I’m not sure we actually know, but it does suggest that the microbiota may be involved at least in alcohol addiction.

Building a Better Microbiome

Dr. Aiken: And how does a person develop a poor microbiome health?

Dr. Dinan: Well I suppose the initial architecture of our microbiota is determined at the point of birth. If we are born per vagina the initial microbiota is largely determined by the lactobacilli that are required passing through the mother’s birth canal. And for the first two or three years they are the dominant microbes in somebody who is healthy and born per vagina. If one is born by Cesarean section, the initial microbiota is radically different and is acquired from microbes on the skin of the doctor, on the skin of the mother, just from the general environment. And I think this is relevant because C-section rates globally are increasing very dramatically. You know the World Health Organization reckons that we should have about 12% of babies born by Cesarean section. Here in Cork it’s at least 30%. In Manhattan it’s over 50%. You know there are parts of the world where it is much higher. Brazil has an incredibly high C-section rate. China does,does probably as a hangover effect from the one-child policy that the communist party followed for so long and people wanted to have a healthy baby so they delivered almost everything by C-section. 

So I think the initial microbiota is relevant, but over the first three years whether one was born by C-section or per vagina, there’s a convergence by three years. I’m not saying that they totally converge, but there is certainly a convergence. 

After that, the main determinants would be one’s diet. So you know if you’re on a diet of fast food, that is not gonna produce a good microbiota. Now we can talk about what a good diet is in a minute, but basically diet is a big determinant. 

Medication is a big determinant. At least 75% of all the drugs that are prescribed by doctors in the U.S. and in Europe, we know impact on the gut microbiota. And it’s even more so in psychiatry. I mean we published a paper recently looking at a variety of psychotropic drugs; most of them impact on the gut microbiota. So drugs are important and I’m not talking here just about antibiotics; I mean obviously they impact the gut microbiota, but drugs in general. 

Dr. Aiken: Is there any evidence linking antibiotic use to depression?

 

Dr. Dinan: Interesting question. If you look at meta-analyses of antibiotics, overall antibiotics tend to be associated with an increase in rates of depression. Now, of course, that’s in meta-analysis where they are looking at all sorts of antibiotics and, of course, all antibiotics are not the same. I mean if you look at vancomycin it doesn’t really get out of the gastrointestinal tract. That’s not the same as ampicillin obviously. So look, all we have at this stage are a number of very large-scale meta-analyses which do strongly suggest or indicate that taking antibiotics does increase the risk of depression. 

Dr. Aiken: Do these analyses control for the fact that infection itself can raise the risk of depression?

Dr. Dinan: To some extent they do. They do look at the reasons that people took the antibiotics, so that in some of the analyses has been controlled for. It obviously is a potential confounder.

Dr. Aiken: What else influences the gut microbiome?

The other factor I suppose that is relevant is aging. You know we all want to age in a healthy way. We don’t want to be frail as we age. And there’s no doubt about it that if one develops a less diverse microbiota as one ages, frailty follows very rapidly from that. So there is a relationship between a complex microbiota and a lack of frailty in elderly people. 

And that, of course, then relates to a number of things, including the fact that we know that exercise has a very positive benefit on the microbiota – not just through the diet, but a direct benefit. So people who let’s say engage in a lot of aerobic exercise, and I would always advocate that my patients whether they’re depressed or not engage in some form of vigorous aerobic exercise. Look, I’m sure your viewers would be the same as I am; I’m always astounded by how lacking in exercise you know many of patients are. You know you have a 25-year-old who turns up with an anxiety disorder or depression and you tell him to exercise and he comes in the following two or three weeks later and he says, “Yeah, I’ve been walking a mile a day,” and I think my God for a 25-year-old that is not exercise, like that’s for your 85-year-old grannie. It’s ridiculous what some people do define as exercise. But there’s no doubt that exercise has a dramatic impact on promoting microbial diversity in the gut microbiota. So there are just some of the things.

So there are many factors, but I think the factor is there is we can instill in our patients because I genuinely believe that if you know we want to maintain good mental health in our patients that nutrition and exercise are very, very important, and they are the two things that we should try to instill in our patients, particularly those who suffer from recurrent mood disorder that their diet needs to be appropriate and they need to get regular aerobic exercise.

Food Cravings

Dr. Aiken: I’ve heard that the bacteria in our gut actually influences our food choices. So that if we grow our microbiome from fast food and diet soft drinks, they’ll send signals to the brain that drive us to crave more of that, but if we feed them healthy food and prebiotics the opposite will happen – bacterial strains will grow that make us crave more of the healthy stuff.

Dr. Dinan: Well, that’s an intriguing question. Clearly, you know, if there are microbes there that like refined sugars; you know if you have a sweet tooth as I do (I love apple pie and whatever, you know), I often wonder when I have a craving for that in the afternoon with a cup of coffee or whatever, is it my brain telling me this or is it my microbes that are feeling a bit deficient, you know. But what is certainly clear is our gut microbes will alter depending on our diet. So that, as I say, I like sweet things; if I was to eliminate those from my diet and look at my microbiota in two weeks’ time it would have altered; I would be losing certain microbes or certainly they would be depleting after a two- or three-week change in nutritional status.

Dr. Aiken: So I think you saying that’s interesting speculation, but we don’t yet know that they influence.

Dr. Dinan: No, we don’t. No. It’s something I’ve often speculated upon, but really I can’t say that we have any solid evidence. 

Freeze Dried Bacteria

Kellie Newsome: Gut health influences mental health, but does improving the gut microbiome help psychiatric disorders? In our online issue Dr. Dinan delves into that research and clarifies which psychiatric disorders benefit from a change in their bacterial strains. Dr. Dinan believes that diet and exercise are the best ways to improve microbiome health….

Dr. Dinan: I think really it’s that you know I think the food matrix; good food is an ideal delivery system. You know I suppose Big Pharma is always trying to develop better delivery systems for their drugs and for good reason obviously. But I think that good food you know provides a really good delivery system for a lot of nutrients. 

Dr. Aiken: Our online edition outlines specific probiotic foods, but you also need prebiotics – which are the nutrients that healthy bacteria thrive on – and we list those as well. Some patients, however, benefit from a taking a probiotic supplement, and that’s the mode of delivery that most of the several dozen controlled trials on microbiome health and psychiatry used. Dr. Dinan believes these probiotic capsules are risk-free as long as your patient is not severely immunocompromised, such as through chemotherapy or HIV, but that the greatest risk is that the probiotic capsule may be a dud.

Dr. Aiken: One thing you’ve got to clear up for me. How is it that these freeze dried bacteria are still alive? 

Dr. Dinan: It’s incredible. I mean bacteria are incredibly resilient. I mean bacteria have been found in the most in terms of temperatures, incredibly high temperatures that no human cold possibly survive. I mean bacteria are far more resilient than we are and maybe that’s why they’ve probably been around a hell of a lot longer than we have.

Dr. Aiken: Are they just like in a dormant state?

Dr. Dinan: Indeed, in essence yes.

Dr. Aiken: They’re certainly not getting food and water?

Dr. Dinan: No they’re not and they don’t need it; as you say they’re in a dormant state, but they’re alive and they do function when they go into the intestine and they are quite resilient. I mean at the end of the day if you take a capsule you know with lactobacilli or bifidobacteria they’ve got to be very acid resistant. Remember the acidity of the stomach is very high and most of these probiotic bacteria are capable of going through the stomach – not always. 

I remember about ten years ago I was asked by a company to work with a probiotic bacteria, and it was so acid sensitive it was ridiculous. There was no possibility that this thing 

(55 minutes) could ever get through the stomach because it was so sensitive to acidity. But there’s lots of probiotics out there and they’re completely immune to the activity of the acid in the stomach. They go straight through and they’re absolutely fine.

Check out our online edition where we list X probiotic products that are ready for clinical use. The products use the same strains that were employed in the psychiatric trials, and were tested by independent laboratories to insure their quality.

About Ted Dinan

Ted Dinan is a professor of psychiatry at University College Cork, Ireland. His research focuses on depression, irritable bowel syndrome, and the influence of the gut microbiota on brain function. He has published over 500 scientific papers and numerous books including 2019’s The Psychobiotic Revolution.

Double Orientation

And now for the word of the day…. Double orientation

There was something odd about schizophrenia that struck Eugen Bleuler (like Boiler), the

 Swiss psychiatrist who first described this psychotic syndrome. Many patients maintained their functioning in everyday life, working as cooks or elevator operators, while believing that they were King of England. It was as though the real world was an illusion to them, and they continued to function in it while living a psychotic reality inside their heads, undisturbed by the contradiction. Bleuler called this “double orientation,” and his term is sometimes translated as “double book-keeping.” He wrote that although his patients believed themselves to be “Kings and Emperors, Popes, and Redeemers,” they engaged, “for the most part, in quite banal work.[…]. None of our generals has ever attempted to act in accordance with his imaginary rank and station.”

The discordance between the patient’s delusional life and everyday reality only highlights the nature of delusions: They are impervious to evidence. The French psychiatrist Jean Esquirol summed up this stubborn nature of delusional thought in his interaction with a patient. “You are right, said the patient, but you cannot convince me.” 

On a practical level, the ability to function in the real world while internally propelled by delusional ideas is a strength, and one that we should nurture in our patients. We also need to be aware that some patients are not disturbed by their delusional world, and find a sense of comfort and identity within it. These are times where antipsychotic therapy may not be well received. As psychiatrist Karl Jaspers put it in his classic text General psychopathology, “[The patient’s] world has changed to the extent that a changed knowledge of reality so rules and pervades it that any correction would mean a collapse of being itself, in so far as it is for him his actual awareness of existence. Man cannot believe something that negates his existence.”

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