October 3, 2018

Mood and the Microbiome: Exploring the Science and Practice of Microbe Manipulation and the Mind

Sponsored by Klaire Labs

In this podcast, we take a guided journey with noted professor and neuroscientist, Jane Foster, PhD, as she explains how animal models have elucidated the complexities of the gut-brain axis and role of gut microbes in mood and mental wellbeing. From a sound scientific footing, we join practicing psychiatrist, Scot Bay, MD, as he shares his experience with the integration of a mood-targeted probiotic blend in challenging cases and complex therapeutic interventions.

Approximate listening time: 35 minutes.

About the Experts

Scot Bay, MDScot Bay, MD, is board certified in adult psychiatry. He was educated at the University of Rochester and New York Medical College. He completed his residency in psychiatry at St Vincent’s Hospital in New York City. Bay specializes in the evaluation and management of mood, anxiety, and thought disorders and has special interests and expertise in psychopharmacology. He has extensive experience with numerous psychiatric medications and has lectured all over the Southeast regarding practical and innovative uses of psychiatric medications.

Jane Foster, PhDJane Foster, PhD, joined the McMaster University faculty in 2003. She holds a research appointment with the University Health Network in Toronto, Ontario, Canada, as well as a scientific position with St Michael’s Hospital.

Foster is an active researcher with 2 translational networks, The Province of Ontario Neurodevelopment Disorders Network (POND) and the Canadian Biomarker Integration Network in Depression (CAN-BIND). Her research focuses on the role of immune-brain and gut-brain interactions on neurodevelopment, behavior, and brain function.

About Klaire Labs

Since 1969, Klaire Labs™ has been dedicated to developing clean, efficacious nutritional supplements to ensure optimal outcomes for the most sensitive individuals. It is this dedication to purity, potency, and performance that has guided the development of our legacy formulations including the highest selling professionally distributed probiotic brand in the United States, Ther-Biotic, as well as our novel, indication-targeted probiotic products such as Target gb-X™ (gut brain axis) and Target b2™ (breast and baby).


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, we will be discussing the gut/brain axis as it relates to mood and mental health. I have 2 experts joining me today, researcher Dr Jane Foster and clinician Dr Scot Bay. Before we begin, I'd like to thank the sponsor of this interview who is Klaire Labs.

Gazella: Dr Foster, I'd like to start with you and then I'll switch gears and get a clinical perspective from Dr Bay. Dr Foster, how does the human microbiota communicate with the brain?

Jane Foster, PhD: The human microbiota actually covers all of the surface of our bodies. However today I'm going to talk mostly about gut microbiota. That's a key component of the gut/brain axis. There are several pathways of communication between gut microbes and the brain. Neural connections are very important. In particular, the vagus nerve, which is a bi-directional nerve that can communicate from the gut to the brain but also from the brain to the body, that includes communication with the immune system and the gut, has a well-established role as a communication pathway between the gut and the brain.

The enteric nervous system, which is the mini-nervous system that wraps the gastrointestinal tract, responds to signals from microbiota in the lumen of your gut, and this influences both the host physiology at the level of the gut but also communications with the central nervous system.

These neural pathways are important, but there's also humoral pathways that are important. We know, and we have for a long time, that the brain can influence gut function and microbiota through the production of hormones such as cortisol. The interaction between stress and our microbiota is actually where a lot of the work that currently goes on started. But in the past decade we've been learning a lot more about how microbiota participate in bottom-up communication through the immune system and through other systems. But by influencing immune cells themselves or by influencing the immune molecules produced by the peripheral immune system such as cytokines and other molecules, the microbiota can influence this immune cascade signal to the brain.

One of the big areas of interest in the field is metabolism. Gut microbiota influence metabolism through the composition and function of gut has been shown to influence things like tryptophan metabolism bot locally and across the body, which may influence mood through modulation of central serotonergic systems.

And finally if we think about the microbes themselves, microbes can produce neurotransmitters and their lack of molecules. Although the role of microbiota-produced neurotransmitters might just be in the local area of the gut between microbes themselves and some of the gut tissue, there's a big interest in understanding how these might influence microbiota brain communication. Microbes also ferment dietary fiber, and through this fermentation they produce short-chain fatty acids including things like acetate, butyrate, and propionate. These short-chain fatty acids are important for crosstalk between microbiota themselves and promote healthy gut physiology.

Some of the evidence suggests that short-chain fatty acids can communicate beyond the gut, and in the case of propionate it's very important in the portal vein system and communication with the liver. In the case of acetate there's evidence that it can systemically communicate to the brain.

Gazella: That's fascinating. Why is it so important for us to understand this complex communication that's taking place?

Foster: Evidence from both pre-clinical studies and clinical studies supports a role for the microbiota-brain axis in these communication pathways in both physical and mental health. From the mental health perspective there's several potential benefits for understanding these connections. First, there's a great interest in the potential use of interventions that may target the microbiome, such as probiotics or prebiotics, but also diet and exercise and how these interventions might improve mental health.

Second, understanding the molecules and some of the signal transception pathways that mediate microbe/host or host/microbe interaction may actually provide novel targets for drug development outside of these microbiota-related therapies.

And finally one of the most interesting things from my perspective is the remarkable interpersonal differences in microbiota composition such that in fact between you and I our differences are in the range of 90% at the level of our microbiota composition. And such it seems that each person's microbiota is their own. This feature is really interesting when we think about heterogeneity and psychiatric illnesses or mental health in general. As the field moves toward more precision medicine approaches where we really do need to identify biomarkers that will help understand how individual biological differences might influencing what treatment might be best for each person.

Gazella: You mentioned the research. Can you describe some of the more significant studies that indicate how microbes influence brain function and mood?

Foster: Yeah. The foundation for our understanding of how microbiota influence brain function and mood has really come from a long history of animal studies that manipulated microbiota both in early life and in adulthood to show how connections between microbiota and behavior exist and also in these studies identify key signaling systems in the brain that are influenced by the microbiome but include things like our stress circuitry, our fear circuitry, systems that influence anxiety and depressive like behavior.

One of the ways that people have taken this animal work and started to think about are these systems actually operating in people has been to actually do the fecal transplant experiments where they've actually taken fecal samples from depressed patients and put them in rodents and demonstrated that rodents that received that depressed fecal sample actually have an increase in depressive-like behaviors and in sometimes anxiety-like behaviors.

That just supports this connection between microbes and the behavior, but a small collection of studies so far has also examined the composition of that microbiota in healthy and depressed individuals and shown that there are actually differences in the microbiota composition in depressed individuals when compared to healthy volunteers. A few of these studies have actually taken that a little bit farther and showed a direct association between specific taxa and clinical symptoms and disease severity.

If I can just highlight a couple of things about that that really are interesting and the sort of observations that I think will move the field forward. In a study by Chang in 2015 and colleagues, they shed a reduction in a very abundant bacteria called faecalibacterium. A reduction here was associated with an increased severity in depression. What's interesting about that is this is it's an abundant bacteria in healthy adults and a major producer of that short-chain fatty acid I mentioned butyrate. A reduction in this bacterial taxa has also been reported in other studies in depression but also in individuals with gut functional disorders. Suggesting this link between gut dysfunction and mood could be related to some of these key taxa.

If I can just tell you one more study that really links the bacteria to the brain is the work that comes of Kirsten Tillisch's group and Emeran Mayer's group at UCLA where they've shown some key taxa in healthy individuals are actually associated with brain connectivity using both DPI and structural imaging and then have also shown that the same taxa might actually be involved in emotional response using functional imaging. These sort of studies really do start to connect specific bacteria to brain function and behavior.

Gazella: Yeah. I think it's fascinating. When we're trying to target a microbiome to change the composition, you mentioned that there are some key factors that can influence gut health and therefore hopefully influence brain health. You mentioned probiotics, prebiotics, diet, lifestyle. Can you tell us some more specifics about how we can influence this gut/brain axis connection?

Foster: There are several factors that influence the composition and the function of gut microbiota. There's a lot of interest in the field to determine how both genetics and the environment and that interface influence the microbiome and how those interactions might influence both physical and mental health. A key factor that influences the microbiome is genetics. There's a whole series of twin studies that provide evidence for a role for host genetics or the DNA that we inherit influencing your microbiome.

The first evidence that showed this was this observation that monozygotic twins that have exactly the same DNA have more similar microbiomes than dizygotic twins but not perfectly matched suggesting that while genetics is an important role other things might also be important. There's extensive literature both in animals and in humans that looks at the importance of genetics but also highlights the influence of these other environmental factors. Some of those are important to consider in mental health.

Age, for example, influences microbiota composition and function. Our relationship with our microbiomes happens very early in life as we travel down the vaginal tract and are colonized by the bacteria. The dynamic changes that occur in early life really do influence all sorts of health outcomes, including risk of particular allergic responses, but also potentially mental health. Age-related changes that occur later in life also could have a direct impact on gut health and brain health.

Another big factor to consider is diet. There's a direct impact of diet on gut health and brain health but also understanding which specific taxa are influenced by the diet and how the related molecules and signaling systems that influence the interaction between diet, microbiome, and mental health really has to be addressed in a very systematic way.

The final factor, I think, that we all know about and pay attention to are the impacts of drugs on the microbiome, the most obvious being antibiotics. There's one large epidemiological study that suggests exposure to antibiotics increases risks of anxiety and depressive disorders, but recent evidence actually shows that both antibiotics and non-antibiotic drugs have direct effect on microbiota composition. The impact of the influence of these different drugs on the microbiome and how that bottom-up mechanisms might influence the side effects or the direct action of drugs is very important.

Gazella: What about probiotics? You mentioned prebiotics and probiotics. What role can they play in influencing the microbiome and then influencing mood and brain function?

Foster: There's enormous public and scientific interest in probiotics and other psychobiotics as you mentioned such as prebiotics but also naturally fermented foods, which have been around for a long time, to improve mental health. There is extensive preclinical literature that demonstrates benefits of probiotics in mood and brain function. Interestingly within this literature even when it's a challenge in an animal model that has nothing to do with mental health outcomes, the addition of a probiotic tends to improve some of the emotion-related behavior such as anxiety-like behaviors in these animal models.

The first evidence to support microbes can influence and probiotics specifically can influence brain function came from a whole series of probiotic studies in healthy adults. These studies administered probiotic cocktails or single probiotics to healthy individuals for a period of usually a month or longer. The benefits included things like reduced inflammation, reduced stress hormones, and improved anxiety and depressive measure, and that's in healthy individuals.

A key report in this area that actually launched some of the interest of Dr Bay who we're going to speak to later was a randomized control trial conducted by Laura Steenbergen and colleagues in the Netherlands that showed that this particular probiotic cocktail, Ecologic BARRIER, which is now in the US as Target gb-X, reduced cognitive reactivity to sad mood and reduced ruminative thoughts in those healthy individuals, suggesting again this link between microbes and a benefit on mood. But there's only been to date maybe 1 or 2 but 1 particular randomized control trial by Akkasheh and colleagues in 2016 that showed probiotics administration in depressed subjects reduced depressive scores and was accompanied by reduced inflammation and reduced serum insulin.

The field is certainly supporting the hope for therapies such as probiotics and prebiotics influencing mood.

Gazella: Perfect. Your last question Dr Foster. When it comes to gut/brain research, what would you like to see emphasized in the future? What more do we need to learn? I would imagine it's a long list.

Foster: I have a long list, and in fact the interesting thing about this field is its multidisciplinary nature and that as a neuroscientist in the field I also get the great advantage of associating with microbiologists who have never considered mental health in their research. I think this crosstalk between these different disorders helps us try to define what is a healthy microbiome, which is actually a critical step of the field right now, before we can figure out how alterations in the microbiome influence illness, whether it be physical illness or mental illness.

One of the things that I think is needed from a research perspective is actually, particularly in mental health, it's some longitudinal studies so that we can understand how dynamics of the microbiome and perhaps perturbations of it over time influence mental health. And also we need more studies examining the microbiome in psychiatric populations, paying attention to some of these individual differences that we know are emerging that might influence the gut/brain axis's impact on mental health.

If I go back to an earlier comment I made, if we think about the field in general and the researchers that have advanced some of our technology, the field's really very interested in functional readouts of the microbiota-host interactions. A lot of studies have looked at the composition of the microbiome. Knowing who's there is just the first step along the path of understanding how these communication pathways impact health. In particular, people are now using shotgun metagenomics to get a more comprehensive profile of what the functions of the microbiome are using genomics to look at the genes that are being expressed and metabolomics in both fecal, urine, and plasma samples to understand what the functional outcome of these different taxa have within our whole system.

This is a great advantage to psychiatry because depression and anxiety are really very heterogenous disorders. Understanding how the microbiome and the related signaling systems are linked though, clinical presentations of these disorders is important. What might be very important is understanding using these sophisticated tools, how individual differences in these microbiome readouts or proxies for the microbiome can identify a microbiota-brain signature that might actually allow us to cater treatments to individuals based on their own microbiome and their own depression or anxiety symptom profile. That way the trial-and-error component of treating individuals with psychiatric illness may be improved.

Gazella: Yeah. That's a great goal, and it's going to be exciting to watch this area of study as it evolves.

Okay, Dr Bay, it's now your turn. Dr Bay, much of your work has focused on psychopharmacology. What prompted your interest in the gut/brain axis?

Scot Bay, MD: I've always been looking through the literature for new and interesting developments in the field both to stay current on the latest developments in case you care but also because I had a weekly mental health–related podcast for many years and I was looking for new and interesting topics to discuss on that. Over the past several years I've been seeing more and more articles documenting research studies about the effects of probiotics in mood and also as Dr Foster mentioned even the effects of certain fermented foods in things like anxiety and also depression. That really struck a chord with me because I've always observed that there's a lot of promorbidity between states of anxiety and depression and gastrointestinal disorders. And again Dr Foster very elegantly laid out how the gut and brain are connected, so that always made perfect sense to me that people who have mental health problems are likely as not to have also gastrointestinal issues. It's just one of many ways I think that mental health problems affect the body physically.

People with depression but also especially with anxiety almost always have some kind of somatic or physical symptoms that are a manifestation of their disorder. Having gastrointestinal-related symptoms is a very common manifestation of the things that we psychiatrists treat on a daily basis, the depression, anxiety, and other adverse mood states.

Gazella: What type of GI issues are you seeing in your practice in people who have mental health issues?

Bay: Things like irritable bowel syndrome, which could either be prime persistent constipation or diarrhea or switching from one to the other, bad reflux, gastroesophageal reflux disease, and also other just non-specific functional bowel complaints that may not have a particular diagnosis associated with them but nonetheless affect people's gastrointestinal functioning.

Gazella: That is an interesting connection between mental health issues and the GI issues. Were there others that you wanted to mention?

Bay: Gastroparesis is another one. It's commonly associated with certain medical conditions especially diabetes but can also be affected by mood. And then there's also the other consideration being many psychotropic medications can affect motility of the intestines, so there's that consideration as well.

Gazella: I'd like to talk a little bit about treatment resistance because you have been focusing on psychopharmacology. How common is the issue of treatment resistance, and why is that such a challenge for many clinicians?

Bay: Right. I would say the treatment-resistant patients, in other words people who I guess by some definition had failed trials of 4 or more psychotropic medications, this is a very difficult problem because when you have people who don't respond to the normal typical treatments, it's very difficult to get them any symptomatic relief whatsoever. There's only a limited number of treatment alternatives to consider. The other part to that is when people wind up seeing psychiatrists, they've often cycled through several treatments already through their primary care physician. There are too few psychiatrists, so people often don't start their treatment of their mental health problems with us. It's usually started with primary care, so by the time they get to see us they've already struggled to not get any relief with the treatments they've been getting. It's even more difficult by the time that they see us.

The way I see it, we have patients who have their experience of their illness and all of them are as unique as their individual DNA, but the illnesses that we treat are not so unspecific that any treatment would be effective. For example, if someone has a bacterial infection it's very cut and dried. You send it for a culture. You know exactly what antibiotics will or will not kill it. You pretty much know what results you're going to get when you give the patient the treatment.

But when it comes to psychiatric problems, we just don't have a way of knowing in advance what treatments will work or not. When people don't respond to several treatments, that unfortunately indicates often a guarded prognosis. Another reason why I'm always looking around for other additional ways to help people who don't respond to the standard psychiatric medication treatments.

Gazella: That makes a lot of sense. I'd like to switch gears a little bit and talk about probiotics specifically. What are the clinical applications of using probiotics in patients who have mood issues like depression, anxiety, or other mental health disorders?

Bay: So far what I've been doing is adding this to the regimen of medications that I have my patients on. Initially what I did was to have people add the probiotic who were already on medication but still having symptoms to see if it would do two things, address their gastrointestinal symptoms and also bring about further improvement in mood.

When I first started doing this I had a limited supply of Ecologic BARRIER, which is the version made by the original manufacturer in Netherlands, Winclove. The company was kind enough to shoot me some samples. Initially since I had a limited supply I was just saying let me try this out on the people who are really bad off, maybe chronic, severe, treatment-resistant conditions, very complex regimens of medications, or polypharmacy and see how they respond because they're the people most in need of relief. Sure enough they all saw at least slight improvements in mood, and in many cases very rapid relief from their gastrointestinal symptoms.

But since the product is now available in the States and has been for quite some time under the name Target gb-X, I'm expanding that to people who are not necessarily only treatment-resistant as far as their depression and/or anxiety to people who aren't necessarily on complex regimens of medication with polypharmacy, even who may not necessarily have co-morbid gastrointestinal symptoms to see how this would help people.

I often get the question as far as another potential applications, I'm not getting support yet, but when I've discussed this with other clinicians I get the question, "Have you ever tried to give this to people to help them get off their psychiatric medication?" I haven't because initially the issue is helping people feel better who are only getting partial relief from their medication. But that's definitely something I plan to explore in the future.

Gazella: I definitely want to talk about some of your specific patient outcomes, but first can you please tell us the name again of the product and also tell us why you chose that particular product because there are a lot of probiotic products out there. Tell us the name of the product and why you chose this one.

Bay: Right. It's called Target gb-X, and it was originally only available through the original manufacturer in the Netherlands, Winclove. The reason I chose it going back to my always scanning for articles in the mental health field and looking for new developments and seeing the literature about probiotics, the study that Dr Foster mentioned earlier by Dr Steenbergen, that really caught my eye. This is what really, I think, initiated my getting involved in using probiotics in my clinical practice. As Dr Foster explained, Dr Steenbergen and her colleagues found that this particular probiotic helped reduce cognitive reactivity to sad mood and the aggressive negative ruminative thinking that is common in states of major depression even though in the study there were healthy adults, not depressed.

That really caught my eye when I saw the article about that study. I said to myself, "Wow. If this probiotic will do that, I need to get some of that and get some of my patients on it because so many of my patients are dealing with symptoms like that." I reached out to Winclove. They were kind enough to respond very readily and quickly. Kind enough to ship me some samples, and when I saw the results in my patients, that's when I realized that this could be very helpful.

To get back to your question why this one, the main reason is that because I saw the research study documenting that this particular one had benefits for those types of symptoms that I commonly see in my patients. But then also looking at the specific species that are contained in this particular probiotic, Bifidum bacterium species is one of them, and also Winclove really dialed down to not the specific subspecies in terms of which bacteria they included in their product. I have seen other studies besides Dr Steenbergen's in the literature mentioning probiotics that contained Bifidum bacterium species as far as helping with mood.

That's really why I said this probiotic seems to have the species that I've seen in literature can help with psychiatric symptoms and there's a study to back up that it treats symptoms that are common in depressed patients. That's why I said this one definitely has value as far as helping psychiatric patients.

Gazella: Yeah. It's always good to use the exact product that was used in the study. I think that's a really important factor. Before I get to the outcomes of your patients, it seems like dosing is always challenging. Do you dose the same with all of your patients and what dose do you typically prescribe to your mental health patients.

Bay: Right. The dose that's recommended by the manufacturer is the one that I typically prescribe, which is one sachet it's called, really just a packet of powder, in several ounces of tepid or lukewarm water once a day on an empty stomach. On occasion, I have suggested to patients that if they did not respond to one packet a day to try one packet twice a day. I've made that recommendation in the case of people who have especially severe gastrointestinal symptoms as well as mood symptoms or in people who they only had a very modest response to one packet a day or maybe not much of a response. But the vast majority of the patients that I've had try the Target gb-X have only been taking it once a day, and they have found that very effective.

Gazella: Okay, perfect. Describe some of the outcomes you've achieved in your practice using this particular probiotic.

Bay: In the original case series that I did when, again, I only had the samples shipped from the Netherlands, there were about 8 patients. They all had very rapid and thorough relief from their gastrointestinal symptoms such as irritable bowel syndrome symptoms, whether that was constipation or diarrhea. One older lady had this chronic severe diarrhea despite being on 2 antidepressants that are notorious for causing constipation. That was especially puzzling, but on the probiotic her diarrhea stopped.

I had another male patient with just very, very severe treatment resistant depression. He had tried multiple antidepressants of all different classes of drugs. No relief whatsoever, and he was only able to tolerate a very low dose of a much older generation antidepressant. But also he had chronic, severe, unremitting diarrhea. This man literally wore out his gastroenterologist's office and was not able to get any relief from it. The diarrhea stopped almost immediately upon staring the probiotic. That was amazing, and he was quite surprised, too.

These are the types of outcomes that I've seen as far as the GI symptoms. As far as mood symptoms, they were not as immediate or as dramatic, but usually after months, sometimes after 2 months, patients were able to look back and say you know what, I do think my mood is at least somewhat better than it was before I added this. It definitely has been successful as far as bringing about improvement in mood symptoms as well as improvement in gastrointestinal symptoms.

Gazella: Yeah, that's great. This as been a lot of great info, and once again I would like to thank the sponsor of this interview who is Klaire Labs. And I would like to thank you Dr Foster and you Dr Bay for joining me today.

Foster: Thanks very much, Karolyn.

Bay: Yes, you're very welcome. Thank you. It's been a pleasure.

Gazella: All right. Have a great day.

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