Major Depressive Disorder Podcast

The Role of the Gut Microbiome in Major Depressive Disorder: Where the Research Is Now and Where It Is Headed

Madhukar Trivedi, MD; Jane Foster, PhD


June 09, 2022

This transcript has been edited for clarity.

Madhukar Trivedi, MD: Welcome, Dr Foster, to the discussion on the gut microbiome and its impact on depression. Dr Jane Foster is professor of psychiatry at UT Southwestern Medical Center in Dallas, and also professor of psychiatry and behavioral neuroscience at McMaster University in Canada. Welcome, Jane. I am very excited to hear from you about your thoughts on the impact of the gut microbiome. As the audience may know, you have been at the forefront of trying to really understand the gut microbiome–brain axis. I'm very excited that you're here. Maybe we start initially with your description of what the gut microbiome is and how one looks at components of the microbiome.

Jane Foster, PhD: Hello, Madhukar. Thanks for inviting me to join you here today. The microbiome has been exhaustively studied in the past 20 years and in the past decade, more so in the area of neuroscience and psychiatry. But it actually refers to all of the microbes that include bacteria, viruses, fungi, protozoa, and parasites that cover all the surfaces of your body. The composition varies depending on what part of the body we look at, meaning that your gastrointestinal or your gut bacteria, which mostly is what we study, is very different from your oral bacteria, those found in your mouth. In fact, we have 100 trillion gut bacteria. We have a trillion bacteria on our skin and we have 10 million bacteria in our mouth. We are actually more microbes than we are eukaryote, because we have more microbes than our own cells in our body.

Trivedi: Fortunately, it is not all the microbes that really have an impact on disease and health. In terms of the work on the gut microbiome and its impact on the brain, what do we know from animal models?

Foster: We know a few things that are important to the brain. One is that microbes are there effectively for pathogen defense. They keep the bad microbes away, but they also are critical to nutrient uptake and metabolism. This is one area where whatever we take into our diet interacts with their microbes. And that interaction, those little factories, which are the microbes in your gut, can actually produce all sorts of active chemicals, such as short-chain fatty acids. Those, in fact, can influence your gastrointestinal health but also get into your bloodstream and act on your brain. It's this microbial metabolite that is one of the signaling pathways from your gut microbes to your brain. Another important pathway is the immune system, because without our microbes, we wouldn't actually develop that adaptive arm of our immune system, those T lymphocytes and those B lymphocytes that are critical to both maintaining your inflammation in general, but also signaling what's happening in your gut to your brain. Those are two very important pathways on the host side that are influenced by those gut microbes right from birth throughout life.

Trivedi: There is a component of these microbes that really provides protection against inflammation, against infection, and that really is one of the major functions. Is that right?

Foster: Correct. One of the ways that they do that is that they influence that barrier integrity right at the level of that epithelial cell. They can influence the local mucosal immune system, but they also affect other systems — for example, tryptophan metabolism. They can produce a whole host of molecules that are acting both locally and remotely. One of the things they do is improve the barrier by reducing inflammatory processes. There are some microbes that are more detrimental and inflammatory in nature, and potentially in some disease states, we might lose some of our beneficial microbes and gain some of these more detrimental microbes. That balance is one of the things that we can look at by looking at a person's microbiome.

Trivedi: Are there specific microbes associated with the impaired gut-brain axis or is it the distribution across different microbes? What really drives the impairment?

Foster: A lot of the focus has been on the composition of what's there, but really what's more important is the function of those microbes. So, as I say, they have a whole host of different metabolic pathways. If we think about just the genetic potential of your microbiome, we have about 23,000 or 24,000 human genes, but the microbes have about 2000 genes. They have this biochemical flexibility whereby they can actually generate a whole host of different signals that can influence things. There probably are key microbes within the system and there are certainly some beneficial microbes that are known to be abundant in most humans' gut, but they're more classed in two types of bacteria or families of bacteria, which we can look at. Those that are short-chain fatty acid producers that are probably more important to maintaining that balance. There are other bacteria that, for example, metabolize proteins and amino acids. Those might also contribute to a different signaling system. There are bacteria that promote a healthy immune balance and there are some that contribute to activating the immune system. What's interesting is that even if we have a peripheral infection, the metabolites in those gut bacteria change almost immediately. They're very responsive to both things happening in their body as well as things in our environment.

Trivedi: Are there particular types of microbes that have been associated with onset or perpetuation of anxiety and depression?

Foster: There have been quite a few studies that have looked at differential abundance of particular taxa. What happens is that there tends to be a reduction in some of these — what are referred to as butyrate producers in depressed individuals, for example, or in individuals with bipolar disorder. They tend to have a reduction in some of these protective bacteria and an increase in some other bacteria that are known to promote inflammation. One of the important things is that there's a lot of bacteria in there. Understanding the crosstalk within the bacteria themselves, there's probably a population or a community of bacteria that are beneficial. The evidence suggests that in mood and anxiety disorders, so that that beneficial community is reduced.

Trivedi: How do we correct that? Is there any evidence that it can be changed to diet, or do we need to be thinking about probiotics? What are the steps that clinicians can now talk about?

Foster: There are several levels of evidence to suggest that microbes or microbiota targeted therapies might be of benefit to psychiatry. One is, even if we just look at healthy individuals and administer probiotics — and people have done this in both case-control studies or in randomized controlled studies — they tend to reduce stress level, stress reactivity, and improve mood. More recently, some of these attempts to look at microbiota targeted therapy in clinical populations have shown some benefit. So again, in randomized controlled trials in depressed patients and in bipolar disorder, there has been improvement of depressive or anxiety symptoms in those clinical populations. One of the challenges is trying to determine who is going to benefit from those interventions. It's not really a panacea. It's one of these situations where, like any clinical treatment, we need to get better biomarkers to help identify which individuals are going to respond to a particular treatment. That would be the same for the microbiome-targeted therapies. There's a good study coming out of Australia where they've actually demonstrated that nutritional interventions have a very positive effect as an augmentation therapy to treatment as usual.

Trivedi: Based on what you're just describing, we should be spending effort on trying to identify the signature for individuals and then match them with the right nutritional changes. Is that what you're recommending?

Foster: Correct

Trivedi: And so in terms of the next steps, are there ongoing clinical trials that you are aware of where people are beginning to do that?

Foster: There are quite a few ongoing clinical trials in the probiotic area. I think one of the things that needs to change is the idea of actually using a biomarker at the front end to randomize people into the clinical trials. We want to be able at baseline to take a look at that signature and then determine whether, based on your profile of bacteria or maybe some other host readout (such as an imaging signature or your peripheral immune system) somebody, first of all, should have a probiotic or a drug or both vs other interventions. The other thing that the microbiome might be useful for in that space is that we might be able to find microbial biomarkers of clinical phenotypes and still use standard treatment, not necessarily microbiome targeted treatment. We could determine what antidepressant best matches their biological profile. The microbiome, as I see it, is a snapshot of your life history, because it is a combination of your own genetics and your environment and how you have come through life. At any sort of time point in life, it might actually be a good representation of your own gene environment interaction to date.

Trivedi: But in some ways what you're describing is what we are running into with a lot of interventions. More important, with biomarkers in psychiatry and depression, particularly with neural circuits, it is beginning to be clear that we really have to be smart about identifying the signature and then matching them with the right treatments rather than throwing the same treatment at everybody. So for people without reward circuit dysfunction, if you then give them something that changes the reward circuit, that doesn't help. Something similar is what you're identifying with the gut microbiome. Is that fair to say?

Foster: That's correct. One of the advantages of the current advances in the microbiome area is the tools for measuring both what's there and what it's doing, the presence of the composition through metagenomics or 16S ribosomal RNA sequencing and using the metabolomics. Just in the stool itself, you can get a really good picture of that complex and dynamic interaction, and that probably has a lot of ability to look at the profile. It's probably a better representation to generate individual differences because each of us has a microbiome as our own. And so if we look at both the microbes and the metabolites, and then potentially if we had a proxy for what those are doing by looking at blood or some other host system, that would be a pretty comprehensive, integrated biosignature to predict from the baseline what the subtype of the individual might be and what they might respond to.

Trivedi: Can you speculate on the next 5 years, 10 years. What would be the kind of clinical situation that we're going to run into? Where would somebody be getting a microbiome assessment, have the signature identified, and then be matched with the right treatment? Is that what is likely to be within our reach in the next few years?

Foster: Yes, it probably has to include the response of individuals. So if we use a comprehensive microbiome signature to characterize people at the front end of a trial, and then we link that to outcomes, I think we're ready to develop the type of algorithm — the bioinformatics in this area has really advanced in the past decade. We have these algorithm tools where we can integrate very comprehensive and dynamic datasets to get that individual readout of that individual. Then we have to trial that. We can define the tools and define these signatures. Then, we have to design the right randomized controlled trials to test those signatures. We'll be ready to test the biomarkers probably in the next 5 years. And then that will lead to better clinical outcomes in the long run.

Trivedi: That is one of the major aspects of what you're going to do by joining us at UT Southwestern. We are going to identify these signatures and then try to do randomized controlled trials. That is very exciting work beginning, and then matching that with some of the imaging and EEG work so that you can identify a full signature for an individual. That is what our work will be in the next few years. Patients and clinicians can't wait. So for today, what would you advise if a clinician or a patient has had difficulty getting better with the current treatments? What would be the best way that people can at least augment their current treatments? How would somebody take what is already known and put it into practice?

Foster: One of the things to consider is whether or not people are actually looking at a more holistic review of an individual with anxiety, depression, or bipolar disorder, considering GI disturbances, diet and other lifestyle factors, when considering what the appropriate treatment would be. Because in fact, if we're looking to improve somebody's microbiome, if we actually target good heart health, it tends to be a good gut health, right? So just introducing an assessment of gut health from the perspective of the clinician and engaging the patient, that's one area that people can immediately expand their medical history. And the other thing is that there is evidence. There are clinical people using some of these probiotics and other strategies in order to improve outcome, and at this point it's warranted to use them, I would expect, based on the evidence that augmenting treatment is useful for somebody who might have a GI-related issue. Also important to think about is the of risk for depression. So when we have people who are at a first episode, the animal literature and some of the evidence in healthy individuals is that if you put a probiotic or a prebiotic on board during a stressor, the impact of that stressor is less after the fact. So this is a place where if somebody's struggling a little bit — and as we know, there are a lot of people, particularly young people, struggling at the moment — the evidence suggests that if you put a probiotic or a prebiotic and a good dietary and exercise program, even though they get the acute effects of stress, the long-term effects of stress are not as impactful, suggesting that maybe in those people at risk we could reduce the transition into more serious illness.

Trivedi: And in fact, clinically, I see a lot of people describing that their stress level is affected by the type of food they eat from time to time. And so monitoring some of that may be the other aspect that is worth starting now, because what you're describing is that these microbes can really have an impact on how stress response is really happening in people.

Foster: That's an area that's been quite well studied. In fact, the groups in UCLA have done that work using imaging and in healthy individuals, giving them fermented milk products with probiotics for 30 days and imaged before and after. And there's a subset of individuals with a particular profile of bacteria that have a response to stress reactivity. The probiotic reduces that response, and that's in healthy individuals. So certainly mitigating stress by improving diet and even targeting with probiotics or other microbiome is indicated in the current evidence.

Trivedi: That is a very common question I get from our work in the school networks and in pediatric medicine networks. Parents often ask if their children, especially teenagers, are having some difficulty with stress response, have a higher risk because there is family history, etc., what can they do to protect them? It seems like what you're saying is figuring out the best way to really address this population that has some risk factors, some difficulty with stress response, and that changing their diet and their dietary intake may be worthwhile considering and studying.

Foster: There's one really important study that I just want to highlight that you reminded me of there, Madhukar. There's a study where they looked at the benefit of a high-fiber diet vs fermented foods, plus high fiber. They looked at people's stress levels at the beginning of the study and at the end of the study, and people who had a particular profile of bacteria that included bacteria that are good at metabolizing fiber benefited from both diets. People who didn't have those short-chain fatty acid–producing bacteria that benefit from the fiber, didn't benefit. But if they gave those people without that bacteria both the fermented foods and the fiber, those people benefited; and the people that benefited the most from that fermented food and fiber were the ones with the highest anxiety at the front end. It seems to be that, again, that's pretty strong evidence that there's something going on here. We don't have that exact mechanism worked out, but that's the sort of approach that we could take. It's not just that high fiber is good because it feeds the microbes, but if high fiber isn't the only solution, adding some of these fermented foods, where the microbes have already produced those beneficial molecules, is also a strategy.

Trivedi: It sounds like a balanced diet may be a first starting point.

Foster: That's a good place to start.

Trivedi: Any final thoughts on how you see the research in this area going in the next few years?

Foster: I think one of the things that's very exciting is that there's been a lot of work in the animal area, as you and I are both aware. But there's some great work where people are now thinking about these microbes and their function and translating that to looking at clinical populations — getting some more mechanistic information to understand the causal role of microbiome, both in beneficial bacteria and detrimental bacteria in clinical populations and even in healthy individuals. That's where I think the biggest leaps are going to be in the next 5-10 years.

Trivedi: Thank you very much for your time. This is something that patients and their families often ask about. We in the medical field have been much less informed and educated about it. So I am very excited that you gave us a preview of this because I think, going forward, more education about nutrition, diet, and the impact of the gut microbiome is going to be a major part of the curriculum in medical schools. So, thank you very much.

Foster: Thanks very much for including me.



Modulating Brain Function With Microbiota

A Systematic Review of Gut Microbiota Composition in Observational Studies of Major Depressive Disorder, Bipolar Disorder and Schizophrenia, search for phase 3 studies, recruiting, and keyword "probiotic"

Review Article: The Future of Microbiome-Based Therapeutics

A Randomized Controlled Trial of Dietary Improvement for Adults With Major Depression (The 'SMILES' Trial)

Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity

Gut-Microbiota-Targeted Diets Modulate Human Immune Status

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