In this podcast episode, we speak with Ross Pelton, RRh, CCN, about the variety of mechanisms of action that probiotics have when it comes to reducing cancer risk. Pelton also talks about colon cancer, H. pylori, and probiotic safety and dosage. Finally, he describes how to support a healthy microbiome with a healthy lifestyle.

(Approximate listening time is 32 minutes)

About the Expert

Ross Pelton, RPh, CCN, is Essential Formula's director of science, in addition to being a practicing pharmacist, clinical nutritionist, and health educator in Southern Oregon. Pelton earned his bachelor of science in pharmacy from the University of Wisconsin. A certified clinical nutritionist, Pelton was named as one of the Top 50 Most Influential Pharmacists in the United States by American Druggist magazine for his work in natural medicine. Pelton teaches continuing education programs for healthcare professionals to use natural medicine and integrate it into their practices. He also has authored numerous books, including The Drug-Induced Nutrient Depletion Handbook, which is a gold-standard reference book for health practitioners.

About the Sponsor

Essential Formulas Incorporated (EFI) was established in 2000 as the sole US distributor of world-renowned microbiologist Dr. Iichiroh Ohhira’s award-winning probiotic dietary supplements and skin care products. Always an innovator, EFI introduced REG’ACTIV in 2015, containing ME-3, a probiotic catalyst that produces the “master’” oxidant glutathione inside the body's cells. A family-owned and operated business, EFI was founded on the philosophy of providing high-quality preventative, supportive, and comprehensive pro-health products for the entire family. EFI continues to flourish and grow through a strong company and product integrity and the knowledge that they’re providing scientifically proven products that positively impact the health and well-being of their customers.

Transcript

Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, our topic is reducing cancer risk with probiotics. Before we begin, I'd like to thank the sponsor of this interview who is Essential Formulas Incorporated. My guest is integrative pharmacist and nutritionist Ross Pelton who is an expert on the topic of probiotics and health. Ross, thank you so much for joining me.

Ross Pelton, RPh, CCN: Hi, Karolyn. It's really nice to be with you. I enjoy our conversations.

Gazella: Yes. Now, first of all, how does the scientific literature stack up when it comes to probiotics and cancer prevention? Are there published human clinical trials?

Pelton: Well there's really not a lot of human clinical trials, but there's really quite a bit of research that has been conducted looking at cancer with probiotics. Human clinical trials are lacking, but there's a lot of work that has been done, cell culture studies and animal studies. There's a lot of work being done in this area. We just don't have the longterm human clinical trials which are very expensive to do. I think there's a lot to talk about because we've got substantial studies that have been published on the relationship between probiotics and cancer.

Gazella: Right. So I'd like to begin by having you give us an overview of exactly how probiotics influence the microbiota to reduce cancer risk. Now, there are several mechanisms of action. So go ahead and fill us in.

Pelton: Sure. Well some of your probiotics produce compounds that have antioxidant activity. Some of them have anti-inflammatory activity. They help to regulate detoxification. A lot of these functions are due to the fact that your probiotic bacteria produce secondary compounds or secondary metabolites that are called postbiotic metabolites. This is really the new frontier in microbiome science, starting to learn more about the compounds that your probiotic bacteria produce when they digest and ferment the food that you give them. Remember, these compounds have anticancer activity or protectant mechanisms that help protect against cancer.

Gazella: So I'd like to focus on these mechanisms of action as they relate to reducing risk of cancer. So let's begin with a more well-known mechanism and that is, as you mentioned, probiotics influence immunity. Describe what the scientific literature tells us about probiotics and the immune system.

Pelton: Well we know that 70% to 80% of the cells in your immune system reside in the gut. So it's really critical to have a healthy microbiome, a healthy gastrointestinal tract because that is the bulk of your immune system cells. One thing a lot of people don't realize is in the first 6 months of life, the primary function of your probiotic bacteria is to train your immune system. So it's really critical that kids get a good start in life with a vaginal delivery and adequate breastfeeding and for kids that don't, that's a compromised immune system. The gut is the seat of the immune system, and your probiotic bacteria are what trains the immune system.

Gazella: So now, what about maybe a little less known activity which is, as you mentioned, the antioxidant potential of probiotics? This may not be on the radar of some practitioners. Describe this mechanism of action.

Pelton: Sure. We know that free radical damage causes DNA damage and can increase your cancer risk. In a highly inflammatory condition in the gastrointestinal tract, there's a lot of free radicals being produced and a number of your probiotic bacteria have antioxidant activity and they also produce compounds that have antioxidant activity. There's 2 things going on here. Some of the bacteria themselves are antioxidants, but more importantly, they produce compounds that have direct antioxidant activity. In that respect, they're reducing free radical damage and reducing cancer risk especially for colon cancer which is a site of a lot of the free radical activity in a highly inflamed colon.

Gazella: Yeah. We're going to definitely talk about colon cancer, but now, when it comes to this influence on immunity and antioxidant potential, are there research studies in vivo or in vitro studies indicating probiotics, which probiotics can help with immunity and antioxidant potential?

Pelton: Sure. There's both some of the lactic acid-producing bacteria, Lactobacillus strains, and also some of the Bifidobacteria, bacteria that reside primarily in the large intestine and colon. One of the classes of antioxidants that they produce, they're called exopolysaccharides. That's a big word for people, but it just means that there are chains of sugars that the bacteria produce and then they excrete them and they have antioxidant activity. So this is just one of the mechanisms of action by which both Lactobacillus and Bifidobacteria are able to produce antioxidant compounds that reduce cancer risks.

Gazella: So the research tells us that probiotics can influence gene expression. Tell us how this impacts cancer risk reduction.

Pelton: Well various different strains of probiotic bacteria can influence gene expression. They can influence apoptosis, which is the rate of cell death. They can influence metastasis. They can influence cancer stem cells. They can up-regulate tumor suppressor genes. So a number of different ways that probiotic bacteria and the compounds that they produce, these postbiotic metabolites can influence gene expression which ultimately is going to influence cancer risks.

Gazella: So now, there's a significant amount of evidence and research showing that toxins can increase risk of cancer. What role do probiotics play in neutralizing some of these toxins or in supporting the detoxification of some of these toxins?

Pelton: Sure. This is actually a pretty broad category. There's a lot of different ways that probiotics can have detoxification capabilities. Some strains of bacteria can detoxify or decrease the absorption of a cancer risk factor called bisphenol A. There's a lot of studies on that substance now that show that it increases cancer risk. This is a compound that's in a lot of products that are on the market, especially baby products.

Some strains detoxify some of the agricultural pesticides. One of the Essential Formulas' products, Reg'Activ, contains a strain of bacteria called Lactobacillus fermentum ME3, and that strain of bacteria up-regulates a group of enzymes called paraoxonase enzymes. Those enzymes directly detoxify things like organophosphates, which are one of the commonly used pesticides in the agricultural industry.

Other strains can directly bind some of the heavy metal toxins like mercury and lead and cadmium. They also decrease the absorption of these heavy metal toxins when they bind them up so they don't get absorbed into your system. They get excreted. Some strains actually metabolize cancer-causing food preservatives like sodium nitrate, and Bifidobacteria are able to degrade and detoxify a very serious compound called perchlorate. We get exposed to perchlorate from fertilizers in the environment and a lot of that in the agricultural industry.

Heterocyclic amines are frequently caused by cooking meat at high temperatures. So our middle America, meat and potato people, they're out there with their barbecues and they're producing these heterocyclic amines. Some of the Lactobacillus organisms reduce the toxicity from heterocyclic amines. That's just a number of the different ways that your probiotic bacteria function as detoxifying agents in the gastrointestinal tract.

Gazella: Yeah. It's a long, impressive list. Now, I want to get back to the ME3 that you mentioned. Are there scientific studies on that particular-

Pelton: There are.

Gazella: ... strain, the ME3?

Pelton: It is a really, really fascinating topic because Lactobacillus fermentum ME3 synthesizes glutathione. Glutathione is the master regulator of your detoxification throughout your system and every cell produces glutathione, but it's hard to boost your levels of glutathione because, when you take it orally, it gets oxidized, it gets broken down and destroyed so you don't absorb it. But now we've got a strain of bacteria, this Lactobacillus fermentum ME3, where the bacteria actually synthesize glutathione.

Yes, we have human clinical trials showing that the antioxidant activity of glutathione produced by the ME3 probiotic bacteria will reduce levels of oxidized LDL cholesterol so you're reducing your cardiovascular risk, and it does a good job of increasing detoxification throughout your whole body. The human clinical trial, people taking ME3 had an astounding 49% increase in the ratio between oxidized glutathione to reduced glutathione with the reduced glutathione is the active form. A 49% increase in the ratio of the reduced to oxidized glutathione is a huge, huge meaningful marker.

This is really a revolution in healthcare and medicine to be able to boost your glutathione levels on a regular basis because, as I mentioned, glutathione regulates your detoxification. It's also called the master antioxidant and probably protects more of your body than all the other antioxidants combined. This is one area that is just really astounding both in terms of antioxidant protection and detoxification capabilities.

Gazella: That's great. So I'd like to switch gears and I'd like to talk about specific cancers. When I think about probiotics and cancer, I often think about colon cancer. You mentioned that previously. What role can probiotics play in reducing the risk of colon cancer?

Pelton: Well there's a number of ways that this can happen. Pathological bacteria will convert bile acids into secondary metabolites that promote cancer. When you have the proper acid-base balance in the GI tract, there's a dramatic reduction in the conversion of these bile acids into the more cancer-causing secondary metabolites. So maintaining the proper acid-base balance, which is what the probiotic bacteria do when they produce things like short-chain fatty acids and organic acids and nucleic acids, they create the proper acid-base balance which reduces the conversion of bile acids into secondary cancer-causing metabolites.

Your probiotics can also inhibit the activity of carcinogenic enzymes. They suppress growth of bacteria that produce enzymes that deconjugate carcinogens. What I mean by that is that a lot of carcinogens get bound up and they're supposed to be excreted when you have bowel movements, but if you don't have good elimination and so things stay in the colon too long, those cancer-causing things that are bound up can get released and reabsorbed. So probiotics can actually suppress the growth of bacteria that produce these enzymes that are deconjugating these carcinogens. Good bacteria are actually keeping these carcinogenic byproducts bound up so they get eliminated from your body.

Gazella: Well speaking of bacteria, it's widely known that there's a connection between H. pyloriand cancer. Can you describe that connection and tell us how probiotics can help prevent or even reverse H. pylori?

Pelton: Sure. That's another big topic because now that H. pylori has been discovered and understood, we realize it's the primary cause of stomach cancer and cancers in the upper small intestine. This is an interesting bacteria. It's got kind of a corkscrew tail on it, and it can just burrow its way into the lining in the stomach or the lining in the small intestine. When that happens, you've got a hole in your intestinal wall. Then you get the acids and the digestive enzymes leaking through, creating inflammation, and you end up with a higher incidence of cancer.

If you have a good, healthy microbiome and adequate numbers of your good bacteria, you suppress the growth or the overgrowth of H. pylori. There's a little bit of a controversy about whether people should try to totally eradicate H. pylori. Some people, some of ... Martin Blaser is one of the leading scientists that's exploring this and saying maybe we shouldn't totally eliminate H. pylori, but people that have H. pylori overgrowth certainly do have increased risk to gastric cancer and small intestinal cancers. It's having a good microbiome and adequate numbers of your good bacteria that will keep the H. pylori in check and not get overgrown so you reduce your cancer risk.

Gazella: What are some of the symptoms of H. pylori overgrowth? I mean how does a doctor recognize this in their patient population?

Pelton: Well as I described, the bacteria has this corkscrew tail that burrows through the unprotected mucus lining in your stomach or your small intestine. When you get that hole in the lining, you've got an ulcer. It's painful. Your digestive acids, your stomach acid, and your bile acids and small intestine. Then they go through the mucus membrane which is your protective barrier, and they come into direct contact with the cells that line your GI tract. When that mucus protective layer is breached, then those acids contact those cells that line the GI tract and it's painful. You've got an ulcer and you say "Oh, man. This is sore." So people actually oftentimes stop eating because every time they eat, they get more digestive juices in that ulcerative location. You need to heal that ulcer. Getting rid of H. pylori is one thing, but you also have to take time to heal the ulcer.

Gazella: Yeah, that makes a lot of sense. Now so far, we talked about colon cancer, stomach, upper GI. Are there any other cancers when it comes to using probiotics? I mean do you pretty much recommend probiotics as a risk reduction strategy across the board?

Pelton: I do because your immune system is so directly related to cancer risk factors. A lot of people don't realize that probiotics have an effect outside the intestinal tract. We now know that things like short-chain fatty acids get absorbed into your system and can actually reduce the risks of liver cancer. It's a whole body effect. These bacteria are not just a local effect in the gastrointestinal tract. I kind of use the analogy of Mission Control at NASA where those computers are controlling your space flights. Well your probiotics and the postbiotic metabolites in your small intestines and your colon are really Mission Control for all health-regulating effects in your whole body.

There's a new study that I wanted to share with you, Karolyn, published just recently in a journal called Oncotarget. It's a cancer journal. It says cancer killers in the human gut microbiota. One of the things they're reporting here is that they identify intestinal bacteria that exhibit potent antimalignancy activities on a broad range of solid cancers and leukemia. So this is a relatively new paper just published in July of 2017, identifying that postbiotic metabolites and your probiotic bacteria are helping to reduce both solid cancer tumors and leukemia. It's just an exciting new report giving more emphasis on the anticancer capabilities of your probiotic bacteria.

Gazella: Yeah. I think this area of research is going to just really explode. Now, a lot of patients go into their doctor's office and they say "Oh, well I'm fine. I don't need a probiotic supplement because I eat yogurt everyday," or something like that. How easy or difficult is it to get the probiotics we need from diet alone?

Pelton: It depends on what you mean by diet. If people are eating fermented foods, that's a really good source of probiotic bacteria, but most people aren't eating sauerkraut and kimchi and tempe and things like that. Most foods don't have probiotic bacteria. People think about yogurt, but commercial yogurts have a lot of sugar which actually promotes the growth of your pathological bacteria and yeast like candida. So commercial yogurts are generally not a good idea either in terms of just not getting a good source of probiotic bacteria. You're really working against the health of your gastrointestinal tract and your microbiome.

If people produce their own yogurts, there are some good ones. Yes. But you're really not getting a diverse level of bacteria in yogurt, and a healthy microbiome is a diverse microbiomes which means you want to get a lot of different types of strains of bacteria. The best way to do that is to consume a diet that has many different types of fiber-rich foods, especially the multicolored vegetables. That's the number one food source for your bacteria.

Gazella: Right. We have to feed those good bacteria.

Pelton: That's right.

Gazella: So now, you represent a specific type of probiotic, the Dr. Ohhira's brand. Why do you recommend that specific brand of probiotic?

Pelton: Well I'm glad you asked that. I'm the scientific director of Essential Formulas, and Dr. Ohhira's Probiotics is our primary product line. Dr. Ohhira's Probiotics are made differently than every other probiotic in the world. In fact, it's kind of confusing, but Dr. Ohhira's Probiotics is really not primarily a probiotic. It is primarily a fermented food.

The Dr. Ohhira's Probiotics are produced in a fermentation production system. We have large fermentation vats in a warehouse, and we start with 12 strains of probiotic bacteria. Then at seasonally appropriate times throughout the year, we shred and harvest dozens of different types of organically-grown foods. There's fruits and vegetables and mushrooms and seaweeds. Then the bacteria get to digest and ferment these foods for 3 years before the product is finished.

During that fermentation process, the bacteria are breaking down the foods and producing this wide range of compounds that we now refer to as postbiotic metabolites. As I mentioned earlier, these are the master health-regulating compounds in our system. So Dr. Ohhira's Probiotics have been tested and we find out there are over 400 postbiotic metabolites in Dr. Ohhira's Probiotics. We are not primarily just delivering probiotic bacteria. We're delivering over 400 of these postbiotic metabolites that rapidly create change in the GI tract. You rapidly reduce inflammation, rebalance the acid-base level, promote the growth of healthy new cells that line the GI tract, cell signaling and gut-brain communication directly with postbiotic metabolites.

We get what we call rapid microbiome restoration or rapid microbiome repair. Other companies are just giving you bacteria in a capsule. That's kind of like a starter culture. Those bacteria haven't done any work yet. Our bacteria have been working for 3 years producing postbiotic metabolites by the time you ingest them. That's the big difference. Dr. Ohhira's Probiotics is different than every single other probiotic in the world. The new science in the microbiome, the new frontier in microbiome science is starting to realize that it's these postbiotic metabolites that have the master health regulatory effects in the gastrointestinal tract and health-regulating effects for the entire body. So by directly delivering this postbiotic metabolites, we get rapid improvement in the microbiome in the gastrointestinal tract for people who take Dr. Ohhira's Probiotics.

Gazella: Now, I know this particular product does not have to be refrigerated. Why is that?

Pelton: Well these bacteria learn to thrive and survive at room temperature during the 3 years of fermentation. They don't need to be refrigerated, which makes them very user-friendly. Also they are in a patented capsule that stays hard in the harsh acid environment in the stomach. Then it preferentially releases the contents in the small intestine. So it doesn't make any difference if you take it with food or on an empty stomach. Any way you take it, just the main thing is 2 capsules once a day. Get Dr. Ohhira's in on a regular basis and you'll be maintaining a healthy microbiome.

Gazella: Yeah. I'd like to talk a little bit about dosage because honestly it seems like you can ask 3 different experts about dosage and they'll give you 3 different answers. When it comes to dosage specific to cancer prevention, is that the 2 caps per day? What does that deliver in terms of CFUs or different strains for that two caps per day?

Pelton: Well 2 capsules a day is the recommended dosage. One thing we emphasize, we're not concerned about how many million or how many billion bacteria we have. There's a numbers game that is really a misconception by people when we're talking about probiotics that they call the bacteria that are available CFU which stands for colony forming units. It really means just the number of viable bacteria, but people have a misconception that more is better. They say "Mine has 30 billion. Mine has 50 billion. Oh, mine's got 100 billion." They think more is better.

One of the most critical factors in a healthy microbiome is balance. If you take massive doses even as a healthy strain of bacteria, you're not working in favor of balance. You're actually working against creating balance in the microbiome. So it's not important to have high strains of, high dosages and high numbers. It's better to have a multistrain probiotic, a lot of different strains but at lower dosage levels.

I really talk in my lectures and seminars against the high-dose probiotics. I'm not saying they're never appropriate. A product like VSL3, which is a prescription probiotic, I think it has 112 billion bacteria per dose. Those people have some good research and have documented benefits from their high-dose probiotic, but I don't think high-dose probiotics are appropriate on a longterm maintenance basis. You want to strive for balance and diversity.

Gazella: Yes, I would agree with that. How many strains are in the Dr. Ohhira's product?

Pelton: Dr. Ohhira's has 12 strains. We start out with 12 strains in the manufacturing process. We are a multistrain probiotic. I'm not sure, but Dr. Ohhira may have been the first scientist in the world to understand the concept and the importance of a multistrain probiotic because he created Dr. Ohhira's Probiotics 30 years ago.

Gazella: Yeah. So let's talk a little bit about safety. When it comes to cancer prevention, are probiotics safe for the majority of patients or is there any patient or group of patients who should not take probiotics to help reduce cancer risk?

Pelton: No, everybody should take probiotics. One of the most important things for health is a healthy microbiome. We now understand that a healthy microbiome is the foundation of health. I think it's important for everybody to realize that supporting and maintaining a healthy microbiome is a critical factor for health regulation. There's no contraindications.

I do want to mention briefly, Karolyn, there are 2 studies that were recently published in the journal Cell that have gained a great deal of publicity because they cast doubt on the effectiveness of probiotics. The scientists who conducted these studies stated that their results suggested probiotics are almost useless. There's been a lot of pushback after the publication of these studies. It turns out there was some methodological shortcomings in the way they set up their studies, and there were a very low number of people. I think there was only 8 to 12 people in these studies.

What's more disturbing is that it has been learned that the scientists that conducted these studies, they have a personalized approach to probiotics that they promote in their studies. Turns out that they have a vested interest. They have financial interest in this company that's promoting this personalized approach. So it's a very serious flaw and their conclusions should not be generalized of the whole field of probiotics. Allowing studies to be published in which the authors state that probiotics are almost useless is really grossly misleading and a disservice to the general public.

Gazella: Yes, I would agree. Now, I often like to ask experts to grab their crystal ball and look into the future. In your case, I'd like to have you tell us what you'd like to see happen when it comes to probiotic or postbiotic metabolite research in the future. What do you want to see happen as we go into this next phase? Because I'll tell you, there's a lot of exciting stuff happening. There's a lot of different directions we could go into.

Pelton: You're absolutely right. It is a very exciting field and rapidly evolving. As I've talked about these postbiotic metabolites, the compounds that your probiotic bacteria produce, in the future, we will learn a great deal more about the health-regulating effects of these compounds that your bacteria produce and we'll learn more about which strains of bacteria are more effective at producing some of these health-regulating postbiotic metabolites.

I think in the future, we'll probably make a great deal of inroads and progress in designing personalized probiotic programs for people. We'll be able to assess your own innate microbiome and be able to know more accurately how to promote and enhance the growth of your own innate what we call your probiotic fingerprint, the bacterial population that you've developed early in life. I think we'll get into more of a personalized microbiome and personalized approach to probiotics to help promote health in individuals.

Gazella: When you think about cancer specifically and reducing cancer risk, I mean now obviously, it's estimated that 1 in 2 men and 1 in 3 women will develop cancer in their lifetime. I mean this is now reaching near epidemic proportions. How critical is it that we look at things like probiotics when it comes to reducing cancer risk?

Pelton: Well again, I go back to the immune system. It's absolutely essential that people have a healthy microbiome so that they have a healthy immune system. This is really where it starts. Your gastrointestinal tract and your microbiome are literally the foundation of your health for everything that happens. It is the number 1 thing that people need to be aware of and it's not just the microbiome.

As we mentioned earlier, you have to learn how to feed your probiotic bacteria well. This is another key message of mine. This is why diet is so important because you're not eating just for yourself. You're eating to feed 100 trillion guests. It's a pretty big party that's going on down there. Every time you eat, you have to realize that you're feeding your microbiome, and your microbiome is the center and the foundation of your health and your immune system and your anticancer activity. So people need to realize how important it is on a regular basis to eat a wide range of different types of fiber-rich foods, especially the multicolored vegetables, because a more diverse fiber-rich diet will promote the growth of a more diverse microbiome which means your bacteria will produce a wider range of these health-regulating postbiotic metabolites and you will be a healthier person with a stronger immune system.

There's a recent study that was just published that shows that, reports that people that consume more probiotics take less antibiotics. That's just another insight into probiotics being able to support your immune system. So these people using probiotics more have a stronger immune system. They have less need over time for antibiotics.

Gazella: Yeah. That antibiotic issue, that's something that we ... That could be whole other topic for us.

Pelton: It's a big one.

Gazella: But as an integrative pharmacist, you share a philosophy with our listeners who are, most of them are integrative practitioners. It's not just about giving a pill and calling it a day. It's a very comprehensive approach, and I like the fact that you focus so heavily on diet and using a healthy diet to feed the probiotics and the bacteria and that you use probiotics hand-in-hand with that comprehensive lifestyle approach which I'm assuming, beyond diet, you counsel people to exercise and get enough sleep and those other lifestyle factors as well.

Pelton: Absolutely. Those are critical factors. There are studies now that show that your probiotic bacteria respond to exercise. Exercise needs to be emphasized. So it's diet and exercise, lifestyle. All these healthy things go into creating and maintaining a healthy individual and having a healthy aging process. It's not just probiotics and it's not just diet as you mentioned. It's exercise and sleep and learning how to avoid environmental toxins. There's lots of things that go into it.

Gazella: Right. Treat your microbiome well and it will serve you for a long time to come.

Pelton: It will work for you. Absolutely.

Gazella: Well great. Well Ross, this has been very informational as per usual. I want to thank you for joining me. Once again, I'd like to thank Essential Formulas Incorporated for sponsoring this topic. Thanks so much, Ross. Have a great day.

Pelton: Nice to be with you, Karolyn. Always enjoy speaking with you.

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, 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, 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).

Transcript

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.