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Now displaying: August, 2018
Aug 14, 2018

This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.

In this interview, naturopathic physician and probiotic expert Donald Brown, ND, discusses the role of probiotics in supporting the gut microbiome. Brown also describes the mechanisms of action and clinical applications of probiotics, as well as strains, dosages and potential contraindications.

About the Expert

Donald Brown

Donald J. Brown, ND, is one of the leading authorities in the USA on the safety and efficacy of dietary supplements, evidence-based herbal medicine, and probiotics. Brown currently serves as the director of Natural Product Research Consultants (NPRC) in Seattle. He is a member of the Advisory Board of the American Botanical Council (ABC) and the Editorial Board of The Integrative Medicine Alert. He was a member of the Board of Directors for the International Probiotics Association (2008-2010) and its Scientific Advisory Board (2006-2008). He has also previously served as an advisor to the Office of Dietary Supplements at the National Institutes of Health. Brown is the author of Herbal Prescriptions for Health and Healing (Lotus Press, 2002) and was a contributor to The Natural Pharmacy (Prima Publishing, 2006), the A-Z Guide to Drug-Herb-Vitamin Interactions (Prima Publishing, 2006), and The Textbook of Natural Medicine (Churchill Livingstone, 2006).

About the Sponsor

Allergy Research Group

Founded in 1979 by molecular geneticist Stephen Levine, PhD, Allergy Research Group® is one of the very first truly hypoallergenic nutritional supplement companies. For nearly 40 years Allergy Research Group® has been a leading innovator and educator in the natural products industry. Our dedication to the latest research about cutting-edge nutritional supplements continues to this day.

Our purpose is to provide customers with products they can use to improve their patients’ quality of life, through scientific based innovation, purity of ingredients, education and outstanding service.

ARG is proud to be a sponsor of the Clinical Education LinkedIn Forum, a closed peer-to-peer group on LinkedIn where healthcare professionals can ask clinical questions and receive evidence-based and clinical-based responses by experts in their field.

Visit www.clinicaleducation.org/linkedin for more information & to sign up for free!

Visit www.allergyresearchgroup.com for more information on ARG and our products.

Transcript

Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today we are exploring the impact that probiotics can have on the gut microbiome. Before we begin, I'd like to thank the sponsor of this topic who is Allergy Research Group.

My guest is naturopathic physician and a leading probiotic expert, Dr. Donald Brown. Dr. Brown, thank you so much for joining me.

Donald J. Brown, ND: Hi Karolyn. It's a pleasure to talk to you. It's been a long time.

Gazella: I know.

Brown: How are you?

Gazella: I'm doing great. I know. This is like old times. And you know, before we dig into this topic, I have to tell you that I am just fascinated by the human microbiome, and it seems like the research in this area has really exploded. Why is that?

Brown: Well, I think, again, it's ironic as a naturopath talking about it because we've always talked about the impact that the intestinal tract has on health in general. Immune health, skin health, so forth and so on, and I think that what's happened is that particularly probiotic research has led us to realize that there's these microbes on our body. And we have a tendency in probiotics to focus on bacteria, but what's exploding in this area is that we have resident microbes that are viral microbes. We have fungal microbes that are natural inhabitants of our body.

So looking at this, we're really talking about 40 trillion microbes, predominantly bacteria, and sort of the balance that we have with these microbes which are part of our body. And it's funny because the research [inaudible 00:01:54] dramatic, and we have 10 times more microbes on us and in us, mainly in us, than we have cells. And the new data is really indicating that that's not the case; it's about 1.3 to 1.

So people who get itchy when they think that they have more bacteria on them than cells, it's not quite as dramatic as we thought. Again, I think it gets back to the fact that we're recognizing the fact that these things play such an interesting part in our health and our wellness, and when it tips in the wrong direction, our illness too. So expanding it out so we're not just looking at the microbes in the GI tract, but the microbes in other parts of our body as well.

Gazella: Yeah, I think that's really some of the most interesting parts of this research is that it does expand beyond the intestinal tract. So as it relates to the human microbiome, remind us of the mechanisms of actions that probiotics have. How and why do probiotics even work?

Brown: Well, probiotics ... When you think about the GI tract, the analogy I like to use, especially when I'm talking to the public ... talking to healthcare professionals here ... is it's sort of like a busy parking lot. And you have organisms that are health promoting, and then you have organisms that are potential pathogens, and they're looking for parking spots. Remember that bacteria ... viruses are the same way ... have to adhere to cells to be able to be either health promoting or disease promoting.

So that's one of the first things that probiotics are doing is they're competing for spots. And once they actually set up house, they then start creating a micro-environment that is inhospitable to potential pathogens, producing things that are anti ... compounds that are antimicrobial. They alter the pH slightly to make it inhospitable for these microbes and really create a situation where, "Hey, this is our home. This is our neighborhood, and you're not welcome here" kind of a thing.

The other thing that should resonate with most of the doctors on the phone is the whole idea of leaky gut and intestinal barrier function, too. It's one of the things that probiotics do once they set up house is they're also helping to produce mucin and to sort of keep those tight junctions in the intestinal tract, the cells healthy and intact. And that's very, very important.

The other thing that they do is they also, in the colon, are producing short-chain fatty acids which are associated with reducing risk of cancer as we age. Production of short-chain fatty acids act to help with digestive health as well. And then one of the really interesting things that's really been discovered over the last, I would say, eight to 10 years, is that when these little bacteria actually bind, they're communicating through the intestinal wall with what are called dendritic cells which are funny-looking, little, sort of odd-looking starfish type things that send little feelers up through the ... into the epithelial cells. And the probiotics are actually communicating with them to sort of modulate the immune system. So they produce a little bit more of this, produce a little less of this. Inflammatory responses are also modulated through it.

And then the last thing and one of the really, really interesting things right now is we're beginning to realize that the intestinal tract is communicating with the brain. So the gut-brain axis is what that's called, and we know that stress, for instance, can actually negatively impact the probiotics in the GI tract, the healthy bacteria in the GI tract, and in turn, through the vagal nerve going up to the hypothalamic-pituitary axis, actually modulates that response.

So we're now finding out that probiotics may actually be involved in ... I'm sure you've done interviews where you talk about the HPA axis and stress response. We're now finding out that the GI tract is very, very directly involved in that. So it could be negatively impacted by stress but can also positively impact the HPA axis, which is a whole new mechanism of action which is wild.

So we've got gut health, digestive health. We have immune health based on responses with the GI tract. Now we're finding out that there's actually effects on mood, stress response, that sort of thing. And that's not even covering the female genitourinary tract which has its whole population of probiotics that are positively affecting genitourinary tract health as well, so it's big. It's a vast influence on the body.

Gazella: Yeah. There is a lot going on here with probiotics. I think that's why I like the topic so much because there's just so much to talk about.

So when we're looking at the scientific literature and the research, what conditions have the most compelling research in terms of improved outcomes? I realize that this may be a pretty long list, given the mechanisms that you've just described, but take us through that list from a research perspective.

Well, I think what I like to do is I like to start with the things that are accepted by the larger medical community. And one of those is the fact that we've known for a long time that probiotics have a positive effect on prevention of antibiotic-associated diarrhea. So I would put that probably at the top of the list of, hey, if I'm in a room and I've got people who are skeptical of alternative medicine, integrative medicine, that's always a good starting point because we have really solid data that antibiotics definitely are good at preventing that.

My background is in pediatrics, and I think another area that has sort of reached a critical mass is actually ... it's fascinating ... is the prevention of atopic dermatitis in children who are potentially at risk. The studies started ... First one was in the Lancet in early 2000s, and basically the studies are looking at mom particularly but also whoever the partner is, and risk of ... that have a background of atopic diseases, allergic diseases, and actually starting to give mom probiotics during the second half of her last trimester. And then once the baby is born, if mom's nursing, continuing to give the probiotics to the mom until she stops. And then, anyway, it varies on the study, but usually then the infant starts to take the probiotics.

What they're finding is that it's reducing the incidence of atopic dermatitis by about 50%. That's amazing to me because if you look at sort of tracking the use of the antibiotics in children on a graph and you look at the increase in atopic diseases, so you're looking at eczema, atopic dermatitis. You look at asthma. They track almost exactly if you look at from 25 years ago to now, they track almost exactly. And also cesarean births contributing to that as well where the microbiome, so that's really fascinating to me.

I would say the other area, sort of shifting gears, that I think has reached a critical mass is also adjunctive use of probiotics in female genitourinary tract health. So treatment using standard treatments for things like bacterial vaginosis would probably be the top area, but also prevention of recurrence of urinary tract infections.

We're, particularly in the bacterial vaginosis area, I think really reaching a point where we have enough data to sort of suggest that, hey, using these things really can help with prevention. And then I would probably put the last one, as we move into the immune system and we really have reached a critical amount of data. Not a lot of pediatric data but adult data now that suggests that routine use of probiotics seems to reduce the incidence of upper respiratory tract infections. So, again, I could go on and on and on.

Gazella: Right. Yeah.

Brown: There's a lot of stuff. There's a lot of stuff that's emerging and that we're sort of on the edge.

But one of the things I think the listeners need to know about is the fact that I think we like to think about alternatives too, but one of the great things about probiotics is that adjunctive use. Obviously it's antibiotics, but Helicobacter pylori, for instance. The standard treatment of that is very rough on people. Recurrence rates are really high, so one of the themes that I always like to talk about when I talk in my lectures to healthcare professionals is that remember that a lot of the treatments that we use for ... Let's take urinary tract infections. E coli are really good at setting up what are called biofilms that are these little bits like taking a Visqueen sheet and putting it over themselves so that you can get to use the antibiotics. You can get to the ones that are not underneath the protective shield, but the ones that are under there don't get affected.

So one of the things that probiotics are great about is going in and helping to break up that biofilm and actually make standard treatment perform better, and then continuing to use the probiotics actually reduce recurrence rates. So, and there's reduced recurrence rates, and there's a whole litany of examples of areas where if we use probiotics. I mentioned helicobacter pylori but also UTI's, bacterial vaginosis, where probiotics actually help the treatment go better, outcomes are better, and then really reduces recurrence rates.

Gazella: Yeah. That's such a good point and you know, you mentioned antibiotics and how they disrupt gut flora and how probiotics can help reverse that dysbiosis. Are there other medications that kind of do the same thing as antibiotics where they disrupt that gut microbiota diversity and that probiotics may be able to help reverse that?

Brown: We're thinking that some of the more aggressive inflammatories that people take may have an affect. That's still sort of in the early phases. One of the early ones, interesting ones that there's still a limited amount of data, but I actually reviewed it, was a study with a proton pump inhibitor, so things that we're using for reflex and that sort of thing, having a very negative effect on the microbiome. So, we're sort of still in the early stages of learning what specific drugs and the effects are. Obviously antibiotics would the be the easiest case study, because we can actually look at the what affects. They've done studies with people who are getting the triple therapy for helicobacter pylori and realizing that during that therapy, the healthy bacteria in the G.I. tract can be reduced by as much as 80%. If we use probiotics, during that treatment, it reduces that to 40 to 50% and then if we continue to use it after, people tend to bounce back quicker. There are other drugs that we know are beginning to emerge that have negative effects, but stay tuned on that one.

Gazella: Right. Right. Now, let's switch gears and talk little bit about strains, because I know that that's a hot topic. So, specifically for the conditions that you mentioned in helping to restore gut microbiota that's been disrupted by medications like you were just talking about, what are the more common strains used for these types of clinical applications?

If you don't mind my backing that up, I am very, very disturbed when I hear people lecturing who say that strains don't matter. I go to a lot of international conferences. I sit on committees that set standards, international standards for probiotics and it is something that experts who know a lot more about this area than I do are upset about, because there are people out there who are saying that it's species specific and strains don't matter. I beg to differ.

I think that it's very, very important that health care professionals realize that, particularly health care professionals realize that ... and Karolyn, you've known me for a long time. We've done interviews about [bontanical 00:16:20] medicine that I'm an evidenced based person. I like to see the ... particularly if we're talking about treating a condition. And so when we go from species level where there's very little research to strain level, we emerge into an area where we know what the dosage was, that was used in the study. Particularly when we talk about pediatrics, we talked about people who might be immune compromised. We talked about older folks like myself. It's important also to ... safety is pertinent too and that's one of the areas that is a little bit of a red flag for me with the whole probiotic area. Particularly on the commercial side where we have this race to do all these different things and some of the species level stuff that's being sold has not been clinically studied.

And so, very, very important that people realize that some of the standards that go around a strain or viability is the lack of bacillus or the bifidobacterium strain that you're using shown to be viable. Does it actually adhere in the intestine is one of the things that we now have the ... within the persons body, but we now have technology that can actually show that these things sort of do adhere, and how long they adhere, and how long they stick around.

Another thing that's really important that I've given many lectures to health care professionals is they don't think about is that we also don't want these strains, what's called trans located, we don't want them to go from the intestine to the blood stream. And they're having case studies. There was a paper published a number of years ago on people who were really severely immune compromised where the probiotic that was being ... it was a specific strain actually trans located into the blood stream and caused sepsis. People then had to be treated with very aggressive antibiotics. So, we don't want them to go from the intestinal tract into the blood stream.

Another one that's [inaudible 00:18:39] ... we're talking about antibiotics, I always chuckle when I remiss on this one is also we realized that hey, probiotics are good for people who are taking antibiotics, but we also want to be sure that the probiotics strain has been tested for not blocking the ability of the antibiotic to do it's job. So, it's called antibiotic resistance. And it can be transferable. They have run into organisms that we think are probiotics that actually have a negative effect on an antibiotic doing it's job, so that's important.

I already talked about safety and efficacy. I'm all about that. A silly one that I just want to toss in that's talked about internationally, that I still bump into in the U.S. more so than in other areas is the fact when we talk about being a probiotic supplement, we want to look at the label, and we want to be sure that these stability, or the shelf life of the product is actually been proven to the time expiration. There are still a lot of probiotic products that are sold in the United States that actually declare their potency at the time of manufacture, which is like, well okay, but I have a vitamin C product. They told me the potency when it was manufactured, but it says it has a two year shelf life. Have they actually tested that? Has that actually been proven? And so, remember, these are living organisms. Very, very important that stability or shelf life be proven for these as part of the choice of picking a supplement. 

Gazella: Well, I was just going to say, do you have some go to strains that you like to focus on when it comes to recommending probiotics?

Brown: I think there's a lot of them right now, actually. That's another area where we could probably go on and on about. There are what I like to call legacy strains that have been around for a while that have a lot of research on them that have ... and we also understand their mechanism of action really well. The one that people probably know the most is lactobacillus GG, which is a rhamnosus strain that was discovered by a couple of guys in Boston. I always like it when they give their own name to the strains. It was Gorbach and Goldin I think were their names, so they named it lactobacillus GG. But anyway, that one has been around for a long time. A lot of really, really excellent research. Some of the bifidobacterium strains from Japan from [Morinaga 00:21:24] is the name of the company, have a lot of research, particularly in the pediatric area. Been around really since the ... lactobacillus GG, since the early '60's, the Morinaga [inaudible 00:21:38] really since the '50's. The Japanese were doing isolation in human studies long before we were doing them here in the U.S.

Brown: Another one that I really like is lactobacillus acidophilus DDS-1. It's an interesting strain that was discovered by a guy named Dr. [Shahani 00:21:56]. By the way, all of these strains that we're talking about are derived from humans. These are human derived strains and this one was actually discovered and isolated first in 1959. And like the lactobacillus GG and some of the Morinaga strains has a lot of clinical research. It also ... in vitro research that shows that it adheres, that it survives. And then human trials, actually looking at it's ability to treat things like travelers diarrhea, prevent antibiotic associated diarrhea, those sorts of things.

When I look at products, I always look at what's the indication? What's been studied? There's commercial strains the lactobacillus, I'm sorry rhamnosus HN001, for instance, in the atopic dermatitis prevention area that has phenomenal studies. And so there are a number of strains out there that have reached that critical point of whether its specific to one condition or have been looked at in other areas that have really excellent data. And again, being somebody whose background was in pediatrics, I'm always also looking at what's your safety data as well. That would be an example of a few strains that I think have really excellent data.

Gazella: Yeah. That's good. And you know, not that long ago, we were seeing maybe just one or two species, one or two strains. Now we're seeing multi species, multi strains in these formulations, sometimes six, nine, twelve different species or strains in one formulation. Is that a good thing?

Brown: Sometimes it's a commercial thing. Here's my theory and I could easily be misproven [inaudible 00:23:58], but or unproven. Are you misproven or unproven? Which-

Gazella: I'm not sure.

Brown: Called out for my lack of proof. My answer to that, when I get asked that, and it's more common when I'm lecturing to the public or to managers of supplement sections is that probably for wellness purposes. So if I'm taking a probiotic or if I'm a doctor and I'm recommending a probiotic supplement to be taken daily, I probably would use something that's a little bit more of a multi strain. Sort of a balance between the lactobacilli family and the bifidobacterium family. That's a sort of my go to. And as you get into the senior population, seniors have a tendency to have a drop in the bifido. That's probably dietary related, because fiber and that sorts of things, they like to feed on ... They're probably eating less fiber in their diet.

But anyway. Having a balance of a number of strains, is there a magical number of strains? I don't think so at this point. I don't think anybody's proven that. I think the difficulty ... what I say to people is, is that when you shift, it's much easier to talk about a single strain or a combination of a couple strains. You know, in irritable bowel syndrome, inflammatory bowel disease, BSL-3 has eight different strains in it. I mean, that's a lot of strains. It's been around for a long time. They use very high doses, but its easier to look at disease endpoints when we do a clinical trials, because we have very clear outcomes that we're looking for compared to what's a placebo, for instance, Wellness studies are really hard to do, so I don't know that there's an easy answer to your question because I don't know if the company after I ... know a lot of them, and some of them have a lot of ... have deep pockets. I don't know who's gonna do a wellness study that shows that, "Hey, if you do this many strains at this potency, that it works better than if you only do one strain at this potency, or if you do nothing." 'Cause those are expensive studies to do.

Gazella: Yeah. Totally. And I'm gonna ask you another unfair question, and it's regarding dosage. You know that can be somewhat controversial, still debatable. How do you dose probiotics or recommend ... What's your philosophy on the dosage?

Brown: Well, I always start with what is the clinical. If I'm treating a specific condition and I'm using an evidence-based strain I dose it at the dose. And it's interesting, 'cause there's extremes and that's one of the issues when we look at meta-analyses that have been done, so stuff like say, not only was there this cacophony of strains that were used, going from one strain to five strains. That sort of thing. But the dose, the potency and we measure the potency of probiotics, what are called colony forming units so we talk about milligrams or gram amounts of these things. So I always try to look up with what the research showed.

Again, leading back to wellness and sort of, regular use. I have a patient who's take a multi-vitamin, who's taking fish oil every day and I say, "Hey, one of the things you should think about is keeping your intestinal tract healthy and probiotics are gonna contribute to that, keeping your immune system healthy." I don't have an easy answer for that.

I typically use multi-strains and I'll probably usually go in the 10 to 50 billion CFU per day. Is that correct? Is there clinical data to back that up? The answer is no, I don't know for sure. But that's sort of how I think.

The one thing that I can tell you is that I remember a client who decided to go high potency and high potency is definitely [inaudible 00:28:23] was like 25 billion CFUs per instance, it was like a shot across the balance. It was 12 years ago. And I'm freaking out because [inaudible 00:28:33]. You can't go run 5 billion CFUs per day or people gonna be having a [inaudible 00:28:41] reaction or getting thrown out of dinner parties 'cause they're farting and having to go to the bathroom all the time.

So what I can tell you is that we have enough data now in healthy people that if we go to, even, 100 billion CFUs per day that we're not seeing any adverse effects. We're usually with this ... How much of that is actually ... adhering how much of it is actually having an impact versus 40 billion, 50 billion or even 10 billion for that instance. So that's another one that's gonna be interesting to see how that evolves. There's obviously, particularly on the retail side in this race to see who can come out with the highest potency with most strains and we'll see how that goes.

Gazella: Right, yeah. Well, I think that was a difficult question and you answered it brilliantly. So now it seems like many probiotics on the market are actually synbiotics because they combine pro and prebiotics. Now, what's your view about this combination and why are more companies going in that direction? And am I right, are companies going in this direction?

Brown: Well, here's my criticism of that and I like synbiotics. I think the whole concept is an interesting one. On the retail commercial sense, it's been difficult for consumers to wrap their head around a probiotic and then also there's this concept called prebiotics and then again for people who are listening, a prebiotic is basically something that acts as a food for probiotics to feed on and grow and encourage growth even on their own.

The issue that I have with a lot of products that combine probiotics and prebiotics, whether it's FOS, GOS, XOS now is another one that's used. Now these are basically complex sugars. Really, for all intents and purposes, kind of fibers. All of the FDAs now said that they are probably not gonna qualify to make the cut.

The problem is that if you look at the studies on the prebiotics, the dosages are way higher than what you're gonna put into a capsule.

There are some probiotic products that I've seen that have ... that are powders or that are in the sachets where you can actually get the prebiotic up to a dose that actually has any meaningful effect clinically.

So remember with prebiotics, we're rack out a low of a gram and many of the studies were as high as 10 to 15 grams. So again, really important to sort of ... And I know this is a challenge for people who are in clinical practice because they're trying to treat some patients with what they think is the best, but it's really an issue of, again, getting back to sort of ... Does the company make an attempt to sort of match up the dosage of the prebiotic that actually showed an effect, a positive effect on probiotics? And that's a challenge. That your delivery yet [inaudible 00:31:50] in capsules, it's under dose. You don't get enough of the prebiotic.

Gazella: Yeah, that's really interesting because I was not aware of that. So, that's a good heads up there. Now you talked about safety, but are there any contraindications that clinicians should be aware of? Direct contraindications that says, "This patient should not be on probiotics"?

Brown: The area that I'm most cautious about ... I used to think it was premature infants, very low growth weight infants, but there's been enough research. When you ask, probably why the other thing too, that would be our [inaudible 00:32:24] list of things that have really reached critical masses, prevention of what's called Necrotizing Enterocolitis and in very low growth rate entrance ... fascinating and it worked. It's basically saving lives is what we are talking about. The death rate from that is quite high. So used to saying, "Hey, these kids are born ... GI tracts not really developed." That's a potentially dangerous use in that population.

The answer to that is "No, actually. It's actually good." I would still continue to encourage on healthcare professionals to be very selective in strains that they use in people ... HIV positive, AIDS, people with really severe immune deficiencies. Cancer patients who ... technically more advanced cancer. Be very selective and try to get to the best of their possibility, look at the data and say, "Okay, this is strain that actually was used in that population and works." That would not ... Those two populations are ... that collection of population severely immunocompromised people is not one that I could, probably just use any probiotic supplement. Particularly multi-strain, high potency without doing any sort of research.

I'm very selective and usually do one strain or two strains in that population that I feel have enough safety data.

Gazella: Yeah, that's good advice. Anything else that you'd like to add on the topic of probiotics for listeners that you'd like to leave them with?

Brown: Again, I just think that it very, very important to first and foremost, and I'm repeating myself. First and foremost look at if you're using it for specific use. We didn't even get into female genital urinary tract health nursing. Really amazing stuff going on in that area. Your oral use of probiotics to actually, finding that they're populating in the vagina and that you're getting significant effects, which is amazing. We used to think you'd have to use everything with ... through a vaginal, pessary type of an effect. So that's it.

I think again, trying as much as possible to deal with companies that are trying to ... that are working with strain suppliers or strain suppliers that are manufacturing products for them that are looking at the essentials that we talked about at the beginning. It's really, really important to me. And also again, trying to insist that companies refer back to the data on specific strains as opposed to just saying "It doesn't matter, you can use anything you want." I'm horrified when I go to professional lectures and I hear ... For instance, medical doctor getting up and saying that it's [inaudible 00:35:14]. So it goes against every thing that is accepted in the probiotic world. So, again, a lot of white noise in this area. Healthcare professionals are going to be as susceptible to it as consumers are but that's a couple of areas where I think you can sort of cut through that and try to get to what really has been shown to be effective and safe.

Gazella: Yeah. I mean, it's a big topic for sure. We're going to have you back to dig in a little bit more deeply on some of these topics, but I want to thank you for definitely shedding some light on this important topic, and helping us get through it. And I'd also like to once again thank the sponsor of this topic, who is Allergy Research Group. So Dr. Brown, thank you again for giving us all this wonderful information and I hope you have an awesome day.

Brown: Thank you Karolyn.

Aug 14, 2018

This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.

In this interview Natural Medicine Journal's editor-in-chief, Tina Kaczor, ND, FABNO, and Steven Sandberg-Lewis, ND, DHANP, discuss the integral role of the gut microbiota in mood and cognition. A review of how the gut and brain communicate through both the nerves and gut microbial metabolites is discussed. They also talk about how intestinal permeability and brain permeability are associated and what you can do about it. As a naturopathic clinician with over 40 years' experience, Sandberg-Lewis shares some clinically useful pearls along the way. 

About the Expert

Steven Sandberg-Lewis

Steven Sandberg-Lewis, ND, DHANP, has been practicing since 1978, teaches gastroenterology at National University of Natural Medicine and has a private practice at 8Hearts Health and Wellness in Portland, Oregon. He lectures, presents webinars and interviews on issues of digestive health.

He is the author of the medical textbook Functional Gastroenterology: Assessing and Addressing the Causes of Functional Digestive Disorders, Second Edition, 2017. His column Functional Gastroenterology Bolus appears regularly in the Townsend Letter.

Within gastroenterology, Sandberg-Lewis has special interest and expertise in inflammatory bowel disease, irritable bowel syndrome, small intestine bacterial overgrowth (SIBO), hiatal hernia, gastroesophageal and bile reflux (GERD), biliary dyskinesia, and chronic states of nausea and vomiting. He lives in Portland with his wife, Kayle. His interests include mandolin, guitar, writing, and lecturing.

Transcript

Tina Kaczor, ND, FABNO: Hello, I'm Tina Kaczor with the Natural Medicine Journal. I'm speaking today with Dr. Steven Sandberg-Lewis and our topic is the gut-brain axis. Dr. Sandberg-Lewis has been a practicing clinician for over 40 years now and he is the author of Functional Gastroenterology: Assessing the Causes of Functional Gastrointestinal Disorders, and that has come out in a second edition as of March 2017. He's also adjunct full professor at the National University of Natural Medicine. Dr. Sandberg-Lewis, thank you so much for joining me today.

Steven Sandberg-Lewis, ND, DHANP: You're welcome.

Kaczor: Alright, so I think our talk about the gut-brain axis is extremely timely because of the media attention now given to the bacteria and the effect of our microbiome on our physical ailments and I think it's beginning to look at how it effects the brain both cognition and mood as well.

And so, what I'd like to do is really start at the beginning and can you just give us a quick overview of what exactly do we mean when we talk about the gut-brain axis?

Sandberg-Lewis: Yeah, naturopathic medicine seems to always be at least 30 years ahead of the rest of medicine. We've been talking about this a long time but now we have a lot of research to back up what we talk about. So, the gut-brain axis probably has many more players than we're aware of but the ones we know about are, of course, the microbiota, a lot of people call that the 'microbiome'. But it's the bugs. About 100 trillion of them and they are, of course, not just in the colon but in the small bowel, in the stomach, which is not sterile and the oral and esophageal areas.

The true meaning of microbiome is the genome of the gut floor which has way more, at least 100X more genes than the human genome, which is 26,000. And when you put the two together, you call it the 'holobiome', which is the human genes and the microbial gene. But really, you need to do that because they interplay so much and the bugs really control our genome so intensely.

Then there's that whole genetic piece then there's all the, what we call the metabolon. What the bugs and the enteric cells make, all their metabolic products and that includes secretory IGA, short chain fatty acids, lipooligosaccharide, bacterial hormones and neurotransmitters and cytocinesis. We can talk about all those kind of details.

And then of course there's the enteric nervous system speaking to the vagus and the vagus speaking back. And there's the HPA axis and then there's the immune system and the gut. So, it's huge. It's so much talk it's deafening crosstalk.

Kaczor: It is interesting and one of the pleasures, I think, I've been practicing nearly 20 years and I know that you've been practicing over 40 eyras so, it's quite a long time to watch the evolution of thought processes in medicine as well as the population at large.

And in some of the folk medicine even, naturopathic medicine, but good old folk medicine, an apple a day and staying regular and keeping the bowels moving, it's amazing how that comes back at us and now we're talking about it in scientific terms which is fascinating to watch the pendulum swing.

Okay so, when we talk about how they communicate, you gave a little overview of some of the ways, when you mention the vagus system, what do you mean exactly?

Sandberg-Lewis: On every new patient, I like to have them open their mouth, stick out their tongue, take a look at their palatal arch and their uvula and then have them say 'ah'. When they phonate, we've all done this, check the vagus nerve. The place you can check the vagus nerve directly is there in the palate because the levator palatini muscles on either side raise the palate when you say 'ah' and when you phonate.

So, I'd like to see both arches go up symmetrically and not an asymmetrical rod. Occasionally you see nothing. The patient says 'ah', nothing happens. There's no palatal rise and you can have them do it over and over and nothing happens. So, that's a sign that the vagus isn't really firing the way it's supposed to and there are lots of ways to try and improve vegul tone. But that's a good thing to know about your patient.

The next thing is the vagus nerve gets sensory information from the enteric nervous system and the neuroendocrine cells in the gut as well as the epithelial cells. It gets input in actually 90% they assume, 90% of the crosstalk is from the enteric nervous system to the Brian through the vagus.

So, it's mostly the gut talking to the Brian and then the brain through the vagus talks back about 10% of the time. So, there's direct transmission through the nerves and then there's all the cytocinesis and other factors and neuro peptides that also speak through the humoral method.

Kaczor: So, what you're saying is the gut itself is sending signals through the vagus nerve to the central nervous system and effecting what exactly?

Sandberg-Lewis: So, yeah. It's pretty interesting what the gut is interested in talking about. Yeah, you wonder, what does my gut have to say? What does it care about? So, what the gut is saying, the 90% of impulse is going from the gut to the brain, it's talking about the shape and the consistency of the bowless of food moving through and scraping up against the ... rubbing up against the mucosa. The sheering forces of the bowless against the mucosa. That's stimulating serotonin locally but there's also this ... That's what the gut's interested in. Is, what kind of food is it, what's the shape, what's the consistency and what does it feel like as it rubs against the enteric cells?

This seems to stimulate taste receptors on the antero endocrine cells that are scattered throughout the mucosa and give information about the composition of the food, there's, again, there's all these neuro peptides and hormones, GI hormones that are released as well. But directly through the vagus nerve, we think it's mostly the gut talking about it's scratchiness of the food and the size and the consistency and the kind of food.

Kaczor: Okay. And I have to clarify for my own self, when you say 'taste receptors', you're going beyond the tongue? Is that what I hear you saying? Is this "taste receptors" that you say along the GI tract, how does that work?

Sandberg-Lewis: Air quotes, well, our genius in our midst, Paul [Calmens 00:08:18], he's been telling me for years that there are taste receptors throughout the entire gut. And especially most pronounced is the bitter, bitter receptors. And I've tried to go into the research and find out what exactly they do. We don't know a lot about what they do but we know that bitter receptors are not just in the tongue and the mouth, they're throughout the whole gut and they seem to trigger the release when they're stimulated. They trigger the release of ghrelin and glucagon peptide one which have to do with blood sugar balance and hunger and my guess is, Flip Wilson used to say, "The devil made me do it" when he did something that he thought was nasty.

But I really think that in many ways, the GI flora and the food that we eat interact to create cravings so that the body can get what it needs. And if you get more ghrelin, you get hungrier. And certain other, like GLP, maybe you're gonna create more sugar.

It's really important, of course, to eat food ... I think this is why Indies think it's so important to eat foods that's close to nature because once you get these synthetically modified foods or their consistency and their flavor and their compositions is altered, it probably throws off these natural mechanisms that tell us when to eat, when not to eat, when our blood sugar is fine, when it needs to go up or down. So, these are really finely tuned things.

Kaczor: Yeah, it's interesting in context, again, of traditional medicines because it automatically makes me think of Ayurvedic medicine and other traditional practices that naturally balance the flavors on the plate, that's a big part of making sure each meal is healthy in that tradition. So, let's talk about the microbiotas some more.

You mentioned briefly that its metabolites are part of the talk between the gut and the brain, can you elaborate on that?

Sandberg-Lewis: Yeah. First of all, I wanted to mention that the metabolic byproducts, the products of the microbiota, it's huge, it's huge. And Emerson Mayor's book, the gut-brain connection, he makes a quote that 40% of the metabolites in human blood are derived from gut flora, which blew my mind completely.

And so, I said, "Where is he getting that?" And I looked, I found it in two or three different articles. And so, to me, that means 40% of our blood chemistry is derived from the intestinal flora. And that makes sense since there are at least 10-to-1 more of them than there is of us in terms of cells. But I never really put that together.

So, there's these metabolites in our blood derived from the flora that do fine tuning of eating behavior, mod, blood glucose, digestive secretion, absorption, motility, just it's mind blowing. It's so important and it makes sense. You can understand that when you go ahead and even just take a broad spectrum antibiotic, we know that greatly increases the risk of kids and even adults, getting inflammatory bowl disease, especially Crohn's.

Just so many effects on immunity and the balance within the body if we knock down the bacteria or alter them or decrease their diversity. So, pretty important, pretty major stuff that everybody's been messing around with since the 1920s and '30s with antibiotics.

Kaczor: Mm-hmm (affirmative). Yeah and you mention a metabolite that caught my attention because I think it's at least in our naturopathic circles, we're paying a lot of attention to the role of that lipopolysaccaride and the LPS, for short. Can you talk a little bit about that? Because I feel like that's, as far as I can see, getting a bit of attention these days in how the gut and brain effect one another.

Sandberg-Lewis: Yeah well, I'm glad it's getting attention, it deserves it. You know, every physician knows about LPS in one particular way and that is, it is the cause of septic shock. It kills people if the LPS is high enough. What we don't usually hear about and we're starting to get more and more research on is, what about physiological levels of LPS when it's not super high?

Sandberg-Lewis: LPS is used in research, they inject it into lab animals to activate the NF kappa B pathway of inflammation and there's a tremendous amount of it. These are from the gram-negatives. The gram-positives also have an inflammatory precursor like this, which is the peptidoglycan. But, mostly we talk about the gram-negative because it's so potent and there were a million copies or so of LPS in each gram-negative microbe and it's not just something that gets emitted when the bug dies, it's also just when it's replicating or if you take an antibiotic and weaken it a little bit, they don't have to die to give off LPS.

And it's thought that in the adult human gut, you have up to a gram of LPS, a thousand milligrams at any one time. So, it's a major player. There's a lot of it and it can trigger the Zonulin pathway, which leads to intestinal permeability, hyperpermeability, which we know is related to autoimmunity and allergies.

Obese humans have up to a three fold increase in LPS compared to lean and maybe some of that also dove tails with the fact that obese adipose tissue has 10X as many macrofacies. So, you got a lot of esocine activity, a lot of TNF alpha.

Kaczor: Mm-hmm (affirmative).

Sandberg-Lewis: And different types of enteric flora have different amounts of LPS. Or even different potentiates. So, antero bacter are thought to have some of the most potent LPS that can be up to 1,000X more potent than some of the other gram-negative bacteria.

So, this is a major toxin, it's a major provoker of inflammation and pre radical activity in all kinds of changes.

Kaczor: So, how does LPS effect the brain directly? Since, I hear what you're saying and I know even in experimental animals LPS is a common way to reliably instill an inflammatory process in a lab animal. So, it's clearly a very potent, inflammatory molecule. How does it effect the brain?

Sandberg-Lewis: So, the bacteria, we get some bacteria trans locating into the blood but they usually get called out after they travel through the portal vein to the liver by the cooper cells. At least if the liver's working well. You're not gonna have a lot of bacteria in the blood but the bacteria can still effect the central nervous system, even if they don't cross the blood brain barrier and never even get there.

First of all, one mechanism is that LPS and the inflammatory cytocinesis that it induces include interleukin one, interleukin six and I mentioned TNF alpha and they can actually up regulate the transcription of these cytocinesis in certain discrete areas of the brain.

And then one of the things that happens with that is, within the brain you get an up regulation of indoleamine dioxygenase, which is that enzyme that converts tryptophan to kynurenine and that can move further to quinolinic acid, which is neurodegenerative. Although, there's quinolinic acid, which is also has a positive effect.

So, depending on how it goes through the pathways, you can have neuro degeneration up regulated. And studies show that depression, anxiety and insomnia can issue from high levels of quinolinic acid. So, there's that.

There's also cognitive deficits and in my book, very important, is increased visceral sensitivity. All the functional disorders of the GI tract, there is increased visceral sensitivity meaning, people perceive their own motility and movement within the gut as pain or strong discomfort. And man, those patients are strong to treat because if you start to activate their GI tract and get it moving again after it's been atonic for years, then they're complaining that they're up all night with abdominal pain. And that's a tough one, we're trying to learn more about how to deal with visceral hypersensitivity.

But, it's thought that LPS is one of the things that triggers that too.

Kaczor: So, I have a two part question. I guess, in our clinical assessment of LPS, is there a means, I mean, I know that we could do testing for small intestine bacteria overgrowth through breath testing but, is there any blood test, I guess is what I'm thinking? Can you tack on any blood test to gauge LPS levels and the second part of this question is, what do we do about it?

I suppose treating the gut in a totality dysbiosis present, is the short answer. Any clinical pearls are certainly welcome.

Sandberg-Lewis: Yeah. So, you can, this is available, you can measure LPS. You can measure LPS binding protein, I believe as well. And you can, in your patients, you can, of course, measure zonulin, which gets up regulated by LPS. So, yeah. By all means, start experimenting with that and then see if you can get the levels down.

Now, yeah. I'm known for spearheading along with some other really busy physicians and researchers. The treatment and in our case, more the natural treatment, of small intestine bacterial overgrowth, you just can't get away from it. It's so key to, we used to say, "Death begins in the colon" when I was in school in the 1970s and now, I think it makes sense to say, "Disfunction and autoimmunity begins in the small intestine". It's just associated with so much and that includes neurodegenerative diseases, like Parkinson's as well.

A practical thing, yeah. Learn how to test for, interpret and treat ... Use your testing and learn how to treat SIBO. Both the hydrogen, methane and hydrogen sulfide types. And don't throw out the yeast with it either because they often go together and get that metabolite base 40% of the blood. Get it into a functional mode instead of a dysfunctional mode.

Kaczor: Mm-hmm (affirmative). Mm-hmm (affirmative). Yeah. And I know, I will say that, you lecture and write a lot on the clinical aspects of this. So, anyone who wants further information can certainly start Googling you and find lots and lots to followup on. I do want to ask another question because this issue that we are in for the Natural Medicine Journal this month is a special on the microbiota and the microbiome. How do probiotics specially effect the gut-brain axis?

Sandberg-Lewis: I don't know that we have enough yet to really have a great answer. Although, there are some docs out there that really have a strong handle on the strain specific effects of probiotics and people like Jason Hawrelak who is a ND and teaches at Western States and practices in Australia, he has totally got that covered. So, I would highly recommend looking at his website Jason Hawrelak, Hawrelak. But I mean, we know that there are studies that show that fermented foods significantly reduce anxiety, especially social anxiety.

And there's a lot more research going on on strains, specific things that show that there are specific effects on anxiety and depression. But it's still really early so, I can't say I have a really good picture of that. When people ask me about probiotics, I usually say, "I don't know anything about probiotics". They don't believe me but, yeah.

Kaczor: So, is it accurate to say that you advocate the whole foods diet, plenty of prebiotics in the form of fibers and resistant starches and things like that and then trust that if that is done well and consistently and then, of course if there is other treatments to kill undesirable bacteria etc. but complimenting ... I mean, the way to encourage the good bacteria is to give the prebiotics more in your view?

Sandberg-Lewis: Well, the problem is a lot of my patients, because they have overgrowth, they can't tolerate prebiotics and fiber. So, when I first start working with them, we can't really use those things except very specific types. We know that partially hydrolyzed program seems to be actually beneficial for people who have overgrowth, sometimes used along with rifaximin in treatment of hydrogen SIBO and it increases the effectiveness of that.

But, there's some GOS's that that may also be well tolerated. But that's a problem in the beginning because if you have overgrowth and then you feed them with a prebiotic, then it just increases symptoms and problems. So, it's a fine balance, it's a fine balance. But, yeah. I really encourage my patients to eat whatever fermented foods, probiotic foods that they tolerate.

So, we use lactose-free, fermented dairy products, we use pickled items like kimchi or sauerkraut, the real stuff not the fake stuff. The refrigerated kind. Or homemade. And things like that. I think all traditional groups of people around the world have their own probiotic foods. Some of them pretty hard to even relate to, like haggis in ... where is that? Scotland. Where they eat the goat stomach that's fermented. Fish and rotten fish in the northern areas of Europe.

There are some really interesting things you'd think, "Why the hell would people ever invent that food?" But these things have tremendous fermentative capabilities. And one thing that I'm sure NDs understand this but it comes up a lot with patients asking, they'll say, "So, you don't want me to eat any fermented food, right? Because I already have ... You want me on a low fermentation diet". And I say to them, "Well, no that's not what I want you to do". Unless you have a histamine sensitivity and you can't handle foods that are fermented, I want you to use those things because if you eat a high fermentation diet that has carbohydrates that are easily fermented, that produces gases. Hydrogen, carbon dioxide, maybe ethanol, methane, hydrogen sulfide in the gut and causes distention and pain and changes the stools and can cause bloating.

But if you eat a food that is a fermented food, the gases have already come off into the atmosphere in the process of fermentation and now you're just getting all the bacteria and the great metabolites without the gas that causes the symptoms. I think that's an important differentiation.

Kaczor: Well, yeah that's a great way to put it. To help them and us understand it a little bit. One last question, we'll end on a fun question, when you hear the term 'gut reaction to something', because we're talking about the gut-brain axis and someone says, "I used my gut" or gut instinct, gut reaction, what do you think?

Sandberg-Lewis: Well, I'll bet physicians with different backgrounds have different ways of interpreting that but clearly if 90% of the input in the gut-brain axis is coming from the gut and if you think about it, if virtually every neuro peptide and GI hormone that's produced in the gut effects insulin and blood sugar and we know the brain suffers within minutes from blood sugar that's too low whereas the other organs may not care for quite some time and oxygen as well, of course, to the brain within three minutes.

There are major effects on life and death related emotions that take place when the gut is feeling like something is wrong and it's gonna make more jittery molecules instead of more serotonin and gaba.

And that's gonna have very rapid effects on the mood and on the functioning of the person's nervous system.

Kaczor: Mm-hmm (affirmative). Alright well, I sure do appreciate the time you took to talk to us today about this. It is a huge topic and I am excited, as a naturopath that everything is coming back to a source, the GI tract, I mean and we've always been taught that we have to remedy the gut and get that in order before we can really keep someone in an optimal health state.

So, sometimes that's harder than others and I do appreciate the time it took to enlighten us today with the gut-brain axis and it look forward to talking to you probably in the realm of gastroenterology again in the future.

Sandberg-Lewis: Great, let's do it.

Kaczor: Alright, take care.

Sandberg-Lewis: Alright, bye.

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