This week Dr. Ruscio interviews Stephen Olmstead, MD, Chief Science Officer for ProThera® Inc., who directs the company’s technical services and clinical trials. Dr. Olmstead earned his residency at Harvard Medical School, Massachusetts General Hospital and is board certified in both internal medicine and cardiovascular disease. They discuss such topics as the gut/brain connection and mental health and the microbiota.
Dr. Stephen Olmstead bio…..1:53
Gut/brain connection vs. brain/gut connection……7:24
Mental health and the microbiota…..11:47
Importance of continued exposure to microbes…..18:00
Stress, leaky gut, childbirth and the microbiota…..21:03
Bacterial and fungal overgrowths……24:46
Impact of microbiota on vagus nerve…..31:51
Quotes and sources from Dr. Olmstead’s article
• “Current research now reveals that most of the communication along the brain-gut axis is from the gastrointestinal system to the CNS and gut activities can modulate emotions, desires, and mood.” (1)
• “Evidence is now accumulating that the gut microbiota is necessary for normal CNS maturation and that it impacts neural circuits controlling motor function and anxiety behavior.” (1) (2) (3) (4) (5) (6) (7)
• “Studies in mice have found that postnatal microbial gut colonization programs the HPA axis for responses to stress.” (1)
• “Germ-free mice have a reduced behavioral, but exaggerated endocrine response to stress characterized by excessive corticosteroid and adrenocorticotropic hormone release compared to control animals with a normal microbiota and no specifi c pathogens (known as specific pathogen free [SPF] mice). The abnormal stress response can be attenuated with gut colonization with bacteria from SPF animals, and could be completely normalized by administering the probiotic Bifi dobacterium infantis. In other studies, chronic treatment with probiotic Lactobacillus rhamnosus or with a combination of L. helveticus and B. longum reduced stress-induced corticosterone and anxiety- and depression-related behaviors in mice.” (1) (2)
• “…there appears to be a time after which stress responses cannot be normalized by acquiring a normal gut microbiota.”
• “Many of the effects of the gut microbiota and probiotics on CNS function have been shown to be dependent on vagus nerve activation.” (1)
1. (10:24) http://www.ncbi.nlm.nih.gov/pubmed/18283240
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The Gut Brain Connection with Dr. Stephen Olmstead
Welcome to Dr. Ruscio Radio, discussing the cutting edge of health, nutrition, and functional medicine. To make sure you’re up today on this and other important topics, visit DrRuscio.com and sign up to receive weekly updates. That’s D-R-R-U-S-C-I-O.com.
The following discussion is for educational purposes only, and is not intended to diagnose or treat any disease. Please do not apply any of this information without first speaking to your doctor.
Now, let’s head to the show!
Susan McCauley: Hey, everyone. Susan McCauley here from EvolveNutrition.com. I am not on this episode of Dr. Ruscio Radio. But, I wanted to let you know about some audio technical difficulties we had. It’s a little static-y, so please bear with us because there is a lot of really great information. Now, on to the show!
Dr. Michael Ruscio: Hey, folks. Welcome to Dr. Ruscio Radio. I am here with Dr. Stephen Olmstead. Today, we are going to be discussing the gut-to-brain connection. Hey, doc, welcome to the show. Thanks for being here.
Dr. Stephen Olmstead: Thank you. Thank you for having me. It’s great to be here.
DrR: I have been following some of the articles that you’ve been writing for awhile now. You’ve really written a terrific series on the microbiota and various updates in that realm of research. One of your pieces that I really enjoyed was a recent piece about the new understanding that there may be more of a gut-to-brain connection than we previously understood. I definitely want to get into that conversation in a little more detail.
Dr. Stephen Olmstead bio
DrR: But before we do that, can you tell folks a little bit about you, your training, and what you are currently doing?
DrO: All right. Well, I trained as a physician. I was a board-certified internist and cardiologist, and practiced for nearly 25 years in Seattle, WA. I became interested in nutritional approaches to heart disease, in particular, and that’s sort of broadened out my interest in complementary and alternative medicine. For the past 10 years, I’ve been working for ProThera as their chief science officer. And largely through my activities at ProThera, I’ve become intensely interested in the gut microbiota; even the mouth microbiota, (or) microbiota just anywhere on your body and it’s relationship to human health and how we have symbiotic relationships with these organisms. These organisms do much more for us than we realize.
DrR: Sure, absolutely. It’s really a fascinating area of research, isn’t it?
DrO: Yes it is.
DrR: I want to provide some of our listeners with just my brief orientation to this. And if you have any points of contention, because I’m certainly open to other viewpoints on this, or anything you want to add to my preface, please feel free to follow with that. But a few things that can help someone listening to this who is not feeling well and trying to figure out what to do. I know a number of my patients have asked about, ‘Well, I think I have candida,” or “I think I have SIBO, and I’ve read that maybe I should do some neurological exercises because the brain controls gut motility. I’ve heard motility is really important for treating SIBO, preventing SIBO, potentially with candida or SIFO, which is Small Intestinal Fungal Overgrowth.
And then they also hear and read things about more gut-based therapies, like prokinetics and antimicrobials and antibiotics. I think sometimes people are confused in terms of what to do – do I do all of these things at once? Might one be better to start with?
So, here’s the way I look at this, in general. And I want to say that this is what I think will work for the majority of people – there’s almost always an exception – but I think this can give a good encapsulation for the majority of people.
So, I think the majority of people will do well to start with – and again, this is for people who are struggling with gut conditions – gut-based testing and gut-based therapies. So, if you think you might have SIBO or candida, I’d recommend testing for SIBO or candida and doing some of the therapies that are directed toward those. Some exemptions might be people who have a history of head trauma, or people who have a history of intense psychological stress or psychological abuse where psychotherapy might be needed to get past those past traumatic events. From a neurological perspective, why might it be important to start with the gut? Because I think some people are confronted with this – I’ve been told I should do neurological exercises to help improve the brain feed into the gut. I think that probably comes from some circles that look at the effect of chronic stress on the brain, and the effect of chronic stress creating what’s called hemisphericity, where, essentially to simplify it, too much stress may impede the brains ability to stimulate digestive function. And that’s true.
But I think one of the best ways, initially, we get the brain to balance itself back out, would be lifestyle, diet, and just some simple things to take stress off the body – maybe not needing to jump into a fancy neurological protocol right out of the gate. Again, I think neurological therapies can definitely help. One of the main reason that I say this, from my understanding – and sorry for being a little long-winded here, Steve, to start, but I want to give people this preface – to look at motility, which is one the main things people are concerned about, much of motility, in my opinion – from the research that I’ve looked at – is fairly local. I think one of the big things for SIBO and preventing a SIBO relapse, is the migratory motor complex, which is a local phenomenon in the health of what’s called your interstitial cells of Cajal, which also is a local immune phenomenon. Once people have looked at that, if they are still relapsing, they may want to do an advanced motility study. They may want to be screened for abdominal adhesions. After that, maybe look into brain-based therapies.
So those are a few of my opening notes for if people are struggling, how to coordinate or maybe sequence these things – how to lead in to that. Steven, any comments, feedbacks, or points of contention with that?
DrO: No, I think that, obviously, we are talking about gastrointestinal health, and we are also talking about symptoms beyond the gastrointestinal tract people – people with SIBO, people with candidiasis sensitivity often have somatic symptoms.
DrO: So, it’s definitely worth, in addition to the usual history and physical examine, it’s definitely worth in these individuals, doing a comprehensive stool analysis to get some idea of the health of the gastrointestinal microbiota.
DrO: For a long time, people have known about the connection the brain and the gut. I mentioned in some of the things that I’ve written, people have spoken about gut feelings, or to have courage, is to have guts. So, this interrelationship between emotions and brain function and gut function has been widely appreciated for a long, long time.
What we know now is that there are many neurotransmitters in the gut as there are in the central nervous system, which is pretty amazing; and that most of the information, most of the communication that’s going on, is actually going from the gut to the brain. The brain is modulating some gut function but most of the information is going toward the brain. And we now have to build in a communication between the brain, the gut, and the gut microbiota. Some of the gut’s microbiota’s effects are directly onto the gut; some of them are not mediated by the gut but are direct effects on the brain. And then it’s clear.
But also the brain issues having an effect on the gut’s microbiota. So, for example, stress. So, in animal studies – and it doesn’t really matter what kind of stress it is; it could be loud noise or painful shocks, or whatever – (we’ve seen) this invariably decreases gut bifidobacterium population. And robust gut bifidobacterium populations are important to any number of conditions – to support against things like obesity, diabetes, so on and so forth.
DrR: Sure, absolutely. I think you make many, many great points there. One of the points that I think is important to echo is how many psychological conditions – depression, anxiety – may come down to a problem in the gut. I think Michael Maes has done some really good research in that regard (1). I will link to one paper from Michael Maes looking at essentially leaky gut causing leaky brain, and that leaky brain causing inflammation that was correlated with depression. Other studies have shown that treating the gut will, as you are mentioning, will help with treating the brain. Anything you want to expand on in terms of specifics in that regard with some of the things you’ve seen in your research?
DrO: Absolutely. Leaky gut – a colloquial term for increased intestinal permeability – can be associated with inflammation, with system-wide inflammation. We know that some people with major depression have evidence of inflammation when you measure inflammatory cytokines and other molecules associated with inflammation. So, it makes sense that there is some relationship there. We also know that the microbiota can affect numbers of opioid and cannabinoid receptors, and can also have affects on neurotransmitters. So, there are a variety of mechanism whereby the gut microbiota could affect brain function and psycho-neurological function.
Mental health and the microbiota
DrR: There were two things in your recent paper that really struck me – One was the contribution of the microbiom to, essentially, modulating the hypothalamic pituitary adrenal access. I guess, via that pathway, the response rate of animals to stress based upon that development. From what I took away from that is it seemed like if you had a different microbiota in development, you may react less or more so strongly to stress. Can you expand upon that at all?
DrO: Yeah. These are studies that have been done with germ-free mice, or also gnotobiotic mice, meaning animals where you know the composition of the microbiota is. So, we know that germ-free mice are far more likely to be anxious and very sensitive, and to have activation of the adrenal cortical access, hypothalamic adrenal cortical access. Whereas normal mice display normal behavior. What’s interesting is if you then transplant the microbiota from normally behaving mice into these germ-free mice, you get some beneficial changes in exploratory behavior. They become more interested in exploration and less anxious, and you have reduced levels of brain-derived neurotropic factor in the hippocampus – so, an indicator of activation of the adrenal cortical access.
DrR: You also cite some human studies. It seems there isn’t a tremendous amount of human studies. But you cite a few human studies showing various…I think it was depression and anxiety perimeters improved after the administration of various probiotics, right?
DrO: That’s correct. The studies are thin – these are really early days, which is part of why this is so exciting; this is all new information that’s being developed. But yes, there is evidence for the benefit of probiotics, specifically lactobacillus probiotics, in the setting of depression. Among the probiotics that have been shown to have perhaps some interest in major depressive disorder include various lactobacilli species – acidophilus, kasi plantarum, sanfranciscensis, reuteri, helveticus; there’s really a lot. And then many, many of the bifidobacterium. So, I think as people start to look for disbiosis and an increased gut permeability in the setting of depression and find it, I think that they will find that these are patients that may benefit from dietary and probiotic modulation of the gut microbiota.
DrR: Absolutely. I agree completely. To pick into this a little more, it’s my understanding that probiotics don’t really colonize – I think sometimes the term is to ‘recolonize’ or to ‘colonize’ the gut; as I understand it, you’re not really recolonizing, because evidence of an administered probiotic usually disappears a few weeks after you stop administering the given probiotic. But it seems like these probiotic organisms probably have a transient affect. Amongst other things that they do transiently would be anti-inflammatory, potentially immunomodulatory. So, thoughts or comments on that?
DrO: You touch on a common misconception that I think it’s important to address. You can divide propbiotic organisms into those that are indigenous, so they normally live in the human gut, and will be there even if you’re not taking them in in your diet; and those that are transient, that are only going to be there when you’re taking them in your diet. The things is, we’ve evolved eating fresh fruits and vegetables and things we pull off of trees and out of the ground. We’ve evolved in conjunction with chronic, ongoing exposure to all these organisms. And so, for example let’s take something like lactobacillus casei. From the name you know virtually isolated from cheese, but it’s present on the skins of lots of fruits and vegetables. It does not colonize us, but we are so in need of being exposed to it conically that the indritic cells, components of the immune system don’t develop normally unless like they are exposed to lactobacillus casei. This exposure occurs prior to…it occurs while we are nursing, because moms have evolved this wonderful way of transferring their own gut microbiota to their nursing infant via breast milk. So, we get that exposure early on. So, a few things will colonize; other things, for example, bifidobacterium infantis, most of us have a predominate bifidobacterium infantis microbiota when we are nursing infants. That goes away when you wean and start solid foods. It has lots of benefits – for example, in irritable bowl syndrome, if you want to get the benefits, you are going to have to consume that is a probiotic or in the food; it’s not going to colonize in the gut.
Importance of continued exposure to microbes
DrR: Right. A couple directions I want to go from that comment: 1. It’s interesting to note, as you noted, the dependence we have upon continual exposure to microbes, and how that potentially shapes our immune system. I’ve discussed this in the past on the podcast, but there are what are know as blue zones and green zones – oceanic environments and more forest-type environments. There have been some very interesting observational data showing people in these blue zones or green zones have lower all-cause mortality, I believe a lower incidence of death from cardiovascular disease, and I believe also lower incidences of depression. And I know some of the literature now is speculating that one of the mechanisms through which this might be is because of the increased bacterial load that we have when we are in a blue zone or in a green zone. It likely may be because of the, amongst others, the immune, and potentially anti-inflammatory affects that these microbes have on and in our bodies.
So, I think that’s really important for people to be aware of. While the probiotics are really helpful, some of these things can be obtained just by having time in nature. In fact, there is probably a lot that we can get from probiotics, and we require contact with nature in order to obtain. Thoughts on that, Steven?
DrO: I don’t disagree with that at all. In fact, I think with a lot of our interventions, if we were actually eating a good, healthful diet with lots of fresh fruits and vegetables, and exercising regularly – I’m just saying, if we did have a good diet, lots of fresh fruits and vegetables, we probably wouldn’t need to take supplements to the extent that we do.
DrO: But, in one review, for example, when people looked at – this was just in terms of multi-vitamin/mineral supplementation, because I think you remember that article coming up on two years ago – enough is enough, telling people to stop wasting their money (and) get everything you need from a diet. But, it turns out, just one-in-10 Americans have a diet that would even meet minimal vitamin needs. So, yeah you can get it through your diet, but most of us aren’t going to.
DrR: Sure, and especially, I think, if we are factoring in the standard American diet, it would be supremely deficient, in both vitamins, and as you saying, many of the healthy bacteria that accompany the healthy foods.
Stress, leaky gut, childbirth and the microbiota
DrR: Something else interesting that I’ve read, and I am wondering if you’ve read along these same lines, is…this is more of a theory, but I thought it was interesting: That the stress of childbirth actually induces transient leaky gut in mom. That actually has a positive impact on the fetus, because it increases the bacterial exposure of the fetus. That helps with fetal colonization and development. Have you heard of that?
DrO: No, that’s really interesting. I’d sure like to read that article; to look at those references. Sure, I could see where that could be a beneficial thing. We know that exposure to maternal micro-organisms begins before birth. There are some studies from Spanish investigators. They’ve looked at amniotic fluid and meconium obtained at the time of C-section, so they could presumably control for contamination, and found lots of different microbes in fetal meconium and in amniotic fluid. So clearly, this microbial exposure from the mom is occurring way before birth. It occurs throughout fetal development. So, it wouldn’t at all surprise me that we get this abolis, because you get abolis just passing through the birth canal…
DrO: …of maternal flora. And, to get even more, of what is essentially transient bacteraemias with leaky gut would totally make sense.
DrR: Yeah, it is an interesting thought. I’ll see if I can dig up the reference to that, and have that accompany the transcript that we will post along with this episode. And it also reminds me of some other studies, and these to me were really fascinating. They studied a group of mothers while pregnant and then followed the offspring to, I think was, age four or five, tracking prominently skin conditions like atopic dermatitis, eczema, and I think seasonal allergies. They found that for every increased animal the mom had exposure to while pregnant – they were looking at farming mothers versus non-farming mothers…
DrR: For every increased animal that the mother had exposure to, they actually saw a corresponding drop off in the levels of skin conditions and allergies, and I think asthma also. And they showed correlations with different blood values that are indexed to the immune system reacting to bacteria in bacteria counts. Again, it just shows you the real importance of mom in the offspring.
DrO: Yeah mom, and also from what you’re saying, the general environment.
DrR: Right, right.
DrO: This gets back to the old friends hypothesis of autoimmune disease and allergic diseases is that we should be exposed to a much more robust array of antigens in our early years. Having that restricted predisposes us to autoimmune and allergic diseases. Yeah, absolutely. It’s good to live on a farm and to have pets.
DrR: Absolutely. Yeah, yeah, some of these things are simple. You know, get a dog – children with dogs and children with more siblings have less allergies…
DrO: That’s right.
DrR: …because of the exposure.
Bacterial and fungal overgrowths
DrR: Now there is another side of this I want to get your thoughts on. You read this sort of information and you almost just want to lather yourself down in bacteria…
DrR: …and maybe go crazy with the prebiotics also. But then there is this other side of people that have a predilection toward SIBO or toward candida. So, this renaissance that we see in a little bit of a higher carbohydrate diet rich in prebiotics. While it’s so alluring based upon some of the evidence we’ve been discussing, there is also this population of people – it seems to maybe be more so in Westerners – that have a hard time regulating bacteria in the gut and have a problem with overgrowth of bacteria or a fungus.
I have my own thoughts on this, but how do you reconcile sorting out what to do for what person, and how research shows that we need more bacteria, and it could be so helpful; but then for other people, they are battling problems of too much bacteria or too much commensal organisms?
DrO: This is where with what the organism. So, yes, for most of us I would venture to say all of us at some point – canadas is a commensal organism. It should be present in very, very low numbers. It’s just like in the mouth – streptococcus mutans is a commensal organism. You’ll find it…it should be in less than two percent of dental plague. But, when it get s out of hand, then it’s causing cavities. I really believe that most of the time it’s not an overgrowth. What it is is a denser than usual colonization burden in people whom are susceptible to mounting an immune response to candida. And then SIBO is a whole different kettle of fish. But it’s not bifidobacteria or lactobacillus that are overgrowing in SIBO. It’s other organisms. As you alluded to at the beginning, the problem is gut motility; what really keeps bacteria and fungal numbers down in the small intestine is gut motility, and especially these migrating motor complexes, which represent spontaneous electrical and muscle activity of the gut. So, that’s why I personally – this is just personal opinion – think there is a role for probiotics early on in SIBO. That’s because we know from animal studies that lactobacillus bifidobacteria probiotics increase the frequency of migrating motor complexes. And I would view that as helpful in SIBO.
DrR: And I would agree with you. I know there is debate on probiotics in SIBO. But there have even been studies using probiotics as a standalone treatment for SIBO…
DrR: and shown success. And also, as you mention the paper showing that it stimulates the migratory motor complex. I am definitely a proponent of probiotics in SIBO. I am a little bit more gun shy with prebiotics…
DrR: …in SIBO. What are your thoughts on the prebiotics?
DrO: Because the whole point of prebiotics is really to increase colonic populations, I would not use them in SIBO – not necessarily because inulin has been shown to be bad, but because it could potentially be bad. And so, the benefits are less clear. There is the potential to make things worse, so I would avoid them. Maybe in small amounts, like 100 mg that might be in a probiotic capsule. But, I would certainly avoid the grams of them. Really, a therapeutic inulin dose is going to be 5 grams bid twice a day if it’s going to be therapeutic.
DrR: And you make an excellent point with the dose, because I really follow these related issues quite closely, and I reference-check things because I think – and I am sure you’ve found – that sometimes things are mis-cited. Recently a paper that was touting prebiotics in SIBO – maybe I should say more accurately symbiotics, meaning probiotics with prebiotics.
DrR: But when you actually read the paper, it was about 100 mg. of prebiotic used, which is really pretty much nothing.
DrR: So, for a paper to conclude that prebiotics are safe in SIBO, but it’s based upon a dose that is so negligible, I really thought the conclusion of that paper was misleading. Sometimes you have to go in and fact check this stuff, right?
DrO: Right. Clearly the conclusion was over-broad. They should have limited it to ‘The dose that we used was not problematic.’ That would have been more helpful.
DrR: And that dose, and you’ll probably have a better handle on this than I will, but in most probiotics, there is small dose of accompanying prebiotic. Is it about 400 mg would you say that accompanies a probiotic?
DrO: Oh, it’s less than that. It’s less than 200 mg as a rule, and you don’t always have to have it, because it’s primarily used as a filler. So, some preparations use cellulose instead, which is going to be inert.
DrR: Gotcha, sure. So, I believe I reached out to someone at Klaire Labs to just double check the amount of prebiotic that was in some of the formulations that you use. I want to say that, maybe, it was 200 mg.
DrR: I mean really, really low. When you look at the prebiotic studies, as you mentioned before, you are looking at gram doses…
DrO: You’re looking grams.
DrR: Which is…you’re looking at a thousand…the conversion, you have to have a thousand milligrams to get one gram. So, to put it in perspective, having 200 mg of prebiotic in your probiotic, but the prebiotic studies are using five, seven, 10 grams, that’s a huge difference.
Impact of microbiota on vagus nerve
DrR: Another thing that I kind of wanted to get your closing thoughts on – we’ve got to wrap up in a couple minutes: You talk about the impact of some of the gut microbiota on the vagus nerve. I know one of the things that some of the healthcare consumers out there trying to learn more about this have heard about the vagus nerve’s impact on digestive function potentially on digestive motility. I’ve had some patients come in doing exercises trying to stimulate vagul nerve function, which I’m not against. But, I haven’t found them to be supremely helpful in a lot of cases; I don’t know if they’ve created a lot of benefit for people. I’m open to it, but I question it. It was interesting that you are noting that the microbiota in probiotics seem to have an affect on that. So, can you expand on that?
DrO: In terms of the mind/gut microbiota access, it appears that there is some evidence that the vagus nerve, which is, of course, iris sympathetic innervation into the thorax and abdomen, is involved with that. So, for example, there were experiments with animals where they gave them…they would do things that would make animals stressed. Like, you make them swim and they think they are going to drown, and that’s stressful. If you give them lactobacillus rhamnosus, they aren’t as stressed. You can actually see changes in GABA receptors. This effect, this reduction in anxiety and regional changes in GABA receptors was dependent upon the vagus nerves. So, if they did the same thing to the animal that severed the vagus nerve, you didn’t get those effects. So, beyond that, I am not sure how we know. But we know that these organisims simulate the production of neurotransmitters. So, presumably, the communication has mediated that with afferent fibers on the vagus nerve to the brain.
DrR: Got it. So again, the gut to the brain connection. And that’s an area where we have more to learn. But it’s interesting to see some of these findings start to merge here.
DrR: So, Steven, in closing, any kind of closing thoughts or thoughts-at-large that you have for people?
DrO: Just one thought is a question that always comes up after a talk like this is, what probiotic would you recommend. The short answer is, I don’t think we really know. But, if you wanted to use a probriotic in the setting of anxiety or depression, the best approach would be a reasonable dose – like a 100 CFU (colony forming units) a day of a multi-species, high-potency probiotic. That’s what I would suggest.
DrR: Is this more of a…because I know some of my listeners probably are familiar with the spore-forming bacillus species compared to the more lactic-acid forming, like lactobacillus…
DrO: There is no evidence that bacillus species mediate any of these connection between the brain and the gut and the microbiota. Not to say that it couldn’t happen. There is one study that looked a bacillus coagulans in irritable bowel syndrome, and certainly people with irritable bowel syndrome have a heightened perception of pain. So I’m not going to rule it out. But the scant research that we have today is basically unlocked the bacillus and bifidobacteria species.
DrR: Got you. And just to reiterate for people, the more spore-forming, or bacillus species, or I guess you would say the probiotics that are in the dirt sort-of-thing, those are the bacillus. Compared to your more classical probiotic – your lactic acid forming, which are your lactobacillus and bifidobacteriam species, amongst a couple others, but those are typically going to be the foundation of those formulations.
DrR: And was there anything else in that closing thought, or was that…
DrO: That’s it.
DrR: OK. So is there anything that you are working on that you want to make people aware of? Is there somewhere if people want to track you down and follow you where people could go?
DrO: I’ll just give people my email address – it’s [email protected].
DrR: OK, and if they have a question, they can just follow up…
DrO: I am happy to answer questions, but I don’t do (unintelligible).
DrR: It’s good that you clarified. All right, Stephen, thank you so much. Again, I want to thank you again for the articles that you are writing and research you are doing. I’ve found it really enjoyable, and I think it’s just great that we have some good minds looking at this and sharing the information. So, thank you for that. And thank you so much for spending time on the show today.
DrO: You are welcome. Thank you.
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