Functional hypochlorhydria is a condition we see so often, yet Prilosec is a top ten medication: what’s the disconnect? Probiotics: which ones, how much, combo or single strain? What does the research really show probiotics are actually doing? Is there any truth to probiotics colonizing the GI tract? And what about soil-based probiotics, any reason to be jumping on that bandwagon? What is the correct lab test for identifying pancreatic exocrine insufficiency (PEI), and what is the optimal range? Is there any utility to testing fecal fats? What enzymes (vegetarian or animal-based), botanicals and other interventions are appropriate for addressing PEI?
Thomas G. Guilliams Ph.D. earned his doctorate from the Medical College of Wisconsin (Milwaukee), where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies, and is an expert in the therapeutic uses of nutritional supplements. As the Vice President of Scientific Affairs at Ortho Molecular Products, he has worked with thousands of integrative and functional medicine clinicians, and has developed a wide array of products and programs that allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients. Tom teaches at the University of Wisconsin- Madison School of Pharmacy, where he holds an appointment as an adjunct assistant professor, and at the University of Minnesota School of Pharmacy. He is a faculty member of the Metabolic Medicine Institute (formerly Fellowship in Anti-aging Regenerative and Functional Medicine).
References discussed during Dr. Guilliams podcast:
- Strategies for the Management of Gastrointestinal Disorders Road Map
- Upper GI pH in young, healthy men and women
- Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women
- The use of betaine HCL to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria
- Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria
Kara Fitzgerald: Hi everybody, and welcome to New Frontiers in Functional Medicine. I am your host, Dr. Kara Fitzgerald and today I am really excited to be here with Dr. Tom Guilliams and let me give you a little bit about his background. He’s one of the really smart, behind-the-scenes guys in the functional medicine community. You may know him, but if not I’m really excited to be introducing you to him. Dr. Guilliams is a PHD and he earned his doctorate from the Medical College of Wisconsin where he studied molecular immunology in the microbiology department. Since 1996, he’s spent his time studying the mechanisms of actions of natural-based therapies and is an expert in the therapeutic use of nutritional supplements. As Vice President of Scientific Affairs at Orthomolecular Products, he’s worked with thousands of integrative and functional medical clinicians and has developed a wide array of products and programs that allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based, and effective tools for their patients.
I just want to throw into Tom’s bio that he happens to be the author of the Standard Roadmap series of books. This is a great, great, great resource for us. I have actually dog-eared copies of his books in my office here. We’re going to be talking about the newly released GI Roadmap book today and we’re going to be actually talking about some concepts from that book today. He’s also got a pretty fabulous HPA book. It’s specifically, it’s called The Role of Stress in the HPA-Axis In Chronic Disease Management. It’s just a great book and I will hopefully be podcasting with Tom on that in the future. So let’s look at a great immunology book too, Supporting Immune Function: A Lifestyle and Nutrient Approach. These aren’t huge tomes, folks. These are really clinically-friendly, you know, relatively slender volumes, however they’re potently evidenced, informed, and there are lots of clinical Monday morning actionable things for us. I think Tom’s done a really good job of gleaning what we need to know as clinicians. Meaty, but also user-friendly. So check those out.
Tom’s also a teacher at University of Wisconsin School of Pharmacy where he holds an appointment as Adjunct Assistant Professor and he teaches also at the University of Minnesota School of Pharmacy. He’s on faculty at Metabolic Medicine Institute, which is formally the fellowship in anti-aging regenerative, and functional medicine.
Tom, welcome to New Frontiers.
Tom Guilliams: Thank you, Kara.
Kara Fitzgerald: Just move into the microphone a little bit.
Tom Guilliams: Okay, can you hear me?
Kara Fitzgerald: There you are. Yup, yup. Yup you’re great, stay there.
Tom Guilliams: Okay.
Kara Fitzgerald: Listen, I just really appreciate those Roadmap books and I hope that clinicians take it to heart and decide to buy these because you’ve really done a great job. I know you just got through telling me that you spent a year writing this GI book and that you reviewed over 1000 pieces of literature and I get it and I want to pick your brain. I want to pick your brain on it and talk about a handful of really important issues. We don’t have enough time to get into everything that’s in this book but let’s just jump in and begin a discussion around digestion and specifically let’s talk about hypochlorhydria. You know, give me an overview of it and then I’ll throw some questions …
Tom Guilliams: So, well thank you. This is an area, obviously GI is a huge area where many, many clinicians have been told for years, you know, treat the gut first, understand the gut, and the area of, when we think of hypochlorhydria or achlorhydria, not making enough stomach acid or maybe making no stomach acid, this has been kind of one of those things that if you’ve been around the functional medicine, integrative, alternative medicine community has been a discussion for several decades, some people assuming that everyone has low stomach acid or certainly low stomach acid as you age and then something needs to be done about it, either you need to change the diet, add something to the diet, supplement or use some sort of acid during a meal or whatever. When you actually look into the literature and you say okay, what’s the evidence out there and how are people measuring stomach acid in the first place? Well when you look at the way this can be measured, of course, you can get a capsule–
Kara Fitzgerald: Yup.
Tom Guilliams: Something that’s called a PH capsule, a Heidelberg capsule, and you can, tethered to a string, put it in the stomach and you can actually look at the PH. It sends out a little radio signal to a computer and you can actually see the PH in the stomach and I don’t know if you’ve done this, but this was somewhat popular in some of the alternative medicine clinics for years–
Kara Fitzgerald: Yup, yup.
Tom Guilliams: People looking at that, and–
Kara Fitzgerald: Yeah it’s–
Tom Guilliams: Go ahead.
Kara Fitzgerald: Well I would refer to it. There was somebody here locally doing it and there’s also the string tests that you can do in-office. I forget who created that. I want to go grab, I actually have one in my cabinet, I still have a handful of them where you would do a colorimetric, you’d apply–
Tom Guilliams: Oh right, right.
Kara Fitzgerald: Pull it out, I don’t know if you remember that one. So that was popular too some years ago.
Tom Guilliams: Right and that’s just a very generic sort of like a PH strip type test–
Kara Fitzgerald: Yup, exactly.
Tom Guilliams: Whereas the Heidelberg or the PH capsule you could have it send every 15 seconds. You could see the change, the PH of the stomach and that plus other things like taking capsules or tablets that have something easily to measure, like, let’s say riboflavin, but the capsule or tablet itself is PH sensitive so when you consume that based on the PH of the stomach only certain amount of riboflavin will end up in the urine and then you can sort of measure that. So that’s the way it’s done in the literature, and when you look in the literature and ask the question, how many people have fasting, so sort of fasting levels of low stomach acid, and typically this is defined in literature as having a PH at fasting levels above three.
Kara Fitzgerald: Right.
Tom Guilliams: So usually you want somewhere below three. Probably healthy people have a PH of fasting at around one. So when you look at that, the literature tells us that about 10% of the population seems to have fasting levels of hypochlorhydria and–
Kara Fitzgerald: Let me just define that again, Tom, really quickly. So fasting optimal PH level is, again, what?
Tom Guilliams: About … Well, in healthy subjects it should be about one to two.
Kara Fitzgerald: Okay.
Tom Guilliams: But generically they say less than three.
Kara Fitzgerald: Less than three.
Tom Guilliams: But I think what people would say is sort of that mark in the sand of when you’d be determined as hypochlorhydric when you’re above three.
Kara Fitzgerald: Okay got it.
Tom Guilliams: But as we know, optimal probably is going to be closer to one to two. So if you look at the population studies, they say about 10% of the population may be above three at fasting levels and this doesn’t seem to be that much higher as you age. There was some groups like eight older Japanese women that had really higher levels for some reason, but generally what we see is about 10%. However, you don’t really need a lot of stomach acid when you’re fasting.
Kara Fitzgerald: Yeah.
Tom Guilliams: So that is not a very good functional test. So even in the Heidelberg test, the best tests that are typically used is where you put the hydrochloric capsule in the stomach, you look at the PH, and then you use some kind of bicarbonate to quench the acid and then you see how long it takes to re-acidify the stomach. And then this can be done in repeated bouts to kind of see how fast that occurs, and that’s really a little more functional test. So what I actually looked at in the literature is okay so, who’s actually looking at that kind of information? Let’s say with aging or whatnot.
And it turns out that I found two papers done by the same group at University of Michigan where they took young individuals, they actually did this two studies a little bit apart from each other, but it was the same design and they looked at young people and older people and what they did is they did the Heidelberg test. They had a capsule in the stomach and they gave them a meal. Unfortunately the meal was not exactly what we would call a very helpful meal. I think it was like a cheeseburger and hash browns. But what they found was essentially that, again, at fasting levels both the older individuals and the younger individuals had similar low PH, about one.
Actually it turned out that the older people had a slightly lower PH, so more acid actually. But after they ate they both saw their numbers jump to about five or six range, which is what you see when you eat a meal, and the difference, however, was that in the younger individuals they were able to re-acidify very quickly, within an hour or even two hours they were back down around two, a PH of two, whereas the older individuals, it took them sometimes up to four hours or longer to get the PH back to its fasting levels. And so really, I coined the term functional hypochlorhydria in the book, to define this idea that looking at fasting levels, not just in this case, but fasting levels of other things as well, we see postprandial glucose having a problem usually before we see fasting glucose, which here we’re seeing that once you challenge the stomach acid production with a meal, as you age, you seem to have less and less ability to re-acidify.
So the question is where in that window do we start seeing protein digestion being inhibited or the ability to break down and solubilize iron and calcium and zinc and be able to reduce the levels of bacteria, and the answer is we don’t know, but it seems like from those two studies done in older and younger that gradually the ability to re-acidity after challenge is going down and likely that is driving some of the decrease in bioavailability of certain nutrients and maybe some of the other GI issues that we list as malabsorption.
Kara Fitzgerald: Well listen, let me just ask you a couple of questions. First of all, I don’t know that my in-office string test that I experimented with has any reliability, hence, you know, I don’t really use it anymore. I go … Heidelberg is great, but it’s really not done much. It’s actually pretty onerous and it’s not, in fact, it’s not really cheap. It was expensive for me to refer my patients over there. So I generally go with clinical science in symptoms of hypochlorhydria or I’ll look at on a stool test maybe increased compounds in the gut, these short-change fatty acids that are produced, these specific ones. I mean, how are we going to make this diagnosis in a reliable way? Do we just assume that it’s happening or do we look at gas and bloating, et cetera? But in your read, how are we nailing this down that it’s actually happening?
Tom Guilliams: So in reality, you’re right. Most people aren’t doing the Heidelberg test. They’re not looking at other clinical measures. They’re using sort of empiric or anecdotal kind of things. We know that some of the assumption that we can see in, let’s say reduced protein digestion, maybe like you said putrefaction in short-chain fatty acids, which are sort of a residue of having undigested peptides–
Kara Fitzgerald: Yup.
Tom Guilliams: That could be a sign and symptom, gas and bloating, these other kinds of things. I think empirically supplementing or giving betaine hydrochloride has been probably very common way that a lot of clinicians have done this.
Kara Fitzgerald: Well doing the challenge, doing that whole challenge protocol and titrating up.
Tom Guilliams: Right. And the assumption is, and of course, like I wrote right in the book, I actually kind of outline how clinicians usually give betaine hydrochloride at higher doses and kind of look at their symptoms. There’s really nobody’s that’s symptomatically looked at that and evaluated it in sort of a clinical trial to really evaluate the efficacy of that. There’s obviously thousands and thousands of clinicians that have done that and believe that that’s a good measure of knowing when someone may need that additional acid and based on, usually postprandial symptoms.
Kara Fitzgerald: Has anybody looked at using HCl, just observing what exogenous HCl does to Heidelberg? I mean, has that been investigated at all?
Tom Guilliams: So that’s an interesting question. So you’d assume that with all these thousands of people over decades having done this that somebody would have done that and unfortunately nobody in the functional medicine community seems to be really interested in that data yet. But I did find drug companies that were interested in that–
Kara Fitzgerald: Mm-hmm (affirmative).
Tom Guilliams: And the drug companies who are interested in that are companies realizing that there’s a huge population on proton-pump inhibitors, which are obviously inhibiting stomach acid, and at the same time giving drugs that require an acid environment for proper bioavailability. So there was a couple different studies that were done where they took healthy subjects, in this case put them on PPIs, specifically to block stomach acid–
Kara Fitzgerald: Right.
Tom Guilliams: And then to see what would happen when they gave them betaine hydrochloride what happens to the stomach PH. And so they put Heidelberg capsules into healthy individuals, put them on PPIS. Well they were on PPIs for several days prior to that, and then the morning of the study they put them on the last dose of PPI to stabilize their PH at about five, so they wanted to keep it at a hypochlorhydric place, which is obviously the intent of having a PPI, and then they gave them 1500 milligrams of betaine hydrochloride in two capsules, so two 750 milligram capsules, and what they saw was the PH of the stomach went from about five to about point five in about three minutes or four minutes, so it was almost instantaneous. A few people took a little bit longer but most people were down there below one in less than five minutes.
Kara Fitzgerald: Wow.
Tom Guilliams: And of course, because you still have the PPI onboard, it took a while to quench that and so they went back up after about an hour to two hours, they were back to their PH of about five and they followed that study with a second study showing that the acid soluble drug that they were using did in fact absorb better when you combined PPI with hydrochloride. So we do know that it does acidify. We don’t have good data on the combination of that and not-fasting, so a meal and betaine hydrochloride so–
Kara Fitzgerald: That’s pretty … Yeah, that’s pretty remarkable when you consider that we’re prescribing this whole titration. Capsules are generally somewhere in the neighborhood of 500 milligrams so literally I talked to a new patient yesterday who was taking with another clinician, she was taking 15 caps. That’s just astonishing to me. And we look for that slight warmth sensation to indicate that ones been taking too much and she wasn’t experiencing that so she kept increasing and so finally the clinician who she was working with told her to stop at five caps. But you know, even that from this interesting study, that’s all we’ve got suggests that three is very sufficient, although as you point out they weren’t looking at it with food. I think that’s a big deal.
So listen, let me ask you another question, a couple questions. One, if you could send that reference and then if anybody wants to read those two studies I’ll just pop it on the site with this podcast. The other thing is, is that Prilosec is a top 10 drug in the United States. Everybody is on it. Everyone’s on this drug. So we’ve got this global hyprochloridic situation. And actually the explanation, the colloquial explanation given is always that patients are making too much stomach acid, so let’s shut it down. And yet, we know from the research that you’ve just cited and everything you’ve just said, that is in fact not the case. People are hypochloridic. So what’s going on here?
Tom Guilliams: So the other side of that is, like you said, the idea that the assumption is that when you’re having esophageal reflux that you’re getting the heartburn and the pain that that’s associated that that therefore must be due to over-production of stomach acid.
Kara Fitzgerald: Yeah.
Tom Guilliams: And therefore … And the obvious reason that we believe that is if you block stomach acid, the pain goes away. So it seems very intuitive when we think about it that way. But if you actually look at the data, just ask yourself the question, of course, using Heidelberg and other tests, actually this study was done at USC where they took 1500, almost 1600 patients with symptoms of GERD and they looked at their average fasting gastric PH and they found that there was really no difference between those that were suffering with GERD and those who weren’t suffering with GERD, meaning there was no change in the stomach acid. The difference is that they were having more reflux and it doesn’t really matter what your stomach PH is, let’s say relative one, two, three, or four, or whatever, all of that is too acidic for the esophagus.
Kara Fitzgerald: Yup.
Tom Guilliams: So even if it’s not adequate for the stomach, if you’re getting any reflux you are going to have, the esophagus is not designed, the cells are not designed to handle anything really that’s not neutral. So the issue has nothing to do with the amount of acid that’s produced. It has to do with the fact that it’s in an inappropriate place where there’s no mucus barrier, which is in the esophagus. So interestingly when they looked at that, this is actually a study looked at those individuals that had more supine, so as they’re laying down, more supine-related reflux or GERD symptoms, they actually were statistically more likely to be hypochlorhydric.
Kara Fitzgerald: Okay.
Tom Guilliams: Now there’s some theory behind this and that is if you’re not making enough stomach acid, the stomach works harder and longer to digest the food before it releases it into the duodenum and the extra and perhaps postural effects, as well as the extra working of the stomach, actually produces more reflux. Obviously that’s not really been studied and looked at in detail, but that’s the theory behind why somebody perhaps with lower stomach acid could get more reflux, even if that reflux PH is at three or four or five, that’s still going to be a problem for the esophagus. So it has nothing to do with the notion that there’s any relationship between low stomach acid production or high stomach acid production in this case and reflux. However, if you completely shut off stomach acid production and your PH of your stomach is five or six, then you’re going to reduce the likelihood that any reflux aid is going to cause symptoms. So there is a relationship between shutting off stomach acid altogether and having lower symptoms, but it really doesn’t, as you recognized, doesn’t address any root cause. The root cause is obviously something else. It’s not high levels of stomach acid production.
Kara Fitzgerald: Yeah. That’s just really, I mean, and we’ve known that in integrative medicine forever that it’s not, unless there’s a tumor present or something of that nature, which would be rare.
Tom Guilliams: Right.
Kara Fitzgerald: So there is something else going on, hypochlorhydria obviously being a possibility here in some of these cases, and then anything else to add to that? What else we might be looking at?
Tom Guilliams: Well I think the baseline of that is unfortunately, and as well as you know, because there are so many people on these drugs, getting them off of them and trying to convince them, because there usually is a rebound–
Kara Fitzgerald: Yes there is.
Tom Guilliams: And all these factors that occur. They haven’t really changed their dietary patterns. They haven’t changed whatever the underlying issues are so figuring out what those likely are while you’re tapering them off and doing the kind of things that you want to do is a challenge, but in the long-run you’re more likely to get at those root causes. But as you know, there’s quite a few people that find it very difficult to get off PPIs, especially after being on them a while, and it’s hard to get them not to believe that over-production of acid is not a problem because as soon as they go off the PPI their symptoms come back.
Kara Fitzgerald: Right.
Tom Guilliams: So that boomerang idea is hard to get out of the clinician and the patient’s mind.
Kara Fitzgerald: That’s right. That’s exactly right. And if they’ve got any damage to the esophagus or any evidence of metaplasia there’s this really significant fear. So listen, root causes. Just name some of the biggies that you came across.
Tom Guilliams: Well for GERD you’re talking about, or for–
Kara Fitzgerald: Yeah.
Tom Guilliams: Yeah so I mean obviously anything postural, lower esophageal, sphincter issues. A lot of them are diet, I mean, sometimes you’ve got to find out some people have nightshade kind of intolerability, you have to look at those kinds of things. Eating late at night and postural issues where you don’t have … Obesity’s part of that in some cases. Caffeine, so you know you have to start looking down the list of some unusual things sometimes you’ll look at … Peppermint can sometimes, if it’s not enteric coated or if you’re using peppermint tea that can be a problem. So there’s a number of different things that may be listed there that you want to look at. We actually have a chapter in here that talks about that. We deal with mostly lifestyle related issues, alcohol intake, you know. These are all kind of things … I don’t think in doing this particular research I came across anything spectacularly new, but I think a lot of times because the PPI is so available and before that the H2 blockers, people aren’t even thinking anymore about sort of the original things that we always knew in the lifestyle inducers. So I think going back and asking those questions, and I’m sure yo might have others that you’ve come across, but those are things that I think a lot of people just ignore, some of the things that we’ve known about for a long time.
Kara Fitzgerald: And I think in functional medicine we do really a great, great, great job at addressing GERD and also hypochlorhydria, just sort of the collection, the constellation of issues here, associated gastritis, et cetera. I think we do. But yes in some individuals it can be extremely challenging to taper them off their PPI.
So let’s talk about enzyme function, pancreatic, exocrine status.
Tom Guilliams: Insufficiency?
Kara Fitzgerald: Yeah insufficiency, but just give me the lowdown on changes to pancreatic function and what we might be looking at there.
Tom Guilliams: So when you start looking at the clinical picture on anything related to pancreas or pancreatic exocrine insufficiency, it seems to be clinically related, or diagnosed primarily by lipid malabsorption, perhaps because in humans we produce a lot of protease, a lot of amylase, but the amount of lipase that we produce is on the lower end and as we progressively lose pancreatic exocrine function, lipid absorption seems to be the first sign of that. Whether or not it’s just because it’s easier to measure, it’s probably that case.
So when you’re thinking about the overt signs of chronic pancreatitis or fibrosis or something like this, typically you’re looking at fat in the stool or other ways of measuring fat malabsorption related to low enzyme output and pancreatic exocrine insufficiency. A lot of those studies are not really that fun to do. You have to collect your stool for sometimes three days straight, all your stool for three days straight, and diet that has a very fixed level of fat in it so that we can measure how much is actually being absorbed versus how much is coming out in the stool. Obviously that’s not something that some people like to do, what most people like to do.
So as it turns out probably the way that’s the best now is the measure in the stool of fecal elastase, it’s actually pancreatic elastase one that you find in the feces. It’s actually a protease, but it … So it’s not a lipase but it’s a protease that generally is not degraded by the other proteases, so it’s very stable and when you find pancreatic elastase in the stool, it’s a very good measure of sort of the overall amount of enzymes that have come out of the pancreas. So this is very common. You see several labs producing or have this test within their stool tests, pancreatic elastase, and essentially that level, if it’s really low obviously it tells us that we have low levels of pancreatic enzyme output and it is now somewhat diagnostic of the disease pancreatic exocrine insufficiency, or PEI sometimes it’s called. But what we know is that if you look in the literature and ask the question, well who else has low levels, you know, if they’re not diagnosed with PEI, who else has this? And there’s a list of people and what I discovered was that, again, as we age, we’ve done a couple studies where younger individuals have a much higher level, maybe a level of about 575–
Kara Fitzgerald: Yup.
Tom Guilliams: And as you age it goes down and down maybe 50, 60. You start to see people below 200. Even some people below 100, which is sort of the fixed definition of sort of acute PEI–
Kara Fitzgerald: Mm-hmm (affirmative).
Tom Guilliams: And maybe above 200 it’s considered quote normal that, you know, how many lab tests are thought to be normal when they’re really not normal.
Kara Fitzgerald: Right, right.
Tom Guilliams: And so somewhere between 200 and 400 is likely a sign that the individual is producing less overall pancreatic enzymes and likely could use some help. Obviously in the case of PEI, the standard drug therapy if you want to call it drug therapy is pancreatic or pancrelipase, an animal-based concentrate of pancreatic enzymes given to them in various forms and those types of products are also available to clinicians as dietary supplements.
Kara Fitzgerald: Yup. So that’s really, that’s a very useful pearl, folks, if you didn’t catch that. You know, that optimal pancreatic function is measured by elastase one would be greater than 500 and that’s what they’ve seen in younger individuals, and yet the reference limit is at 200. So if you’re looking at stool tests and you see your patient somewhere between 200 and 400, as Tom just mentioned that should be a flag that something is sub-functional.
So what about looking at fecal fats? Is that a useful marker.
Tom Guilliams: So I mean I think that’s going to correlate. I think we … I don’t know if there is … Some of the labs will perform that, but that’s highly dependent on the meal.
Kara Fitzgerald: Yeah.
Tom Guilliams: So unless you’re controlling the exact amount that’s coming in, like I said, the actual way to measure it in the literature, the old gold standard used to be 100 grams of fat per day for three days straight, collect all the stool and then they do a complete analysis of that to find out what’s coming out. There’s another way you could do it, which is a radio-label fatty acid, which you consume and then do a breath test. So those are … But the ones that you would see, say, in the standard sort of stool analysis, CDSA-type, it might be … If you see it above reference range, that might be a clue when you’re seeing other things, but unless there was a standard meal consumed that data is a little bit limited in how you can interpret it.
Kara Fitzgerald: Although the reference ranges should be a variety of healthy individuals consuming a variety of different meals, so there may be a little bit of control for it there, but I hear you. So fecal fat, not a bad specimen to use, but just consider those caveats, not as reliable as elastase one, which is really easy to get.
Tom Guilliams: Right.
Kara Fitzgerald: Alright so let’s talk about … I want to talk about … Actually let me just say one thing quick and then I want to get into treatment. We also see, and I think the literature suggests, that certain changes, like certain bowel diseases are also associated with kind of ushering in pancreatic insufficiency, excuse me. So I think, and since the literature is really fresh in your mind I want to defer to this, but an IBD PEI association or an IBS PEI association, what have you noted there?
Tom Guilliams: Yeah there really isn’t strong correlations between those, I mean … In the case of IBS, there’s not a strong correlation with, I don’t think I’ve seen anything with pancreatic elastase specifically that there’s any groups. But what we do see is that anywhere you … The overt one would be celiac disease. They do see that in celiac disease, but if you think about how celiac disease creates sort of this villous atrophy and the villi have enzymes that help break down the proteases that come out, so trypsin needs to be hydrolyzed in order to be activated from trypsinogen and that’s actually an enzyme found on the brush border, so if you have villous atrophy you have much less enzyme activity. So you see individuals with celiac disease, the comparison is there. Now we also know that other inflammatory conditions in the gut could cause villous atrophy. Probably at some level they also reduce the enzyme output.
Kara Fitzgerald: Mm-hmm (affirmative).
Tom Guilliams: But I don’t know that I’ve actually seen statistically linked relationships between them, I think probably because it hasn’t been looked at, not because it may not be there.
Kara Fitzgerald: Right, right. Okay.
Tom Guilliams: Like I would assume, perhaps, especially probably Crohn’s–
Kara Fitzgerald: Yes.
Tom Guilliams: And you see, probably Crohn’s more than you see … would probably have some effect on PEI but it may take a while to know that because if you’re measuring pancreatic elastase until you get that level down to a certain amount you may not see sort of an overt sign of that, but you probably have a less efficient digestion. But also in many cases bowel transit time is going to have probably more of an effect on that, on digestion and absorption, so you might have enough enzymes, but if you have a very quick bowel transit time you don’t have time to digest. So there’s other factors than just pancreatic sufficiency that would affect that digestion and absorption eventually.
Kara Fitzgerald: Right, right. Okay. Thanks. Let’s talk about intervention.
Tom Guilliams: Okay.
Kara Fitzgerald: What’s your recommendation for, you’ve identified insufficiency using lab and clinical.
Tom Guilliams: So–
Kara Fitzgerald: What’s our go-to?
Tom Guilliams: So I mean right now there’s … The only intervention that we have really is to add back enzymes at this point. I should say, looking at obviously the diet, other sorts of things, bowel transit time like I just mentioned, if there’s other issues there you want to deal with those. But from a direct intervention standpoint overt PEI there are approved pharmaceuticals, there are pancrelipase products. Essentially what pancrelipase is, is a combination of protease, amylase, and lipase from [horsain 00:35:18], from pig pancreas, that has a slightly higher ratio of lipase activity than say a standard pancreatic product. But available to anybody would be the same thing pancreatin, which a combination that can be provided or [horsain 00:35:31]-
Kara Fitzgerald: Yup.
Tom Guilliams: And then you could augment that with, from a protein digestion standpoint, you can augment that with Bromelain, which is a pineapple enzyme, papain, which is a papaya enzyme, and a series of some kind of, they’re called vegetable, but really fungal analog enzymes. Interestingly, plants and fungi don’t break down lipids very well so most of them are found on wood or woody-type substances so the best way to get lipase is actually through the animal sources because we don’t get a lot of lipase activity outside the animal world, not a lot of other organisms consuming a lot of fat. So the blend of all those options sometimes we can add pepsin, which is a protease enzyme derived from pork stomach lining, because that comes from stomach lining. Sometimes you’ll notice that people add ox bile–
Kara Fitzgerald: Yup.
Tom Guilliams: Or bovine bile. That’ll create a more digestion with fat. Or choleretics or cholagogues, which are mostly plant compounds that stimulate bile production and bile secretion.
Kara Fitzgerald: Yes, such as? Give me–
Tom Guilliams: Well I mean the classic one would be like artichoke, that’s probably the one that we think of the most in the literature as far as its ability to stimulate. Milk thistle, dandelion root, are others that are very common. I mean actually fat is a choleretic and cholegogue. So, and bile is a choleretic and cholagogue, but from a plant standpoint those are probably the ones that people think of the most. There’s a few others that are used in other, but I’d say those are the three that are used most in Western herbal medicine.
Kara Fitzgerald: So in your opinion, do any of these, actually you know what? There’s a whole world of enzymes. There are so many different kinds of enzymes out there in the landscape claiming to do a myriad of things, but just thinking about enzymes for digestion, I mean, what are the ones that really jump up the list for you as being kind of the effective, of course–
Tom Guilliams: I think clinicians should have a few in their formulary because I think, and you know I think you really should have an animal-based enzyme product and those are the ones that have been used the longest. They’ve got the best track record and they’re the closest to replacing human pancreatic enzymes that we have. So pancreatin, probably a high concentration like an eight x or a full strength, something like that. And then, obviously there are people that for whatever reason, religious reasons, other reasons, don’t want to have animal products and they should have sort of … Probably the other gambit would be, the other side of that would be a sort of a list of fungal analogs–
Kara Fitzgerald: Yup.
Tom Guilliams: And sometimes they’re called veggie enzymes but they’re really technically fungal analogs. Sometimes you’ll put Bromelain, papain in there–
Kara Fitzgerald: Right.
Tom Guilliams: So I think clinicians should have several different, and maybe even several different doses of some of those, and then, again, we have to see how the patient feels after taking them–
Kara Fitzgerald: Right.
Tom Guilliams: And that’s going to be probably the best … I mean, if you just go back to like, Beano, we’ve been advertising that, I don’t know if that’s the name of it, but you know, that’s a fungal analog, beta-galactosidase that breaks down some of the carbohydrates in beans that helps prevent fermentation.
Kara Fitzgerald: Yup.
Tom Guilliams: And we know it works so a lot of people use it. It’s very effective.
Kara Fitzgerald: Right.
Tom Guilliams: So those I think can be very effective and the symptoms, in that case people can go noticeably notice the symptom changes that they have. Papain, if you go the other way, a meat tenderizer, you actually put it on the meat and it starts digesting the protein. So we know functionally they work. The question is, at what dose does the patient feel some sort of symptom relief? And that’s kind of where the experiment is.
And I actually think, as I’ve been doing, because I actually do some product development as well, I’m actually making a recommendation that, you know, that we use smaller amounts of digestive enzymes but we use them multiple times through the meal, meaning once the … Because obviously all of these enzymes have to be mixed with the meal itself and it comes out in the duodenum as the meal leaves the stomach, so combining them, perhaps eating them at the beginning of the meal, maybe one in the middle and one at the end of the meal is a better way to do it than trying to do it all at the beginning or … Well we used to tell people take your digestive enzymes with the first bite, but actually it may be better taking it in the middle and end of the meal–
Kara Fitzgerald: Yeah that makes sense.
Tom Guilliams: Because then it’s mixing where the PH of the stomach is maybe higher, like five or six, the enzymes won’t be destroyed as easily and they’re likely to mix with the food right before they leave and go into the duodenum.
Kara Fitzgerald: Makes total sense, it does, and we’ve often advised patients, actually it’s sort of an older approach, which it makes sense, you know, that you divide your HCL up throughout the meal and doing it with enzymes makes a lot of sense as well, and for the quote veggie enzymes or the fungal analogs you’re talking about, one could use cholagogues with them or recommend taking some sort of higher fat meal with it to meet more of the needs–
Tom Guilliams: Right. And obviously in that case if you’re trying to help with and you want to stay away from animal products, you can’t add ox bile or whatever, but you could add like [secholaride 00:41:37] or cholagogues to stimulate bile and maybe some natural fats in the meal like olive oil or something like that.
Kara Fitzgerald: Yup. Yup. Now listen, let me just ask you before we move on and talk a little bit about probiotics. Now as far as the HCL titration that we all use in functional and integrative medicine, do you, I mean, does that still make sense to you or is in your careful read on all things hypochlorhydria suggest a different approach?
Tom Guilliams: Well I mean outside of actually measuring what’s happening there it’s a little bit difficult to know. So I think for the number of thousands of clinicians that have used that technique, and I think relatively safely we haven’t really heard of a lot of sort of backfiring.
Kara Fitzgerald: That’s right.
Tom Guilliams: I mean obviously we don’t recommend it with gastric ulcers or some things like that, but I would say right now it seems like a safe sort of empiric way to do it. I tend to caution on going too high–
Kara Fitzgerald: Mm-hmm (affirmative).
Tom Guilliams: And at this time I’m not sure where that level is. If we think of that one study that was 1500 milligrams, I’m generally cautious once you get above 3000 milligrams betaine hydrochloride–
Kara Fitzgerald: Right.
Tom Guilliams: And I will say that’s somewhat arbitrary. I don’t have a hard data to say that that level is, you know, going to be the line in the sand, but it seems like once you start getting above 3000 milligrams per meal you want to be more cautious and I’m not convinced, and I don’t know of any data that would suggest that all patients that are consuming too much betaine hydrochloride are going to get this burning sensation or kind of a nauseated feeling. I just … That’s the, what I’ve been hearing from clinicians all these years, but I don’t really have any way to confirm that besides just believing what they … So while I do outline what I call the basic protocol that’s commonly used in the book. I’m very cautious about sort of relying upon that as the only way to do this.
Kara Fitzgerald: Right. Well that study that you happened to find in the drug industry is interesting and you know as we’ve seen with quote leaky gut or dysbiosis, I mean, those are concepts that we’ve used in integrative medicine forever and there was just really no data on them at all and now there’s a leap in investigating both and they’re both very well substantiated at this point in the game. So hopefully these too, will be recognized for their importance because clearly it’s significant that we look at both.
Tom Guilliams: Right.
Kara Fitzgerald: You know what’s happening with hypochlorhydria and pancreatic exocrine insufficiency, you know early pancreatic exocrine insufficiency, and I would imagine at some point we start to investigate these in a more careful way.
Tom Guilliams: Yeah and one thing I mentioned in the book which I think is interesting is that because you’re dealing with so many people with PPIs and maybe they’re not interested in going off of them, the one thing that we do see from that one paper is that if you want to improve digestion at least marginally during a meal, it seems to be safe to give them 1500 milligrams or so betaine hydrochloride if they’re on a PPI to help them with meal time digestion because you’re basically going to be back to a PH of five or six within an hour anyway. So there may be a functional way to use betaine hydrochloride in PPI users during a meal only because you know they’re going to rebound back to where they were perfected before so it’s not like you have to really worry about that issue.
Kara Fitzgerald: That’s a really, that’s a powerful pearl, and I did ask you for that paper earlier I think so we’ll just post that citation, folks, if you want to consider using mid-meal 1500 milligrams of HCl for your patients, understanding that they’ll go back to higher PH rapidly.
Tom Guilliams: Right.
Kara Fitzgerald: That’s useful. That might actually help in tapering. Okay. Let’s talk about, this is really helpful, I appreciate this quite a bit. So let’s talk about probiotics.
Tom Guilliams: Okay.
Kara Fitzgerald: You know, there are of course a million of them and I remember when I was at the laboratory and we released the first DNA analysis using PCR analysis of stool, I really thought that we would start at that time. It was not the first release, the research had been doing it for a long time, but it was the first clinical available test using DNA analysis of the stool, and I thought we would be, at that point, leaping forward in really being able to prescribe with a greater precision, probiotics and I was incredibly wrong, so wrong about that. In fact what I learned from that experience in the lab was how important food is, not just the quote prebiotic food but you know a healthy, robust, balanced, big diet in general and taking time to eat it and so forth, but it really hit that home for me. But we still, probiotics absolutely continue to have their place and research continues to emerge and I know you’ve been deep, deep, deep into this area. You can google probiotics online and you’ll see many many clinicians who are famous coming forward and saying “This brand is the best, absolutely you’ll get 100% better if you take it,” and there’s so much misinformation and claims out there. So they are important, but what do we take, what do we do, how do we do it? What have you been thinking about in this world?
Tom Guilliams: So you know going back to that idea that if we knew what was in the gut we could all of a sudden be able to prescribe or–
Kara Fitzgerald: Yes.
Tom Guilliams: Or figure that out. And what we’ve learned is that there’s so much more that we didn’t realize was going on with that.
Kara Fitzgerald: Right.
Tom Guilliams: So our technology is growing and our ability to detect a wider array of organisms and for now we’re just talking about the bacteria but obviously there’s so much more we’re going to learn about viruses and bacteriophages, which are viruses that affect bacteria, so there’s layers upon layers upon layers of things that are there.
Kara Fitzgerald: Right.
Tom Guilliams: So one of the things, there’s a couple of caveats that we’ve learned over the years that are interesting. One is simply that stool analysis is essentially trying to figure out what’s going on in the house by looking at the garbage can and so yes, what comes out in the stool is highly, highly representated by bacteria living in the distal colon.
Kara Fitzgerald: Right.
Tom Guilliams: And not very well representated by those that are living in the much lower percentage of bacteria that are growing in the small bowel, but those organisms may have a much more profound effect on let’s say the immune system because they have a much closer access to the epithelial cells in the small intestine than any of the bacteria living in the colon, which are mostly dealing with fermenting and doing other important things but maybe not same type of things. So I think one of the things we’re learning is stool analysis is a surrogate marker and oftentimes a poor surrogate marker of what is going on in the overall sets of microbiomes in the gut, and so I think that’s one aspect.
I think obviously we’ve learned about all these little micro-niches where certain bacteria may be highly concentrated, but if you compare them to the overall gut they’re almost minuscule and hardly there at all. So, if you’re just looking at their DNA … The new thing was, the old plating idea, what can we plate out on a Petri dish. A lot of these bacteria don’t even grow on Petri dishes so we’re missing them. So looking at their DNA tells us something but even that is limited. So there’s a lot of debate about what we should actually be measuring, what ratios? Is it the filing level? Is it the entero types? Is it certain species, whatever? And then on the other side of that we have probiotics. So we have these organisms that were able to grow in these obviously huge facilities so that we can make them in high commercial available so we can dry them down and put them in capsules and consume them orally. And like I say to most people is probiotics represent a very, very, very small slice of the overall diversity within the gut and they’re highly domesticated versions of their wild-type originators.
Kara Fitzgerald: Right.
Tom Guilliams: And so one of the reasons why we have limited ability to change the gut with the handful of probiotics that we have is because of what I just said. The represent a small slice of the pie and also because of their ability to be grown and manipulated and all these sort of things they’re really not saying … We know human genomes, what genes are expressed and what genes are not expressed, change. Well if you put the originally active bacilli or whatever, that’s pick lactic acidophilus or something growing in the gut having to compete for nutrients and compete against all these sorts of things going on, they’re going to express a different genetic profile then this model culture, given all kinds of nutrients in a big stainless steel vat, that’s able to grow, but you’re optimizing everything in its life so it doesn’t have to produce the same sort of genes, and it may be genomically slightly different than what’s … We know that it’s genomically different than those that were originally isolated in humans or in the soil.
Kara Fitzgerald: Right.
Tom Guilliams: So what that means generally is that we’re limited, but surprisingly adding back probiotics can still have dramatic effects because I think it’s because they create what I call a commensal friendly environment. They tip the scales in favor of other commensals. Now they might have some of their own activities obviously, but they tip the gut in favor of commensal activity that is positive for the host.
Kara Fitzgerald: So they’re not … They’re not apparently colonizing or are they?
Tom Guilliams: Well I consider, right now all probiotics that we know of, and this includes the soil-based organisms and spore formers and all these kind of things, including [bifiteral 00:53:03] and lacto, they should all be considered transient–
Kara Fitzgerald: Yup.
Tom Guilliams: Meaning they, whether or not they colonize or can attach, they never seem to really create a permanent colony, and I think part of the reason that that disturbs a lot of people is they don’t quite understand that there is a high percentage, maybe 25-30% of the microbiome, which is transient, meaning that’s what it does. It’s supposed to come in, have some activity, and float on through and do fermentation, do whatever and just move on out. They stay in the lumen for the most part. Maybe they attach slightly to the mucus layers, but they’re intended to be transient and I think that’s one of the reasons why we have this sort of flexibility and the influence of our diet can be so immediate is because a lot of these transient microbes are part of the overall system. So I have where I talk about the idea that there’s a core microbiome. These are organisms that are much more permanent and don’t turn over very much in individuals unless you blast them with antibiotics.
Kara Fitzgerald: Mm-hmm (affirmative).
Tom Guilliams: Then on the outside you have this transient microbiome, which is fluctuating on a regular basis and then you have sort of this intermediate seasonal where you might see slow changes in that microbiome over time. I call that a variable microbiome because it varies a little bit based on the season and diet a little bit, but I think sometimes we just forget that up to 20% of the microbiome is transient.
Kara Fitzgerald: Yup.
Tom Guilliams: And probiotics are a real part of that and food organisms, whether going back to fermented foods or things like that, I don’t typically refer to the microbes and fermented foods as probiotics, although some people do, but they are still part of that transient microbiome when you’re consuming those fermented foods.
Kara Fitzgerald: So I mean would you call probiotics in their actions somewhat like prebiotics since they’re basically influencing the course of the microbiome there? I mean is that fair or are they more than–
Tom Guilliams: I’m kind of a stickler when it comes to nomenclature so I wouldn’t do that because it would create a lot of confusion.
Kara Fitzgerald: A lot of confusion, but action-wise would you say–
Tom Guilliams: Right, so that’s why I like the idea that it promotes a commensal-friendly environment–
Kara Fitzgerald: Yup.
Tom Guilliams: In the sense of a prebiotic, obviously you think of those or fibers or other components, although there are other … There’s a company that’s trying to sell a product that’s actually a bacteriophage, a virus that infects, and they refer to it sometimes, in their literature, as a prebiotic, because it promotes certain growth of supposedly good bacteria. Again, that’s going to be very confusing if we switch terms like that. But, yeah, I think the idea of probiotics … There are some that might have a slightly different effect because of their specific species or strain, they might, let’s say, produce some enzyme, or produce some sort of protein that can particularly kill off some sort of pathogen. But, I would say the bulk of these species and strains of probiotics, they share about 70 to 80% of the same overall benefit. That is what they do for other non-probiotic commensular organisms living in the gut.
Kara Fitzgerald: So, in the remaining few minutes that we’ve got, talk to me about how we want to dose. What strains are you thinking about as being the most effective? Do we go with single strains, and that kind of thing?
Tom Guilliams: Right. This is obviously when you get into the literature on this, it can be quite confusing, because you would wish that if somebody had a series of IBS patients, or IBD patients, or whatever, and you go in the literature, you assume that they tested all strains or all species of lactobacillus and all [bifital 00:57:32] strains, and they’ve somehow arrived at the ones that work best. When you start looking in the literature, you find the exact opposite.
What typically happens is, people find they do a research trial, they get their IRB to approve it, a clinical trial, and they pick some product. Oftentimes you look and say, “Why did they choose the strains or the products they chose at the dose they chose?” And the answer is, you don’t have any idea. But, if three or four labs, and one of them has a positive outcome, and the others don’t have a positive outcome, and it could be for any number of reasons, nothing to do with the product or dose, then all of a sudden the next group of people that write their grant proposal, say, “Well, we want to use the one that worked,” and then all of a sudden you start getting the same strains being used for that particular condition. And then, when you go back and say, well, how often was this strain really compared to other strains in that outcome? And you found out it’s almost never is tested.
So, I’m a little bit cautious in trying to say that there are certain strains that have really been proven to have specific outcomes in specific types of patients, because most of that is by default. There are not a lot of other comparative trials. I will say that when … The fact that you do see some very different strains having positive outcomes in a clinical trial with the same type of patient population is a completely different strain, tells me that there probably is a little bit more flexibility than most marketers would lead you to believe.
I typically think that based on the way that we get microbes in the diet, and aiding in the literature, that using multiple species at a time is probably more logical. And probably it would make sense to use lactose strains, [bifital 00:59:32] strains, and maybe even adding on there’s a couple strains that maybe like the yeast, Saccharomyces boulaardii.
We don’t have a lot of options. We don’t have this wide range of thousands of different species. We only have a very small handful. Trying to create a diversity of that is probably a better approach, than just trying to find the one strain that could possibly work. It used to be people would say, “Well, I’m going to give lactobacillus acidophilus for three months, and then I’m going to switch over to bifital bacteria, and them I’m going to switch to [lactoterei 01:00:03], or I’m gonna …” I think that’s a holdover from when early on, in the early 90’s and early 2000’s, there was only single strain products available.
Kara Fitzgerald: Right.
Tom Guilliams: So people were doing that back in those days. It sort of made sense, because you didn’t have all these multi-strain products available.
Kara Fitzgerald: Right.
Tom Guilliams: And if we have these multi-strain products available tells me that’s probably where we should go. I think dosing … We’ve got products that are dosed like one billion or less all the way up to 200, 300 billion.
Kara Fitzgerald: Yep.
Tom Guilliams: And some of the doses used in high dose therapy go into the trillions.
Kara Fitzgerald: Yep.
Tom Guilliams: What I think I’ve learned is there’s only a handful of dose response trials where they actually have taken a patient group, give them the low dose, give them a high dose, give them a placebo, and then look at the difference. Most of that data has been on related to antibiotic associative diarrhea. In both cases, the higher dose was statistically better than the lower dose, however in one study, the high dose, low dose difference was 17 billion versus four billion, and in another study it was 100 billion versus 50 billion. They were both effective.
At least in some cases, in the case of antibiotic associative diarrhea and C-diff, it does seem like higher doses are slightly better.
Kara Fitzgerald: Are better. It’s interesting because if you really think about it, relative to the trillions of players in the gut, even a quote high dose is like nothing. It’s sort of interesting to me that we actually … but I also have experienced that.
You had one more thought on that one?
Tom Guilliams: I was just going to say that clinicians should be willing to consider different doses. Realizing that, just to say that this product didn’t work, whatever, I think you should try different doses, and give it long enough to say I think this one is not going to work and be flexible to switch out to something else.
Kara Fitzgerald: Yep. The fact of the matter is, and I have not … In my experience, while understanding the amount that’s growing in our gut, it seems if we even throw 100 billion or 200 billion at our patients that’s still a drop of water in an ocean that is shouldn’t make a difference. But, the fact of the matter is, for some of my patients who are pretty sensitive, like my IBD patients in particular, I need to start them low and slow. Some of them can really flare up with probiotics that you think should be fabulous with. There is an argument that I’ve certainly experienced clinically for going lower and slow. I agree with you with the multiple strains.
Let me ask you one more question, and then we’re going to head home. That’s the soil bacteria. The so-called soil organisms that have been really pretty popular with my patients. They hear about them online and so forth, so they come in and tell me that they’ve really done well with them. If they do well, I’m like, “You know, that’s great, continue.” I did experiment with prescribing them and didn’t see and marked difference as compared to anything else I’m doing. Do you have any comments on those?
Tom Guilliams: The frustrating thing with most of these products is that they’re a bit of a mystery of what exactly is in them.
Kara Fitzgerald: Yeah.
Tom Guilliams: I was talking with … I was at the Antibiotics Association meeting last year and I was talking with the lead researcher at FDA on genetic typing of probiotics. He was scratching his saying he wasn’t even sure how to evaluate the products because normally you list the organisms that are in the product by the amount that they’re supposed to be in. If we have a product of five probiotics, we say we have the most lactobacillus acidophilus that’s at the top of the list. You’ve seen some of these products. They have like 40 different organisms supposedly, and they’re in alphabetical order.
Obviously, the bacteria aren’t in alphabetical order from high to low in there. We don’t really know how to evaluate them. The majority of the bacteria that are listed on the label, whether they’re in the product, we don’t know, but listed on the label, don’t fit the traditional definition of probiotic, which requires that they have some proven benefit in human subjects. Some of these have never been tested in human subjects. What I think is happening is people are saying, we’re taking soil based organisms, we’re not even sure how they’re … They’re not able to grow them, so I don’t want to be disparaging and say they’re just dirt in a capsule, but it’s possible it’s just dirt in a capsule, because yeah, if you go to find dirt, you’re going to find organisms. Not every organism that’s found in soil is a human benefit. I’m very skeptical of some of these products. Almost none of them have had any formal clinical trials and evaluation of the organisms that’s in them.
Based on that, I find it very difficult to give any comment on it, because there’s just no data that I can evaluate. Which is a little frustrating when the pool of data for probiotics generally is very large. But, the data that we have for them is almost non-existent.
Kara Fitzgerald: Right, right, right. Shelf-stable probiotics, are those reasonable? Have we been successful in-
Tom Guilliams: Yeah, so there’s been a lot of technology invested in companies, not only in the manufacturing of the probiotic organism in the preparation for freeze drying or whatever to make them stable, but also in the manufacturing process to reduce humidity and temperature, including desiccants in the bottle and even some fancy bottle desiccants, which are the bottle itself is a desiccant. We’ve been very successful. Obviously companies have to do a little overage. They have to add a little more probiotics to last a year. But, I tell people that … The reason we do that is because we realize everybody can’t carry a refrigerator everywhere with them. We try, as manufacturers, to reduce the need for refrigeration when possible. Those are quote shelf-stable, relative, you don’t want to stick them on your dashboard in 100 degree weather, that’s a bad idea. You want to be somewhat careful with them, and what we call room temperature they should be pretty stable.
I always recommend people buy small bottles that you will use up in a month or the time frame that you’re going to use them. This is not the time to go to Costco or Walmart, and buy a year’s supply of … it’s like I tell people, “Do you buy a year’s worth of bread at a time? No, you buy a loaf of bread at a time or your …” Think of these as short term sort of things. We should treat them, perhaps a little more careful than we treat other dietary supplements.
Kara Fitzgerald: Perfect. Thank you. All right, we’ve covered a ton of material and I really appreciate you joining me today. I look forward to having another conversation. You’ve just done so much work. You’re a real asset to the field, so thank you.
Tom Guilliams: Okay, it was great to be with you.