Hydrogen Sulfide in Health, Disease & Longevity

I always appreciate a well-justified challenge to our current thinking and a chance to build a more nuanced approach that will improve patient results. And in this month’s New Frontiers in Functional Medicine® podcast, Dr. Tom Fabian delivers just that with a fascinating topic of hydrogen sulfide: a compound we clinicians typically think of as the “problem child” behind certain difficult SIBO cases. However, there is a LOT more to know about it, such as its ability to convert to potent antioxidant compounds, and its therapeutic roles in cardiovascular and metabolic disorders (diabetes and NAFLD), neurodegenerative disorders, and more. But how do we start to both broaden and nuance our approach to assessing hydrogen sulfide status? And what interventions can not only supply the substrates for beneficial hydrogen sulfide production, but also help achieve that all-important balance between too little and too much. Listen in to find out, and let us know what you think with a comment, review and rating wherever you listen to New Frontiers! ~DrKF

Hydrogen sulfide has typically been thought of as a problematic compound that is causatively associated, in high levels, with conditions such as small intestinal bacterial overgrowth and IBS-D, ulcerative colitis and even colon cancer. However, a growing amount of research is now exposing the beneficial side of hydrogen sulfide – particularly its ability to generate potently-protective antioxidant compounds. This characteristic, as well as its ability to improve vascular tone in a manner similar to nitric oxide, is deeming it worthy of investigation as a therapeutic against hypertension, for stroke prevention, and other types of vascular dysfunctions. It is also being considered for other conditions such as diabetes, NAFLD, neurodegeneration, osteoporosis, and IBD.

In this podcast hour, Dr. Fabian walks us through what we need to know about the current research on this intriguing molecule. He explains how to think about assessing a patients endogenous hydrogen sulfide status and reviews some familiar functional medicine tools that can be used to optimize levels (and not just by supplying dietary sulfur compounds!). There are some cautions and caveats to know along the way, of course. Ultimately, this emerging thinking is important and will change the way we think about hydrogen sulfide in clinical practice.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to a New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And yes, indeed, today is no exception, I am excited to once again be talking to my colleague and my friend, Dr. Tom Fabian. Let me tell you a little bit about him. He’s a leading expert on the role of microbiome in health, immune function, chronic disease, and aging. As a translational scientist his primary focus is on the clinical application of microbiome research in the integrative and functional medicine space. He received his PhD in molecular biology from the University of Colorado at Boulder, and has worked as a biomedical researcher in the biotechnology industry. And more recently as a consultant in the microbiome testing field. Currently, Dr. Fabian serves as a consultant and science advisor with Diagnostic Solutions Laboratory, and he is also a science advisory board member with Designs for Health. In addition, he is certified as a nutrition therapy practitioner by the Nutrition Therapy Institute in Denver, Dr. Fabian, welcome to New Frontiers.

Dr. Thomas Fabian: Thank you so much, Kara. It’s great to be here today.

Dr. Kara Fitzgerald: It’s always great to be with you. I know we’ve done… And we’ll pull all of this information over into the show notes. We’ve had multiple podcasts, we did a great webinar together, we’ve had fabulous conversations, your conversations are always interesting to people, they get a lot of listens and we are often pinged with questions and today’s is going to be no exception. We’re going to be talking about all things hydrogen sulfide and the microbiome. Tom the first thing is… give me a general overview of hydrogen sulfide and the picture as it’s evolved over time, talk to me about it.

I want you to include, at some point, I want you to divert over to how we think about it in functional medicine. I mean, honestly, hydrogen sulfide if you say it, if I were in my clinical rounds meeting with the physicians and nutritionists on my team and I brought up hydrogen sulfide, everybody would think of it as a bad actor. How do we get rid of it? It’s like the problem child cause of small intestinal bacterial overgrowth that we can’t measure, et cetera. And we would be wanting to think about interventions to knock it out. But talk to me about a high-level overview, how it’s evolved with time? And then at some point let’s move over to thinking about it through the functional medicine lens and how we might need to be really corrected.

Dr. Thomas Fabian: Absolutely. I’d be happy to talk about that. So really this is a topic I’m really excited about for various reasons. It really does involve all this new information that’s coming out recently from the research in the microbiome field. But hydrogen sulfide has a long history in health and has changed over time. So historically going back say to the 1700s, 1800s, it was first recognized as a potentially toxic gas. So in excess at high levels, it actually can cause symptoms that are similar to cyanide poisoning. So it’s thought to be at really high levels. It’s obviously very hazardous, poisonous, and even at high enough levels, it can cause death. So it’s the classic, I think they refer to that as the Janus-faced type compound, where you have both the good side and the bad side.

Dr. Kara Fitzgerald: How would one accumulate? How would we get to fatal levels of hydrogen sulfide?

Dr. Thomas Fabian: So, it’s produced… You think of the geothermal type sources-

Dr. Kara Fitzgerald: Yeah, yeah.

Dr. Thomas Fabian: … Logical sources, but particularly biological sources. So, historically for example swamps, places that have a lot of decaying organic matter, a lot of those microbes that are present can produce large amounts of hydrogen sulfide that can get trapped. So if it’s suddenly released and an individual working in an industry where that is a potential risk factor could get exposed to high levels. So it’s really more of an-

Dr. Kara Fitzgerald: Industrial.

Dr. Thomas Fabian: … Industrial type concern as far as the toxicity at that level. But then there’s also the physiological levels that have been suspected to be a problem in certain scenarios. So primarily in the research, the concerns other than the high toxic levels that are fairly isolated cases, the concerns really tend to be around effects in the colon in particular, because that’s from research we know that’s where it’s produced in the highest concentration, by bacteria in the colon. And we certainly can talk about what’s known currently about which ones tend to produce it and under what circumstances. So one of the key themes here, I think that I want everyone to understand is context is really important. So of course we all know that nothing is strictly good or bad, typically. Hydrogen sulfide is really one of those cases, but it’s in terms of potential negative health effects, the best documentation so far, and it’s still controversial in terms of what levels, what circumstances might cause problems. But those conditions primarily would be ulcerative colitis and then colon cancer.

So there are some concerns there and high levels of hydrogen sulfide may be an issue for those patients, might even play a causal role. That’s the part that’s still not well worked out yet. Then we certainly know that in the SIBO field, that’s one of the three gases that are focused on. And more recently some of the research that’s been noted has suggested a possible role in IBS-D so diarrhea dominant, IBS potentially. And so, we can talk more about that as well. But really what I wanted to do is because of this focus in our field on the negative aspects, there’s this huge growing literature, especially in the last five to 10 years on the potential benefits and physiological roles of hydrogen sulfide.

Dr. Kara Fitzgerald: Dwarfing the negative body of literature?

Dr. Thomas Fabian: Potentially yeah. And I think it has to do with overall the levels that are produced, how it’s produced and certainly location. So high concentrations in the colon, that’s really where the best evidence is that there could be a negative effect. So that’s something we can talk about, certainly in terms of what’s known from, how we can influence that in a therapeutic level. And there’s a lot of ways that we can do that that I think are not really well known among clinicians yet.

Dr. Kara Fitzgerald: Okay, all right.

Dr. Thomas Fabian: So I’m really excited to talk about the therapeutic end when we get to that part of it. But as far as the benefits, there was really a landmark study that came out in, I think it was around 2014, 2015. And I actually have this in front of me, it was titled endogenous hydrogen sulfide production is essential for dietary restriction benefits. So that was really one of the first studies that linked interesting hydrogen sulfide to potentially mediating the benefits of dietary restriction in promoting longevity.

Dr. Kara Fitzgerald: What dietary restriction – is this general caloric restriction or what were they doing?

Dr. Thomas Fabian: It was all around caloric restriction, but they did narrow that down in subsequent studies, particularly to the sulfur amino acids, especially methionine. So as we all know, methionine is certainly of course key to the methionine cycle for methylation, but then that actually also feeds into the transsulfuration pathway, which we can talk about as well, because that’s a major source of beneficial hydrogen sulfide. So this is really the first look at some effects that it may have in promoting longevity. But prior to that, the picture started changing in the 90s.

Dr. Kara Fitzgerald: Let me just make sure I got this then hold that thought. This study suggests that the presence of hydrogen sulfide, GI produced hydrogen sulfide, not endogenously produced hydrogen sulfide, dictated-

Dr. Thomas Fabian: No, so that’s actually a point definitely want to clarify that hydrogen sulfide unlike the other gases that are commonly produced by the microbiome like hydrogen and methane, is actually also produced by our own cells.

Dr. Kara Fitzgerald: … Yeah.

Dr. Thomas Fabian: So that’s considered, and that was actually discovered for the first time in the 90s. And that started this whole new wave of research where prior to that, it was just thought of as a toxin. Now we know it actually has a really expanding set of clinical roles, physiological roles that are really important for health, particularly antioxidant status, et cetera.

Dr. Kara Fitzgerald: Okay. So this would be both endogenously produced and also produced in the GI tract. Both sources of hydrogen sulfide can have benefit?

Dr. Thomas Fabian: Potentially, yeah. There’s now research showing that up to a point hydrogen and then it’s highly reactive. So it reacts with other chemicals, particularly other hydrogen compounds. And that group together is called reactive sulfite species or RSS. So as a group and they can be interconverted, so different types of sulfur compounds can then be used to generate hydrogen sulfide when needed and hydrogen sulfide can be used by the body to convert to these other compounds. And these compounds are thought to have a really strong antioxidant potential. So the idea is that the sources of sulfur particularly diet and the microbiome can influence health, because it can influence systemic levels of not only hydrogen sulfide but these reactive sulfur species.

Dr. Kara Fitzgerald: … That are beneficial. I mean, we often think of ROS is not good actors, but RSS have a role in health.

Dr. Thomas Fabian: Exactly, and that’s the challenge in communicating. This is a rapid paradigm shift. A lot of this research has come out just in the last say, seven years or so, where now they recognize that, of course there’s the reactive oxygen species which we’ve known about for a long time, that can be pretty damaging. Then there’s the reactive nitrogen species, which are mixed, but they can be damaging as well. And then there’s the reactive sulfur species that is widely now thought to be protective and actually protects against the other two types.

Dr. Kara Fitzgerald: Interesting. Okay.

Dr. Thomas Fabian: And they’re actually calling that whole group of the ROS, the RNS and then the RSS or the reactive sulfur species. The term that’s being thrown out now is Reactive Species Interactome or RSI.

Dr. Kara Fitzgerald: Oh, fascinating. Oh, that’s great. By the way folks, on the show notes, we will link to all the papers that Dr. Fabian’s mentioning. All right, so it’s an important player, might be a piece of the mechanism of caloric restriction benefit which is wildly fascinating. I mean, you know I’m interested in looking at epigenetics and biological age as measured by DNA methylation. And there was a caloric restriction in animal models and in a relatively new study, looking at humans doing two years of caloric restriction, it significantly showed slowed down one of the DNA methylation clocks, and could this be a piece of the puzzle having sufficient hydrogen sulfide? Could this be a little something that we want to… Those of us interested in longevity and you are as well, could this be something that we want to be considering about or thinking about?

Dr. Thomas Fabian: Absolutely. Yeah, yeah. That’s been verified in several studies now. So that study I mentioned the one that was published in cell, I think in 2015 or so.

Dr. Kara Fitzgerald: Mm-hmm.

Dr. Thomas Fabian: There have been a several follow up studies since then that have confirmed that wide variety of animal models, hydrogen sulfide signaling (that is the process that is referred to), is now thought to be a central process because hydrogen sulfide is now thought to be a key mediator on terms of signaling in the stress responses. There’s research, for example, showing that it can activate Nrf2, which is the key transcription factor that helps to turn on genes that are involved in protecting against oxidative stress. Also turning on genes involved in phase two detoxification and also anti-inflammatory effects as well, so when we think of aging, we think of inflammaging there’s evidence that physiological hydrogen sulfide actually can be anti-inflammatory.

Dr. Kara Fitzgerald: So fascinating. All right, everybody wants to know how we increase them, but I don’t want to actually get to that conversation yet. I want to talk about it in pathology, age-specific diseases or excuse me, age related conditions. Is a hydrogen sulfide deficit implicated, or… I mean, how do we think about that?

Dr. Thomas Fabian: Yeah. There’s growing evidence now that various ways to measure hydrogen sulfide itself and then the related compounds. So again, these are fairly interchangeable and that’s why it’s referred to collectively as this RSS, the reactive species interactome. So essentially what they found and really interesting key studies recently showing that both in aging, hydrogen sulfide production goes down the genes from the transsulfuration pathway that help produce it go down, the positive effects from hydrogen sulfide in terms of these altered proteins. We can talk a little bit about that as well, there’s a lot, I’m trying to keep it not too technical but hydrogen sulfide mediates some of its benefits through modifying proteins. And I mentioned the Nrf2, and that’s how it can activate the Nrf2. So these sorts of changes have been noted not only in aging itself in some studies, but also in specific diseases.

And they tend to be more the cardiometabolic type conditions so, certainly with cardiovascular disease, that’s probably the best studied in terms of the overall role of hydrogen sulfide and also the beneficial effects of therapeutic hydrogen sulfide. So there’s actually a review article that just came out within the last month or so in nature reviews, cardiology summarizing this status of this research on hydrogen sulfide in cardiovascular disease. So from that article and others, they talk about the fact that hydrogen sulfide has similar effects to nitric oxide and that it helps with vascular tone.

Dr. Kara Fitzgerald: Interesting.

Dr. Thomas Fabian: So it can help reduce blood pressure and it’s being explored as a potential therapeutic for hypertension, for stroke prevention, it’s also been noted as protective in cardiac hypertrophy, IE enlarged heart, our left ventricular hypertrophy, atherosclerosis, arrhythmia, and other types of vascular dysfunctions as well. And then when you add that to its known effects on reducing inflammation in certain circumstances, et cetera, and it’s thought that it can even help with the endothelial barrier.

So it reduces that permeability that can happen when blood vessels are not quite functioning optimally. So there’s a lot of different ways now that it’s been documented to potentially have beneficial effects in cardiovascular disease in particular, but also in diabetes, in non-alcoholic fatty liver disease, it’s being explored in neurodegenerative diseases as well, osteoporosis, IBD, it’s even been explored as a potential therapeutic in COVID 19, and a few others as well. With really the main one that doesn’t fit that picture again, being potentially cancer. So that’s where if patients as is the case with antioxidants in general, there’s concern of the use or overuse of antioxidants for patients who have cancer.

Dr. Kara Fitzgerald: Is that just a hypothetical or is there any evidence?

Dr. Thomas Fabian: There is some research to suggest that high levels of hydrogen sulfide and then its effects particularly in activating genes, like the Nrf2, can potentially help reduce the effectiveness of cancer therapies, for example.

Dr. Kara Fitzgerald: Yes. Interesting. Okay, so then would this be exogenous hydrogen sulfide? How would this actually happen that your hydrogen sulfide would be so high, that Nrf2 would be so on, that you would influence your chemotherapeutics?

Dr. Thomas Fabian: So, the concern is mostly in terms of using what are called hydrogen sulfide donors. So this is a class of compounds that have been explored now. And some of them I think are actually now in clinical use under various circumstances. So there’s pharmaceutical hydrogen sulfide donors, and then there’s natural hydrogen sulfite donors. So of course the natural ones would be things like, N-acetylcysteine, compounds from garlic such as derivatives of Allicin, which is one of the key compounds active compounds in garlic. And then also the isothiocyanates, which are key components in Cruciferous vegetables. Now it’s not clear at this point, whether those dietary sources would be consumed in high enough amounts to really have a major effect, but the use of therapeutic hydrogen sulfite donors is primarily at this point being explored more for cardiovascular disease, some of the others that I mentioned with caution around use in cancer.

Dr. Kara Fitzgerald: … And that’s more of a hypothetical use, or they do have evidence in humans or animal models.

Dr. Thomas Fabian: There certainly are studies in clinical trials, I’d have to go back and look, but I believe some of them may have been approved already.

Dr. Kara Fitzgerald: Okay. Really? That’s very interesting.

Dr. Thomas Fabian: Yeah. It’s actually a pretty vast literature now.

Dr. Kara Fitzgerald: Yeah.

Dr. Thomas Fabian: It’s really been exploding in the last five to 10 years, which is… When I started digging into this a while back, again because my training in functional medicine, I also originally had this negative view of hydrogen sulfide and that was something that was a compound that you did not want to have in excess, and that if it was excessive you want to treat that or look at ways to potentially reduce it or mitigate it somehow. But I think this whole story of the positive side is something that really is, I was surprised that I wasn’t fully aware of this. So once I dug in, there’s really a lot of literature on it.

Dr. Kara Fitzgerald: It’s very exciting. I’m glad we’re talking about it here first. I can get the hydrogen sulfide story out. Actually, I don’t know if we’re first, but we’re early. I mean it’s exciting.

Dr. Thomas Fabian: Yeah, and I think it’s important as clinicians to… We focus a lot in functional medicine on the concept of systems biology on also omics and looking at the big picture.

Dr. Kara Fitzgerald: Mm-hmm.

Dr. Thomas Fabian: So this really is a classic example that we want to know the fuller story in order to take that into account, so that you know really what should potentially be done to fully assess a patient.

Dr. Kara Fitzgerald: Yes.

Dr. Thomas Fabian: Obviously before they’re treated.

Dr. Kara Fitzgerald: I think-

Dr. Thomas Fabian: So if you’re just looking at and considering only one factor or one aspect and using only one type of test, then you may not get the full picture, and you may not be aware of some potential downsides of that treatment.

Dr. Kara Fitzgerald: … Yes. With respect to the fact that we do encounter tough guts and I think some of our interventions are perhaps less successful than they were certainly when I first started my career, I know we have tougher and tougher guts. And so, we expand our horizon looking for other villains and I know hydrogen sulfide definitely is something that’s come up in conversation in our rounds and something we’ve considered clinically in refractory SIBO but, yeah very important to have this nuanced view. I mean, you could really focus on eliminating hydrogen sulfide perhaps and then kick in hypertension and have no idea of the correlation. Is that too outrageous or is that a-

Dr. Thomas Fabian: Yeah. I mean that would be the potential concern because of these cardiometabolic diseases where they have noted that patients tend to have a reduction in these reactive sulfur species, depending on which ones they measure. There’s actually some ways to measure those collectively just in serum, it’s actually a fairly straightforward way to do it. I’m not sure if it’s available clinically, it’s been looked at in various studies to date, but that would be the main concern is really looking at the big picture for the patient. And if this is a major factor in influencing their antioxidant status, and actually we can talk about one of the key studies recently that came out, showing that the microbiome, the beneficial species actually can produce various reactive sulfur species that was shown in the study to contribute to antioxidant status and then antibiotics that reduce them, reduce the overall systemic antioxidant status. So the question is, do we really want to do that?

Dr. Kara Fitzgerald: … Yeah. Interesting. All right, so I want to talk about the microbiome and its role in all of this and how we can support it. I think before we jump into that… What did I want to talk about here? Oh, I was thinking about laboratory assessments and how we might actually measure it. So we can get a methionine easy enough. And we can look at some of the transsulfuration compounds, we can measure glutathione, et cetera. We can look at taurine and we can look at sulfate, I mean, are any of these surrogate markers? If we did some of the more broad classic functional medicine testing, would these be low or out of balance in your read on the literature?

Dr. Thomas Fabian: They could potentially be helpful in giving an overall picture. So again, looking at that omics approach that’s emerging, the microbiome is an important place to look. The metabolome…

Dr. Kara Fitzgerald: Yes.

Dr. Thomas Fabian: … Also some of the compounds that you’ve mentioned, those certainly do give you insights into the overall reactive sulfur species status overall.

Dr. Kara Fitzgerald: We could look at cysteine, yeah.

Dr. Thomas Fabian: Exactly. Glutathione is one of the major ones and that’s been known for a long time. So you can certainly get an overall picture. Tests that also look at measures of oxidative stress can be important, because that would suggest that there is an increased demand for increase in the antioxidant capacity. So certainly getting in the overall picture and we can dive in a little bit. Of course, mostly we want to focus on the stool testing, the gut testing, but there are other types of tests, Diagnostic Solutions Lab also offers metabolomics testing, where you can get quite a few of these transsulfuration pathway metabolites, for example, oxidative stress metabolites, amino acid metabolites, to help you put that picture together for a patient.

Dr. Kara Fitzgerald: Awesome really helpful. And then we can consult with you or some of the other brilliant people that I know over there and to just piece this together, if we’re suspicious-

Dr. Thomas Fabian: Absolutely.

Dr. Kara Fitzgerald: … With our patients, that’s just fabulous, yeah that would be fabulous.

Dr. Thomas Fabian: That is what we’re there for.

Dr. Kara Fitzgerald: Okay. So two areas, I want to just make sure that you’ve covered the dietary components that would help increase the hydrogen sulfide and associated players. And then I absolutely want to talk about the microbiome – we can tuck into the microbiome for a good chunk of time in what we’re looking for and how we might address it, et cetera.

Dr. Thomas Fabian: I’d love to. Yeah. Definitely when you think of ways to influence the overall reactive sulfur species set of compounds, particularly hydrogen sulfide, because that’s one of the major ones, diet is really key. So after a patient assessment and you’ve just determined whether the patient may have a need for increased sulfur compounds to contribute to their antioxidant status or possibly they’re already elevated you suspect, they may be in a scenario where you don’t want to do that. So it’s really important to know what you want to do obviously before you dive in. But as far as scenarios where that’s been confirmed in conditions like cardiovascular disease, et cetera, especially if they have any SNPs or these genetic variations in the key pathways, like the transsulfuration pathway.

And I happen to be one of those and heart disease does run in our family. And so, that’s really where you may want to consider after sufficient assessment, whether you need to have additional compounds that can help promote some of these beneficial, reactive sulfur species. So, really the obvious ones the best studied ones are, number one would be, for the most part the sulfur amino acids. So, methionine and cysteine, and that’s really looking to having adequate levels of those versus a deficiency for example, but beyond that because there are concerns about going too high in some of those-

Dr. Kara Fitzgerald: Well and that’s primarily animal sources, is that correct?

Dr. Thomas Fabian: … Correct. Yeah.

Dr. Kara Fitzgerald: Yes. So, okay, go ahead.

Dr. Thomas Fabian: Yeah. And high protein can have detrimental effects on the microbiome. We can certainly talk about that when we get to talking about the microbiome a bit more. But really the main ones in the diet, aside from the sulfur amino acids are compounds from garlic, for example, from cruciferous vegetables, those are probably the best known, and other plant sources. They’ve actually shown that these tend to be metabolized in the body in a way that releases hydrogen sulfide and then hydrogen sulfide then can be converted into these antioxidants sulfur compounds, again these RSS type compounds. So, that’s one set of sources.

But another line of research that I think is just fascinating has come out recently as well, showing that other types of polyphenols. So these are not necessarily plant compounds that have sulfur as part of their chemical structure.

 So they can’t directly donate a sulfur. They found in several studies that common antioxidants, anthocyanins, rosmarinic acid, et cetera. Also, can cause the conversion of hydrogen sulfide to these other compounds. So in a sense they’re actually detoxifying or converting the hydrogen sulfide and some scientists have proposed that this may be the major mechanism for how these various polyphenols actually have health benefits.

Dr. Kara Fitzgerald: That’s so interesting. My argument is these polyphenols are just wunderkinds of the plant world, because they influence DNA methyltransferases, and the 10, 11 translocation enzymes. They influence key players in regulating epigenetics and I’ve often said that I think perhaps one of the ways they exert their extraordinary pleotropic effects is through influencing the epigenome and gene regulation. But it makes me chuckle that there’s other scientists out there saying that perhaps it’s through influencing…

Dr. Thomas Fabian: Well, it may not actually be mutually exclusive.

Dr. Kara Fitzgerald: Yeah.

Dr. Thomas Fabian: Because some of these effects of hydrogen sulfide interactive sulfur compounds, actually can then result in epigenetic changes.

Dr. Kara Fitzgerald: Or the epigenetic changes can influence them.

Dr. Thomas Fabian: Absolutely. Yeah.

Dr. Kara Fitzgerald: I hear you. But they’re just amazing compounds and they’re involved in regulating a lot, where at a glance mechanistically they might be a head scratcher as to how. What are some of the polyphenols you’ve come across that really seem to play a nice role with activating hydrogen sulfide?

Dr. Thomas Fabian: That’s a great question. So, I don’t have the papers in front of me, but I do recall that the anthocyanins were a class of polyphenols involved. I believe quercetin, rosmarinic acid-

Dr. Kara Fitzgerald: Right. Yep.

Dr. Thomas Fabian: … Green tea polyphenols, and then a few others are also looked at also coenzyme Q10, which has a similar effect. So there’s this whole set of whether they’re polyphenols, they all have this particular type of chemical constituent. And that’s really the part that is thought to be involved in this metabolism of hydrogen sulfide. So when you think about it, there are the ones that contribute sulfur directly. So if you’re wanting to increase the sulfur, the sulfur compounds and the sulfur amino acids may be helpful and that is documented in research, but also if you want to balance and help prevent hydrogen sulfide from being excessive in general, the polyphenols that can convert hydrogen sulfide to these beneficial compounds may also be beneficial for that, from that standpoint as well. There are a few other things. So we know that various minerals can bind hydrogen sulfide. So the best known, I think that’s been used quite a bit therapeutically is Bismuth, but actually zinc can bind hydrogen sulfide as well. So it can be used potentially as an adjunct way to help reduce hydrogen sulfide levels.

Dr. Kara Fitzgerald: Okay.

Dr. Thomas Fabian: I think in the big picture though, and we’ll talk about this more when we get to the microbiome piece, but actually… And this is getting into a little bit more physiology so bear with me. But hydrogen sulfide is primarily detoxified by mitochondria. So there’s a particular set of enzymes it’s called the SQR complex for sulfide quinone reductase. So that’s the main complex that detoxifies hydrogen sulfide, it’s especially elevated typically in the colon to deal with the usual higher levels of hydrogen sulfide produced in the colon. But most of our cells also have the same enzyme in the mitochondria and they’ve actually shown that not only does that enzyme help detoxify, i.e. breakdown hydrogen sulfide. But that same complex is what’s also largely responsible for producing these beneficial, reactive sulfur species. So essentially as long as you have healthy mitochondria, you are potentially able to handle a certain amount of hydrogen sulfide and not just detoxify it, but actually generate antioxidants from that.

Dr. Kara Fitzgerald: It’s so fascinating.

Dr. Thomas Fabian: It is a really fascinating process.

Dr. Kara Fitzgerald: And just again, to underline when we’re really thinking about this cardiovascular disease, number one diabetes, number two neurodegenerative conditions, number three and more broadly the diseases associated with aging, which opens the door to many of them, with perhaps a pause around cancer. Where excess antioxidants or inflammation quenching activity could actually have a negative influence on the cancer therapeutics. Is that correct?

Dr. Thomas Fabian: Yeah, certainly the picture that’s emerging from research, but as always, particularly with the cancer story, that’s quite a bit more research would need to be done to further clarify that, but currently it’s considered a concern.

Dr. Kara Fitzgerald: Yep. Okay, let’s tuck into the microbiome and talk about how we can support healthy hydrogen sulfide and RSS production, and who the players are, we want to nourish, and how we might do that, and how we can use the diagnostic solutions amazing test to guide us through this information. And then maybe we can swing over to, how we might identify excess and how we might think about that.

Dr. Thomas Fabian: Okay. Yeah, I’d be happy to. So as far as the microbiome, again, traditionally, the ones that have been thought of as being the primary hydrogen sulfite producers, were referred to as the sulfate reducing bacteria or SRB, and that’s referring primarily to at least the main ones that were identified over time were Bilophila, and then also Desulfovibrio. So those actually can produce hydrogen sulfide based on a particular process that has a fairly technical name called dissimilatory sulfate reduction. So it’s a bit of a mouthful, but basically that means that they’re able to convert sulfate into hydrogen sulfide. So sources of sulfate in the diet or derived from mucus actually in the gut can be used as substrates to produce hydrogen sulfide. So that was really the main focus and say, were the first recognized and then focused on quite a bit over the years.

Once again, as part of this whole paradigm shift, even that picture is changing and we’re really expanding actually. So now we know actually from recent studies that the main source of hydrogen sulfide, in many scenarios is likely to actually be cysteine. So the amino acid cysteine that process is actually carried out potentially by a wide range of bacteria. The best studied are various proteobacteria. So these are the same bacteria such as E. coli, enterobacter, klebsiella, proteus, and fusobacterium, that we tend to think of as associated with inflammation, inflammatory conditions. So they’re potentially bad guys all around, but this is a major process and actually one particular study that compared the production of hydrogen sulfide actually using stool samples from various patients, found that when they supplied cysteine that hydrogen sulfite production overall was about a thousandfold higher than when they supplied sulfate.

And then when they’ve done various genomic analysis, they find that these cystine pathway genes that are involved in producing hydrogen sulfide are a lot more abundant typically in the microbiome than the genes for that sulfate reduction bacteria process. So the list of microbes has really expanded quite a bit beyond just Bilophila and Desulfovibrio, of course, many of these others that we talked about, klebsiella, E. coli, et cetera, are generally thought to be involved in conditions like IBD sometimes associated with IBS, et cetera.

They can produce other factors like lipopolysaccharide that can promote inflammation. So it’s a little unclear, is it really the hydrogen sulfide they’re producing that’s causing issues, or is it some of these other effects they can have from the wide range of products that they produce? But that’s really the main take home is that we now know of many bacteria… Couple things I want to add to that, one is the genus bacteroides and then others that are in the acteroidetes phylum, also have the genes for producing hydrogen sulfide. And several of those have been characterized in the oral microbiome. So we know that hydrogen sulfide is a common product in the oral microbiome from groups like prevotella, fusobacterium, and a few others. Porphyromonas gingivalis is another one.

Dr. Kara Fitzgerald: Are these guys players that we want or players associated with pathology in the oral microbiome?

Dr. Thomas Fabian: So far to summarize the research overall, the idea is that at low levels, many of them are just normal bacteria. For example, we have E. coli, which is listed as escherichia on GI map under the normal bacteria section, the commensal section. So it performs actually many beneficial roles, as long as it’s not overly elevated. And also it can change its functions under certain circumstances.

So if there’s excess protein getting into the colon, for example, from either a high protein diet or from not digesting and absorbing amino acids very well, which is pretty common. Then you can have a process called protein fermentation happen in the colon, where these types of bacteria then can break down amino acids and generate a whole range of chemicals – hydrogen sulfide, ammonia, and other products – that may have negative effects if they’re in excess. So it’s really more of thought to be a level thing. Actually, some of them are actually essential for certain functions. So just real quick, E coli for example, tends to live in the mucus layer, particularly in the colon. And to some extent in the small intestine, it’s actually been shown to help with intestinal epithelial regeneration.

Dr. Kara Fitzgerald: Interesting.

Dr. Thomas Fabian: Yeah. So-

Dr. Kara Fitzgerald: It’s a friend of Akkermansia. Are they buddies in the mucin…

Dr. Thomas Fabian: … Right next to each other there in the mucus layers.

Dr. Kara Fitzgerald: Well, I just want to go back to the oral microbiome, like p. gingivalis is not something we consider a player that we want around but, again in lower amounts it may be just a resonant of a healthy oral microbiome. Is that correct?

Dr. Thomas Fabian: That one is probably less clear. So I think we get those questions quite a bit regarding the organisms on GI map, because we have these neat and tidy categories. It’s either a pathogen, it’s either a normal commensal or it’s an opportunist, but as you can imagine, there’s variations where something is a mild opportunist or it’s really almost a pathogen, it’s not a good opportunist to have. So they do vary from organism to organism. And I would say overall, at least based on what I’ve read about porphyromonas, it doesn’t seem like something you’d want to have significant levels of.

Dr. Kara Fitzgerald: Okay. So just because it can produce hydrogen sulfide doesn’t necessarily mean it’s a key player, even as we’re recognizing the benefit of this. So, just one other thing. And then I want to just talk about how we might interpret a GI, the GI effects, thinking about some of these guys, it would that make, would we think of N-acetylcysteine then being a prebiotic if we want to stoke hydrogen sulfide giving that cysteine.

Dr. Thomas Fabian: A good question. So I don’t know. It probably has been studied in terms of it’s effects on the microbiome. And unfortunately I’m not familiar with specific research on that one, but that is one of the beneficial antioxidants that has been studied recently and shown to actually also promote the production of hydrogen sulfide and these reactive oxygen or reactive sulfur species, I should say the beneficial ones. So it’s been traditionally thought of as something that leads to glutathione production, which it certainly does, but also it seems to have beneficial effects through hydrogen sulfide and then this RSS. So bringing this a little bit back up to the big picture, the one last piece I want to fill out as far as the microbiome. So we have different types of hydrogen sulfide producers. Some of these are bad characters. They’re the ones that are potentially more inflammatory, et cetera, they’ve been associated with conditions.

On the other side. Really interesting new research has come out recently showing that the normal bacteria, so we’re talking about the butyrate producers, primarily in the clostridia class, also produce reactive sulfur species that have been shown to have antioxidant effects and to actually help contribute to systemic antioxidant status. So this is yet another potential way in which these beneficial bacteria… So we think of beneficial bacteria producing butyrate, producing several other types of common, beneficial factors. This is yet another one that potentially can be beneficial. So if you think of this microbiome, somewhat simplistically as bad guys and good guys, the good guys want to keep the environment basically in homeostatic conditions, meaning no inflammation, they want to keep the gut healthy because they benefit from a healthy gut.

So that’s that mutualistic relationship, the bad guys tend to want to do the opposite. They do better actually under inflammatory conditions. So anything they can do to inhibit the bad guys and then stoke inflammation maybe something that’s not so beneficial. So really it comes down to primarily the balance between good bacteria and then these opportunists and pathogens. So for many reasons, we don’t want to see these opportunists or pathogens elevated and hydrogen sulfide production made one of them, because we don’t want to see that in excess.

Dr. Kara Fitzgerald: So just again, how to think about this clinically you’ve given us dietary interventions, nutrients we can consider CoQ10, NAC, foods, fabulous polyphenols that you listed off how we can look at the microbiome and we can consider the metabolome and the genome. So, we have some tools even as directly measuring hydrogen sulfide and the associated species isn’t yet in clinical prime time. So we can’t directly measure those, we can certainly dance around omically and get a really good snapshot you would say. And you just want to talk about some of the tools that you guys have.

Dr. Thomas Fabian: Yeah.

Dr. Kara Fitzgerald: Again.

Dr. Thomas Fabian: Yeah. So I’d like to first wrap up the stool testing GI map, just to finish that, looking at that more comprehensively. So that is a big part of assessing the microbiome potential contribution. Of course to overall health, but potentially to this hydrogen sulfide picture as well. So we do know a lot of the hydrogen sulfide producers based on research. We actually have some resources on our website that lists the known hydrogen sulfide producers. So that certainly is a good way to get an as assessment of which microbes are likely to be contributing to that if there’s concerns about excess hydrogen sulfide. And then as I mentioned, there’s also the beneficial bacteria, but also there’s the physiological picture. So you certainly want to be looking at the inflammation picture that can give you some great information on the state of the health of the intestinal lining. And in particular, if you don’t have sufficient beneficial bacteria and they’re not producing enough of these short chain fatty acids that can have negative effects then on the health of the intestinal lining, particularly in the colon, that would be the colon cells or colonocytes.

And those are really important for detoxifying hydrogen sulfide. So it’s thought that in inflammatory bowel disease, colon cancer, the risk with high hydrogen sulfide maybe not only just the higher levels of hydrogen sulfide produced by the microbes, but a decrease in the ability to detoxify that and convert that to these antioxidants. So you want to look at both sides of the equation, you want to look at the microbiome balance, but you also want to look at indicators of intestinal health. Another key piece would be digestion.

Dr. Kara Fitzgerald: Yeah.

Dr. Thomas Fabian: So we do know that it’s well documented research that when there’s excess protein entering the colon, that can cause excess protein fermentation. So that’s that process where microbes, particularly the ones that can produce things like hydrogen sulfide, ammonia, et cetera, they convert those amino acids to these negative products. Luckily in research, there’s lots of studies showing that simply supporting the beneficial bacteria, with fiber and polyphenols in particular, that that can help to reduce pretty substantially that protein fermentation process. So you’re going to get far fewer of those negative products produced. That’s actually been well established.

Dr. Kara Fitzgerald: I mean, would you actually recommend a brief low protein diet in this population or is this protein fermentation happening because of a digestive imbalance or both?

Dr. Thomas Fabian: That’s a great question. So when we review patient cases with clinicians, there certainly are relatively isolated cases where they mention that their patient is on a high protein diet. We often do see an elevation in these hydrogen sulfide type producers, inflammatory microbes. In fact I just reviewed one earlier this week, it was on a carnivore type diet.

Dr. Kara Fitzgerald: Yeah.

Dr. Thomas Fabian: So the risk there is that you’re not getting enough of the fiber and polyphenols to help counteract some of those effects. And if you think about it, and this is again, lots of research supports this that when you have a healthy growing microbiome, so they’re getting plenty of fiber fermentable carbohydrates. They actually need amino acids for their own growth. So they’re going to outcompete the bad guys for these amino acids because they’re going to use them to fuel their growth. And they don’t necessarily produce hydrogen sulfide and other bad products from it. They’re just incorporating into their proteins as they’re growing. So it’s really, when you look at this picture, you’re looking at it from the overall ecosystem level, and that’s what you’re trying to get an insight into with stool testing.

Dr. Kara Fitzgerald: It’s so fascinating. I mean, there’s a big discussion going on in higher protein diets right now, a swing from the intermittent fasting, low protein recommendations from Longo, et cetera. And people are moving towards this whole protein model and we’re just creating a little bit of a blog on it, it’s just been a big topic in our space lately and it just makes sense to me. So what I concluded and I am going to trial myself is toggling between very high polyphenols on the classic diet that we used in our research study and the Younger You Intensive we call it, and a little bit of higher protein for muscle building, et cetera.

Dr. Thomas Fabian: Right.

Dr. Kara Fitzgerald: So it makes sense to me. And there are certainly individuals right now who… Or there have been around for quite a while. I mean, we all know them, we see them in clinical practice and you look at their laboratory data, who’ve been doing carnivore these crazy carnivore diets. And at some point that is just going to disrupt the microbiome profoundly, and then there’s going to be systemic ramifications and you’re describing a way that you can pick it up pretty clearly.

Dr. Thomas Fabian: Yeah, I think that’s a significant risk. And I have reviewed a number of cases that basically were that scenario where patients have been on carnivore diets for a pretty long period of time in several cases, more than a year for example. And in most cases they have very what we would consider to be a very dysbiotic microbiome. And unfortunately in some of those cases, even a higher calprotectin, now we can’t say that there’s necessarily cause and effect there because it wasn’t a study, but that’s just anecdotal evidence that we do tend to see what we would expect based on the research. And the research is very clear though that when you can mitigate the higher protein intake or if patients are not quite digesting optimally, you can mitigate that to some extent with increased fiber and polyphenols. That is really well documented.

Dr. Kara Fitzgerald: Yeah, makes sense. You’re just feet nourishing the microbiome and then you could use digestive aids as well. So fascinating. There’s so much, there’s just really a lot of food for thought here. What else do you want to say? Do you want to talk about the big picture labs or is there anything that we missed that you want to circle back to or anything you want to underscore in what we’ve already discussed?

Dr. Thomas Fabian: Absolutely. Yeah. So there couple things I just wanted to wrap up about other types of testing to consider. Since the crux of this emerging picture on reactive sulfur species has to do a lot with the sources which are diet microbiome in terms of external sources, the transsulfuration pathway. So as far as our internal generation of hydrogen sulfide, ways to assess the transsulfation pathway could be helpful, currently primarily that would be through metabolomics for example, blood markers or metabalomics where you’re looking at the sulfur related species that are part of that pathway. So for example, on the OMX test, organic acids metabolomics test from Diagnostic Solutions Lab, in terms of the more directly related markers we have methionine, cystathionine which is one of the intermediates in that pathway, that’s one of the compounds that comes after homocysteine there’s also cystine, which is basically in primarily the blood version of cysteine.

So it’s an oxidized version. It’s two cysteines together. That’s primarily what we see in the blood that’s influenced by various things, including oxidative stress. We also can detect taurine. So you get several of these different components and then there are markers related to glutathione as well. So you can hit a good picture of how a patient’s doing in terms of their compounds related to this transsulfuration pathway. Then in terms of genetics with genomic insights, there’s also really good representation of the genes in that transsulfuration pathway. And as I mentioned, just anecdotally earlier that I do have one of the major SNPs that has actually been identified as a cardiovascular risk factor. And that’s in one of those transsulfuration pathway genes. And that’s also been while studied-

Dr. Kara Fitzgerald: Which one?

Dr. Thomas Fabian: …’It’s called cystathionine gamma lyase, which confusingly is usually the abbreviation is usually CTH, t’at’s the abbreviation t’at’s used in genomic insights, but ’ou’ll also see in research that another acronym is often used, which is CSE. So if ’ou’re looking up the gene name’it’s either CTH or CSE, but that means Cystathionine gamma lyase. And t’at’s the one t’at’s primarily upregulated by Nrf2 for example, under stress conditions to generate more hydrogen sulfide.

Dr. Kara Fitzgerald: And so ’ou’ve got a variant there that just is not as effective?

Dr. Thomas Fabian: Unfortunately, yes.

Dr. Kara Fitzgerald: But when you could stoke your microbiome, it seems, pretty easily to have lots of species who are producing it, right? I mean, would that be a reasonable workaround? Go ahead.

Dr. Thomas Fabian: I try to get mine primarily from diets and supplements. So I do eat a lot of cruciferous vegetables. Unfortunately, garlic doesn’t agree with me, so I can’t do that, but certainly cruciferous vegetables and then various supplements and I try not to overdo it. So, I think it’s when it comes to polyphenols, I think adequate levels are good, but high dose may have some negative effects.

Dr. Kara Fitzgerald: In what way? Sorry, got to ask you.

Dr. Thomas Fabian: No worries. So as we talked about, there’s some concern that really high dose. In some studies there’s actually research showing that high dose antioxidants can have a prooxidant effect. So you can have the opposite of what you would expect. But again, there are these concerns that long term consumption of higher doses, especially if in a scenario where cancer already arises, then high dose may have some negative effects.

Dr. Kara Fitzgerald: So thinking about them in their antioxidant role, we would want to be mindful, but dietary sources, I don’t know, I can’t imagine fall out of consuming too many-

Dr. Thomas Fabian: Right.

Dr. Kara Fitzgerald: … Veggies.

Dr. Thomas Fabian: Yeah. I think the concern is around concentrated sources.

Dr. Kara Fitzgerald: Okay. That makes sense. Okay. What else did you want to add? Is there anything else on the lab testing or, oh you know what I wanted to say to folks listening is we, I had a great discussion on the metabolomics profile with Dr. Betsy Redmond. So I will also pop that into the show notes as well. So people can access that really fun podcast that I did with her on the DSL product that you can now access.

Dr. Thomas Fabian: That sounds great. So there are a couple other things that I wanted to mention real quick, just more potential clinical pearls. So one is that overall there are some lifestyle factors that have been known to also help boost hydrogen sulfide. So if patients have conditions where hydrogen sulfide is thought to potentially be deficient and these reactive sulfur species exercise actually is shown-

Dr. Kara Fitzgerald: You read my mind.

Dr. Thomas Fabian: … Hydrogen sulfide production.

Dr. Kara Fitzgerald: I mean, will it turns up the volume on mitochondria. So, that was my crude mechanism in my head. I’m sure there’s much more elegant…

Dr. Thomas Fabian: Right. Yeah, there’s that hormetic effect where exercise does generate a certain level of reactive oxygen species and oxidative stress. And that probably triggers the protective response that then upregulates hydrogen sulfide and then these reactive sulfur species, and then also fasting. So it’s mostly been studied in terms of dietary restriction, but there are a few scattered studies at this point, small pilot studies looking at intermittent fasting. And so far the results do also show potential benefits. And one of my favorites is for patients who may have high fusobacterium, which is one of the key hydrogen sulfide producers that can have negative effects. For example, fusobacterium has been associated with both colon cancer and inflammatory bowel disease in high levels. When it’s in the colon, actually chocolate, cocoa has been shown to inhibit fusobacterium. That’s one of my favorite bits from research on therapeutic factors.

Dr. Kara Fitzgerald: You can’t go wrong with chocolate. Chocolate actually, those flavanoids are epigenetically active as well.

Dr. Thomas Fabian: Absolutely not. And I certainly don’t hesitate on that one.

Dr. Kara Fitzgerald: Well, as usual, this has been a really tour de force conversation. I know that it will prompt a lot of thinking with the clinicians among us and would love to hear from people who are thinking about hydrogen sulfide and through the lens that Tom has described to us today and what you’re seeing. I honestly, for me, it’s just some of the refractory hypertension cases, people with really clear either heart disease, themselves or family history. I mean, there’s a lot of ways we can think about this. And then of course with my longevity biohacker hat on, I’m very curious to see how they’re talking about this in that space. So, I appreciate you coming on once again and just spinning the prism a little bit differently and giving us an expanded view and insight and really just doing some nice teaching. So, thanks for joining me today.

Dr. Thomas Fabian: My pleasure. You’re welcome. It’s definitely my pleasure.

Dr. Kara Fitzgerald: To be continued.

Dr. Fabian is a leading expert on the role of the microbiome in health, immune function, chronic disease, and aging.As a translational scientist, his primary focus is on the clinical application of microbiome research in the integrative and functional medicine space. He received his PhD in molecular biology from the University of Colorado, Boulder, and has worked as a biomedical researcher in the biotechnology industry, and more recently, as a consultant in the microbiome testing field. Currently, Dr. Fabian serves a consultant and science advisor with Diagnostic Solutions Laboratory, and he is also a Science Advisory Board member with Designs for Health. In addition, he is certified as a Nutrition Therapy Practitioner by the Nutrition Therapy Institute in Denver.

Free Resource: Gas & Histamine Producers on GI-MAP

GI-MAP™ Test and OMX™ Organic Metabolomics Test

Endogenous hydrogen sulfide production is essential for dietary restriction benefits

The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine

Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis

Effect of Long-Term Caloric Restriction on DNA Methylation Measures of Biological Aging in Healthy Adults: CALERIE™ Trial Analysis (PREPRINT)

The cardioprotective effects of hydrogen sulfide by targeting endoplasmic reticulum stress and the Nrf2 signaling pathway: A review

Sulfide regulation of cardiovascular function in health and disease

Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species

‘Antioxidant’ berries, anthocyanins, resveratrol and rosmarinic acid oxidize hydrogen sulfide to polysulfides and thiosulfate: A novel mechanism underlying their biological actions

Intermittent fasting and exercise support hydrogen sulfide production

N-acetylcysteine, taurine, and more, for optimal hydrogen sulfide

The Capacity to Produce Hydrogen Sulfide (H₂S) via Cysteine Degradation Is Ubiquitous in the Human Gut Microbiome

Modulation of colonic hydrogen sulfide production by diet and mesalazine utilizing a novel gas-profiling technology

Additional content from Dr. Fabian and the DSL team on drkarafitzgerald.com:

Latest Insights into the Role of the Gut Microbiome in Healthy Aging

Advances in Stool Testing: The GI-MAP™ GI-Microbial Assay Plus with Tony Hoffman

Dr. Betsy Redmond – The Ultimate Metabolomics Panel for Clinicians

Using Metabolomic Analysis for Clinical Insight

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