H2S Clearance: The Gut Health Factor That Matters More Than Your Microbiome

This key to gut health is all about your own enzymes, not what you're feeding the microbes.

Hydrogen sulfide (H2S) is produced by human enzymes throughout every organ of the body. It is the second most important “gasotransmitter” after nitric oxide, meaning that it is a gas that acts as an important signaling molecule to help cells decide what to do with their resources and when.

As I covered in Maybe THIS Is Why You’re Hangry, S-sulfocysteine is made from hydrogen sulfide and is most likely a normal excitatory neurotransmitter that assists glutamate in the way taurine assists GABA and glycine.

The microbiome also makes hydrogen sulfide. At least 15 different types of microbes, ranging from H. pylori to E. coli to Desulfovibrio and Bilophila wadsworthia, and even certain strains of Lactobacillus can make hydrogen sulfide.

Hydrogen sulfide in the gut directly regulates gut function, just like hydrogen sulfide in the brain directly regulates brain function. Various studies suggest hydrogen sulfide slows or speeds intestinal transit, and the net effect probably depends on concentration and context. In irritable bowel syndrome, higher H2S levels are associated with diarrhea rather than constipation. Irritable bowel syndrome with diarrhea (IBS-D) is associated with accelerated transit time. This is consistent with animal studies suggesting an H2S-producing microbiome drives diarrhea. Overall, then, we should expect that excessive H2S in the gut is most likely to cause faster transit time and diarrhea than slower transit time and constipation. Faster transit time leads to nutrient malabsorption as well, since food moves faster through the gut than the rate at which nutrients can be optimally absorbed.

For clarity, not everyone with IBS-D has fast transit time, and transit time is not the only thing impacting the risk of diarrhea. Water retention in the gut rather than in the body proper is another major factor, so it is possible to have diarrhea with normal or slow transit time.

Acute hydrogen sulfide poisoning usually produces nausea and vomiting rather than diarrhea. Thus, hydrogen sulfide probably has to be produced in the gut to cause diarrhea. However, the intestinal cells themselves make hydrogen sulfide, so that doesn’t mean it has to come from the microbiome.

In much of the body, hydrogen sulfide is pro-growth. In Hydrogen Sulfide Is the New Estrogen, I covered research showing that hydrogen sulfide contributes to breast development, and it is likely a major mediator of estrogen-induced growth in general, including growth of estrogen-responsive cancers. Indeed, hydrogen sulfide is in general a mediator of angiogenesis (growth of new blood vessels) in positive contexts like wound healing and muscle hypertrophy, and in negative contexts like cancer growth.

Hydrogen sulfide signaling is intimately intertwined with the hypoxia response and likely indispensable to it. A central function of the hypoxia response is to accumulate more iron from food and to mobilize iron throughout the body into hemoglobin synthesis, but it has broadly 100-200 targets, and it includes the regulation of the breathing rate and the formation of new blood vessels.

Now think about this: your gut cells can make their own hydrogen sulfide, and they are exposed to the hydrogen sulfide that your microbiome makes, and they want just the right “Goldilox” level of it so they have the proper rate of motility and blood supply.

Does it make any sense at all that which blood vessels you grow in distant tissues like your skin or your muscles, and whether your brain excitement gets turned up or down, should be purposefully regulated to be at the whims of random pulses of activity made by little microbes in your gut?

Generally speaking, your gut is meant to protect you against the environment. The entire gut, from mouth to anus, is “outside” the body. Things must pass through the intestinal cells to enter the “inside” of the body. Thus, the gut produces a massive excess of enzymes that neutralize bioactive chemicals. For example, diamine oxidase is produced by the gut in such excess that dietary histamine should never enter the bloodstream. This is why the histamine in fermented vegetables doesn’t usually cause hives or panic attacks. The intestines also possess the same detoxification enzymes that the liver possesses, and their systematic rejection of foreign chemicals into the feces is the first line of defense against toxins released from our food during digestion.

It would seem from this that the gut should also have a great excess capacity to clear any hydrogen sulfide that exceeds the level needed for healthy intestinal motility and proper intestinal vascularization.

Indeed, a tissue-based map of the human proteome characterized the expression of human genes in many different tissues. The genes for the two major enzymes involved in clearing hydrogen sulfide — SQOR (or SQRDL as it is labeled in this paper) and ETHE1 — are expressed to a 5.6-fold greater degree in intestinal tissue than in non-intestinal tissue. This supports a massive excess of H2S clearance capacity in the intestines.

Similarly, the expression of the three genes responsible for endogenous H2S production, CBS, CSE, and MPST (called TST in this paper) was 2.4-fold greater in intestinal tissue than in non-intestinal tissue. Thus, endogenous production of H2S by human enzymes is also enriched in the gut, suggesting that our gut cells are not going to let us get away with relying on the microbiome to synthesize the H2S needed for proper gut function.

The relative expression of genes is not the only thing that determines flux through the pathways, so we should not read all that much into this, but the fact that H2S-producing genes are 2.4-fold enriched in the intestinal tissue and H2S-clearing genes are 5.6-fold enriched in the intestinal tissue is vaguely suggestive that our clearance capacity is meant to handle half of our H2S coming from our own production and half of it coming from the microbiome.

The question then arises: what is more important for gut health, maintaining robust clearance of hydrogen sulfide, or controlling its production by the microbiome?

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

ETHE1 Deficiency: Genetic Hydrogen Sulfide Overload Wrecks the Gut

The ETHE1 gene codes for the iron-dependent enzyme persulfide diooxygenase (PDO), which is needed to convert hydrogen sulfide to sulfite.

One of the most classical signs of a genetic ETHE1 deficiency is chronic diarrhea. This is a remarkably consistent finding.

The others are intellectual disability; low muscle tone that evolves over time into high muscle tone and muscle tension; orthostatic acrocyanosis, which is a blue, white or gray coloring of the skin in response to standing, usually in the hands and feet; petechiae, which are pinpoint spots of red, brown, or purple appearing on the skin, or purpura, which are red and purple patches on the skin and mucous membranes; seizures; loss of mobility; and sometimes loss of speech, swallowing, or social interaction.

Virtually all of the metabolic disturbance is secondary to hydrogen sulfide accumulation.

Fewer than 100 clinical cases have been reported worldwide, and most have focused on levels of severity that are considered irreversibly fatal in infancy. However, more recently “mild” cases where diagnosis occurred in the teenage years are being reported, and they too almost always have chronic diarrhea.

The critical point for our purposes is that this is a monogenic disorder where there is a single causal change to one enzyme involved in endogenous H2S clearance, and no intervention to change the microbiome.

None of this is to say that the microbiome is not altered, but if it is, it is secondary to poor endogenous H2S clearance.

This shows you that the normal production of H2S by the intestinal cells and the microbiome combined is sufficient to lead to chronic diarrhea in the absence of H2S clearance.

The great excess capacity of intestinal H2S clearance is the reason we do not all have chronic diarrhea by default.

What Level of H2S Microbiome Change Is Associated With Diarrhea?

A study by Mark Pimental’s group found that IBS patients with diarrhea (IBS-D), when compared to those with constipation (IBS-C), had 59% greater H2S in their breath.

The stool abundance of two types of H2S-producing microbes, Fusobacterium and one unknown Desulfovibrio species, had a very weak correlation with breath H2S. The correlation coefficient (r) was 0.33, which gives an r-squared of 10.9%. This means that after farming for all the correlations they could find, only 10.9% of the variation could be explained by two cherry-picked bacterial categories.

The genus Fusobacterium was 68-fold more abundant in IBS-D than IBS-C, while Desulfovibrio was 2.7-fold greater. Many H2S producers were not different between the groups and not all of them were measured.

It is likely that if they had created a “total H2S-producing composite” taxa, it would have had much lower than 10.9% explanatory power and might not have been different between the groups. There were many other differences in the microbiome that were not considered related to sulfur metabolism.

Since the microbial analysis was incomplete and no attempt was made to aggregate the H2S producers, the best composite index of H2S production in this study is the 59% increase in H2S exhalation.

Breath H2S Doesn’t Necessarily Come From the Microbiome

H2S is a volatile gas. Anywhere that it is produced, it will come out the breath, so long as its production exceeds the local rate of clearance. There is no reason to think H2S in the breath necessarily reflects H2S made in the gut rather than the brain, muscle, liver, or any other tissue.

If H2S is measured in farts, and the farts have more H2S than the breath, this would be pretty good circumstantial evidence that the H2S is made in the gut.

However, that would not tell you it was made by the microbiome, because H2S is also made by intestinal tissue, and intestinal tissue is part of the gut.

The appropriate assumption is that greater H2S in the breath reflects a greater excess of H2S production over local clearance, and that’s it.

Some but not all comes from the gut, and some but not all that comes from the gut is made by the microbiome.

A Chicken-and-Egg Problem

Impaired H2S clearance should alter the microbiome. For example, in ETHE1 deficiency, the conversion of H2S to sulfite is impaired, but this leads to increased reliance on an alternative route of disposal that leads to accumulation of thiosulfate. Thiosulfate will leave the cell, and, in the intestinal lumen, it can feed Desulfovibrio and other H2S-producing species. Fusobacterium ferments cysteine, and it is conceivable that a backup in H2S clearance would impair cysteine uptake into cells, leaving more to feed this bacterium. No one has looked at the microbiome changes in ETHE1 deficiency, but it seems almost certain there must be big differences.

In the case of IBS-D, the causation of the condition is up for debate and inquiry. We do not know what happened first: did impaired H2S clearance drive changes to the microbiome, or did something else change the microbiome that increased H2S production?

This chicken-and-egg problem does not exist for ETHE1 deficiency, because a monogenic genetic disorder is a natural experiment where the change to the genome is fundamentally causal.

So we can say that we know for a fact blocking endogenous H2S clearance can wreck the gut, but it is still up for debate and inquiry whether increasing the H2S producers of the microbiome can do the same.

The question then becomes this: can we find anything capable of directly modifying the microbiome in humans to favor more H2S producers and consequently a faster intestinal motility or a greater risk of loose stools or diarrhea?

Our bar to meet is the 59% increase in H2S exhalation associated with IBS-D.

How Can Dietary Strategies Impact H2S Production by the Microbiome?

A Harvard study published in Nature in 2014 found that “diet rapidly and reproducibly alters the microbiome.”

This study compared five days on a plant-based diet based on cereal, vegetables, rice, lentils, and fresh and dried fruits to five days on an animal-based diet based on eggs, bacon, pork, beef, cured meat, cheese, pork rinds, and salami.

Nine subjects underwent both diets. The only acceptable way to conduct such a study is with a randomized crossover design, where there are two orders, plant then animal and animal then plant, and individuals are randomly allocated to each order.

They do not describe the order in which the subjects underwent the diets, and do not refer anywhere in the main paper or in the supplementary materials to a randomization process. This suggests that they avoided describing these factors because they did not do them properly and admitting this would detract from the credibility of the paper. They repeatedly present plant-based data prior to presenting animal-based data, which seems to suggest that everyone did the the plant-based diet first.

Clusters of microbes that changed on the animal-based diet were characterized by resistance to bile acids, so were probably driven largely by increased fat intake. Some of these clusters included H2S-producers, and were increased between 4-fold and 8-fold.

More to the point, total microbial expression of sulfite reductase enzymes were increased 3-fold. These enzymes are capable of converting sulfite to hydrogen sulfide.

This is not the only method of H2S production, so it cannot be considered a “total H2S production” index. As a preliminary conclusion, however, we could say that five days on an animal-based diet may increase microbial H2S production by 3-fold.

While comparing an imperfect index of microbial H2S production to H2S exhalation is not comparing apples to apples, these are the two best metrics we have from each study that form a composite of hypothetical H2S production.

A 3-fold increase in H2S producers on carnivore trumps a 59% increase in breath H2S found in IBS-D, but no one in this study got loose stools or diarrhea.

In fact, intestinal transit time was tracked, and the animal-based diet was associated with slightly slower intestinal motility, in contrast to what would be expected from a tripling of H2S accumulation.

A slightly better-described study published in the American Journal of Clinical Nutrition in 2000 “partially randomized” five healthy men to five ten-day diets with varying meat content ranging from 0 to 600 grams in different orders.

Urinary sulfate, which mainly reflects endogenous human production of sulfate from the sulfur amino acids in the meat, increased 2.2-fold at the highest meat intake and had 78% of its variation explained by meat intake.

Fecal sulfide, which should reflect the uncleared portion of microbial and intestinal H2S production that does not escape into the general circulation, increased 2.2-fold across the diets and 56% of its variation was explained by meat intake.

Transit time had no relation to diet, and there were no reports of meat intake causing loose stools or diarrhea.

The effect of an animal-based diet is probably driven by a combination of sulfur amino acids, fat, and fiber. Sulfur amino acids can directly feed some sulfur-metabolizing bacteria. Fat requires bile acids for emulsification, with longer chain lengths and more saturated fatty acids requiring more bile acids. Bile acids are joined to either glycine or taurine, and taurine contains sulfur. Taurine can directly feed some sulfur-metabolizing bacteria. Fiber feeds microbes, and in its absence, microbes will feed off of the sulfated mucins that make up the mucous secretions of the gastrointestinal tract. A lower ratio of fiber to endogenously secreted mucins will select for sulfur-metabolizing bacteria.

Thus, it is quite likely that animal-based diets are the most powerful way to favor an increase in H2S-producing microbes, consistent with the two short-term studies described above.

However, these studies indicate that increasing fecal H2S production by 2-fold to 3-fold does not alter transit time or loosen stools.

H2S Signaling Depends on Endogenous Sulfur Clearance Enzymes

Unlike classical neurotransmitters and many hormones, H2S does not carry out its signaling by binding to a receptor on the cell surface. If it did, the H2S coming out in a fecal sample would probably be a good indicator of the H2S available to carry out such signaling, because a proportional amount of H2S would be coming into contact with the cells lining the gut.

However, H2S signaling is critically dependent on our endogenous sulfur-metabolizing enzymes inside our own cells.

The details are still being worked out. However, we know a few things:

• Genetic CoQ10 synthesis defects do not cause chronic diarrhea. There is one report of such a defect causing Crohn’s, and a second report of such a defect causing intestinal obstruction, and that is it. These reports also lack descriptions of purpura and petechiae. Thus, while these defects do cause neurological and kidney damage from hydrogen sulfide accumulation, they do not cause aberrant vascularization.

• The first reports of genetic defects in the CoQ10-dependent SQOR enzyme were published in 2020 and covered three children that had profound neurological disturbances but did not have any gastrointestinal problem, purpura, or petechiae.

• Research in cell models published this year showed that hypoxia increases H2S, and that H2S promotes neovascularization, but that blocking SQOR abolishes this effect while blocking ETHE1 does not.

• Separate studies in cells and mice have shown that CoQ10 plays a direct role in chemoreceptors sensing oxygen, that a buildup of ubquinol relative to ubiquinone is necessary to increase the breathing rate in response to hypoxia, and that full respiratory chain function has to be intact.

• Synthesizing all this evidence leads to the conclusion that the growth of blood vessels and the stimulation of intestinal motility depend on H2S-mediated hypoxia signaling, and that this requires the flow of electrons from H2S to CoQ10 mediated by SQOR and does not require the downstream production of sulfite by ETHE1. When ETHE1 is blocked, all of this signaling increases, causing diarrhea and purpura or petechiae. When SQOR is blocked, the hypoxia signaling cascade is blocked, but the toxic effects of H2S on energy metabolism are enhanced. Thus, in SQOR and CoQ10 deficiencies we see profound neurological dysfunction but without the diarrhea and purpura or petechiae.

Suddenly it makes complete sense why we could see a 2-3-fold increase in fecal sulfide production without seeing an increase in quantified intestinal transit, loose stools, or diarrhea: because ETHE1 and downstream enzymes are very rich in intestinal cells, and those enzymes are in control of the degree to which H2S mediates increased intestinal motility.

A Limitation of This Analysis: No Fecal Sulfide Studies in IBS-D

I was unable to find a study looking at breath sulfide and fecal sulfide in the same people, or a study of fecal sulfide in IBS-D.

This prevents direct comparison of the 2-3-fold increase in fecal H2S content or microbial H2S-producing enzymes with the 59% increase in breath H2S found in IBS-D.

The Case of Carnivore Diarrhea

In contrast to the studies discussed above, an internet search for stories of diarrhea on the carnivore diet suggests it has veritable meme status.

Elliot Overton says this is from fat malabsorption, which can be helped with taurine or taurine-containing bile acids, and bitter herbs; bile acid malabsorption, which can be helped with probiotics, butyrate, calcium, psyllium husk, and vitamins A and D; or oxalate dumping, which can be helped with a little chocolate or nuts.

Anthony Chaffee says it’s from coffee, sugar alcohols, or excessive fat consumption.

Carnivore King says this only lasts a month.

Mikhaila Peterson says it happens to two out of three people for two to seven days.

Others report that chronic diarrhea resolves on carnivore.

One of the problems with using cold-turkey plunges into full carnivore for this question is that a sudden disappearance of fiber from the diet can lead to a complete rearrangement in the physiologically processes needed to maintain proper bulk and hydration of stool.

The 2014 Nature paper included plenty of cheese, and calcium activates an intestinal receptor that prevents diarrhea.

In the AJCN 2000 study, even the 600 gram per day meat diet had 220 grams of carbs, and fat was held relatively constant across the diets. It also included cheese at lunch.

Thus, the carnivore diarrhea phenomenon probably diverges from these studies as a result of simultaneously purging fiber and calcium from the diet at the same time, and the fact that it tends to self-resolve argues against a shift to an H2S-producing microbiome as the cause. Indeed, that almost certainly happens and persists over time, but the above studies show that it does not reliably lead to changes in intestinal motility or stool quality.

I would not rule out that many people choose carnivore because of existing health problems, so could have underlying problems with sulfur clearance that make them “H2S responders.”

Conclusions

Genetic deficiency of ETHE1 leads to an accumulation of H2S and an excess of its normal hypoxia-related signaling, and this leads to abnormal blood vessel growth and chronic diarrhea.

Conditions that block the normal H2S hypoxia-related signaling but allow H2S accumulation to poison energy metabolism, such as CoQ10 deficiency and genetic deficiency of SQOR, cause severe neurological problems but not abnormal blood vessel growth or chronic diarrhea.

IBS-D demonstrating a 59% increase in H2S in the breath implies that H2S, from wherever it came, was not being effectively converted into sulfate by endogenous human enzymes.

The fact that dietary manipulations can lead to 2-3-fold greater H2S production by the fecal microbiota but do not lead to increased intestinal motility or reports of loose stools or diarrhea suggests that tremendous variance in H2S production can be tolerated so long as function of endogenous human H2S clearance enzymes remains healthy.

This is consistent with the fact that the human endogenous H2S clearance enzymes are 5.6-fold enriched in intestinal tissue.

The latest cellular research on H2S signaling implies that human endogenous H2S clearance enzymes are required for it to mediate its signaling and that dysregulated H2S signaling requires an imbalance in the endogenous clearance pathways.

All of this suggests that when it comes to H2S and your gut health, YOU are far more important than your microbiome.

My Sulfur Protocol

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Other Sulfur Resources

Keep checking back as my guide to solving sulfur problems will be out soon.

In the mean time, check out these articles:

• Hydrogen Sulfide Is the New Estrogen

• Maybe THIS Is Why You're Hangry

• Is THIS Behind Your Muscle Tension?

• Will Longevity Diets Wreck Your Hormones?

• The Unknown Testosterone Nutrient

• Does Molybdenum Lengthen Lifespan?

• Manganese Toxicity Is a CoQ10 Deficiency

• CoQ10 Deficiency Is Sulfur Toxicity