The Single Molecule Driving Both Your SIBO and Your MCAS (And Why Nothing Has Worked)

If you have IBS, and MCAS, and maybe SIBO — and you’ve been told these are three separate problems that just happen to co-occur in unlucky people like you — I want to show you something.

There is a single molecule that explains all three. It comes from one cell type. And once you understand what it’s doing, you’ll see why nothing you’ve tried has worked the way it was supposed to.

This isn’t speculation. The mechanistic pieces have been published over the last eighteen months in Nature, Nature Metabolism, Cell Metabolism, and Nature Communications. The integration is what’s new — and it’s what the Host Capacity Model has been pointing toward for years.

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The standard story is wrong

Walk into any conventional clinic with a typical chronic-gut presentation and here’s what you’ll be told:

You have IBS — that’s a “functional disorder,” meaning we don’t know why your gut hurts but we can rule out the scary stuff. Take a low-FODMAP diet and an antispasmodic.

You have MCAS — your mast cells are “overactive.” Take an H1 blocker, an H2 blocker, a mast cell stabilizer, and try not to react to too many things.

You probably have SIBO or dysbiosis — your microbes are off. Take rifaximin, then a probiotic, then a herbal antimicrobial, then maybe FMT if you can afford it.

Three specialists. Three diagnoses. Three protocols. You execute every one of them, sometimes for years. The symptoms shuffle. Maybe one calms while another flares. Maybe everything quiets for a few weeks and then comes roaring back. You start a food list. The food list grows. Your social life shrinks. Your nervous system frays.

And underneath it all, the question no one will answer: if these are three unrelated diseases, why do they always show up together in the same patients?

They don’t show up together by accident. They show up together because they are not three diseases. They are three downstream consequences of one upstream failure. And there is a single molecule sitting at the center of all of them.

That molecule is succinate.

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The cell at the center of it all

To understand what succinate is doing, you have to understand the cells that make it: the colonocytes — the cells lining your colon. They are not glamorous. Most people, including most doctors, never think about them. But they are doing something extraordinary that almost no other cell in your body does.

A normal cell burns glucose for energy. Your colonocytes don’t. They burn butyrate — a fatty acid produced by your gut bacteria when they ferment fiber. Burning butyrate consumes around seventy percent of all the oxygen your colonocytes use. They are, metabolically speaking, the most demanding cells in your gut, and they are running their mitochondria at near-maximum capacity all day long.

This isn’t a detail. This is everything.

When colonocytes burn butyrate properly, three things happen at once. First, they make energy for themselves and the rest of the gut wall. Second, by consuming so much oxygen, they keep the lining of the colon at very low oxygen levels — a state called epithelial hypoxia. This low-oxygen state is what your healthy gut bacteria are adapted to. The good bugs — the ones that make more butyrate, the ones that produce the indoles your immune system needs, the ones that make secondary bile acids that protect you from C. difficile — cannot survive in oxygen. The colonocyte’s metabolic appetite is what creates the environment they live in. Third, the byproducts of burning butyrate get sent into the cell as signals that activate genes for mucus production, antimicrobial peptides, tight-junction proteins — the entire machinery of barrier function.

So when colonocyte mitochondria are working: low oxygen, anaerobic flora dominate, butyrate stays high, mucus stays thick, the barrier stays sealed.

And when they fail?

Oxygen leaks back into the lumen. The good anaerobic bugs die off. Oxygen-tolerant bacteria — the E. coli, the Klebsiella, the Salmonella-adjacent species that healthy people barely notice — start expanding. The mucus thins. The barrier fails. LPS leaks into circulation. Your immune system mobilizes. Your symptoms begin.

This is the central claim of the Host Capacity Model: dysbiosis is not the cause of your problem. Dysbiosis is the symptom of failing colonocytes. The microbes you’re trying to kill with antibiotics are growing because the host environment they were supposed to be excluded from has collapsed. You can take all the rifaximin you want. The garden has lost its gardener.

But that’s not where it ends. Because failing colonocytes don’t just stop doing their job. They do something worse. They start exporting a signal — and that signal is succinate.

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What succinate does, and why it changes everything

Succinate is a normal intermediate in the energy cycle inside every mitochondrion. In a healthy cell, it appears for a fraction of a second and is immediately consumed by an enzyme called succinate dehydrogenase. You shouldn’t see much of it floating around.

But when mitochondria are stressed — by hydrogen sulfide overload from sulfate-reducing bacteria, by chronic inflammation, by the metabolite “itaconate” that your own immune cells produce during infection, or just by running out of the cofactors required to keep the cycle moving — succinate dehydrogenase gets blocked. Succinate piles up. It can’t stay in the mitochondrion. It gets dumped into the cell, then out of the cell, and into the surrounding tissue.

And once it’s there, succinate does three things at once. This is the part you need to understand, because it is the explanation you have been waiting for.

The first thing succinate does is reach a receptor called SUCNR1. SUCNR1 sits on three cell types you should recognize: tuft cells (sentinel cells in your gut wall that watch for parasites and microbial trouble), mast cells (the cells your MCAS doctor has been trying to calm down), and certain immune cells. When succinate hits SUCNR1 on a tuft cell, the tuft cell releases IL-25, which activates a class of immune cells called ILC2s, which release IL-13, which causes the gut to expand its mast cell population and put those mast cells on a hair trigger. This is MCAS, mechanistically. Your mast cells are not “overactive” because they were born that way. They are responding to a signal — a signal coming from your failing colonocyte mitochondria, telling them to expand and to fire. Mast cell stabilizers turn down the volume on that response. They do not touch the signal. The signal keeps coming. The receptor keeps activating. The mast cells keep multiplying. This is why MCAS protocols feel like managing a leak with towels while the pipe stays broken upstream.

The second thing succinate does is far more sinister, and it has only been worked out in the last two years. Succinate, once accumulated, blocks an entire family of enzymes called the TET enzymes — and TET enzymes are the editors of your DNA. Specifically, they are responsible for demethylating DNA, which is to say, removing the chemical tags that keep certain genes silenced. When TET enzymes work, dormant genes wake up. When TETs are blocked — which is exactly what succinate does — genes that should be active stay locked off. Permanently, in many cases. This means that the genes your colonocyte needs to repair itself, to take up butyrate, to make mucus, to maintain its barrier function, are now epigenetically silenced. The cell cannot fix itself even when you remove the original insult. The lock has been thrown. This is why people who eliminated their SIBO five years ago still have IBS today. The pathogen is gone. The lock is not.

The third thing succinate does — and this is the discovery published in Nature in 2025 by the Memorial Sloan Kettering group that should reshape every conversation about gut disease — is skew the lineage of intestinal stem cells. When the metabolite alpha-ketoglutarate (which TET enzymes need to function) is depleted because succinate has hijacked the system, your intestinal stem cells stop making secretory cells. Goblet cells — the ones that make your mucus barrier — drop in number. Paneth cells — the ones that make antimicrobial peptides — drop in number. The stem cells start making absorptive cells instead, because the metabolic switch that determines lineage has been thrown by succinate-driven α-ketoglutarate depletion. So now your gut wall is not just broken. It is being rebuilt wrong, day after day, with each new round of stem cell division producing fewer of the cells that protect you and more of the cells that just absorb. The barrier doesn’t just fail. It fails to regenerate.

One molecule. Three actions. Outward, it drives MCAS. Inward, it locks the colonocyte’s repair genes. Downstream, it sabotages the stem cells trying to rebuild the barrier.

This is why your IBS, your MCAS, and your dysbiosis are all part of the same disease.

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Why nothing you’ve tried has worked the way it was supposed to

Now look at what you’ve been doing.

A mast cell stabilizer blocks mast cell degranulation downstream of SUCNR1 activation. It does nothing to lower succinate. The mast cells are still being told to expand and prime themselves. You are managing the explosion, not removing the fuse.

A round of rifaximin kills overgrown bacteria. It does nothing to restore colonocyte mitochondrial function, restore epithelial hypoxia, or reverse the TET-locked epigenetic silencing in the cells that determine which microbes can survive. The bacteria you killed will be replaced — by the same kind of bacteria — within weeks, because the host environment hasn’t changed.

A probiotic adds organisms to a niche that has lost the ability to host them. They don’t colonize. They pass through. You feel maybe slightly different for a few days.

A low-FODMAP diet starves the bacteria producing the symptomatic gases. Symptoms quiet. Then the diet narrows your microbial diversity further, the colonocytes get even less butyrate (because the fiber-fermenting bacteria are gone), and host capacity drops further. The diet works while you’re on it, and the underlying lesion gets worse the longer you stay on it.

Antihistamines, vitamin C megadoses, quercetin, NAC — these are downstream interventions on a system whose upstream fuel source has not been addressed. Some of them genuinely help, in the way that aspirin helps a fever. None of them remove the cause.

You haven’t been doing the wrong things. You’ve been doing the right things in the wrong sequence, on the wrong target, against a model of your illness that doesn’t capture what is actually happening inside your colonocyte mitochondria.

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What this reframes

You are not psychosomatic. You are not “sensitive.” You are not having “an autonomic response to stress.” Your gut is not “in your head.” Your nervous system is not the problem — though it is being driven crazy by the signal coming up from your gut.

You have a specific, identifiable, mechanistic failure in a specific cell type, producing a specific signaling molecule, that drives every cluster of symptoms you have. The failure has a name: loss of host capacity at the colonocyte level. The mediator has a name: succinate. The downstream pathways have names: SUCNR1, TET inhibition, α-ketoglutarate depletion, lineage skew, barrier collapse. This is not vague. It is not “functional.” It is biology. The papers are published. The mechanism is in Nature. The cell type has been imaged. The molecule has been measured in the serum of patients with Crohn’s, with IBS, with fibromyalgia. The receptors have been mapped. The therapeutic implications follow from the mechanism — and they are not what conventional medicine is currently doing for you.

The reason you have IBS and MCAS and dysbiosis is because all three are manifestations of one process. They get diagnosed separately because medicine is organized into specialties — gastroenterology over here, allergy/immunology over there, infectious disease somewhere else. The cell at the center of it doesn’t care about your insurance code. It is failing in one specific way, with one specific output, hitting three specific downstream systems.

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Where this goes

If you’ve read this far, you understand the frame. The question becomes what to do about it — and that is not a question I’m going to answer in a Substack post, because the answer is genuinely individualized and depends on which axis is dominant in your particular case, what your genetic context looks like, what your testing reveals about which specific lesion is driving the failure, and which order to address the cascade in. (These choices matter enormously. The wrong sequence can make people worse. I have seen this in clients who came to me after well-meaning protocols hit the right molecules in the wrong order.)

What I will tell you is the direction. The point of intervention is not the mast cells, not the bacteria, not the symptoms downstream. The point of intervention is the colonocyte. Restore the host capacity, and the succinate signal stops. The mast cells de-prime. The TET enzymes unblock. The stem cells re-balance their lineage commitments. The barrier rebuilds. The microbes that fit a hypoxic, butyrate-rich, antimicrobially-policed gut return — and the ones that fit a leaky, oxygenated, defenseless gut leave. None of this is fast, and it is not done with a single supplement or a single test. But it is possible, and it is mechanistically defensible, and the framework explains why it works when conventional protocols don’t.

The Host Capacity Model is what I have been building over the last several years to make this approach actionable in clinical practice. The mechanism I described in this post — one cell, one molecule, three diseases — is the simplified narrative. The full clinical framework is more granular, includes a tiered testing protocol that maps which specific lesion is dominant in a given patient, and stratifies intervention sequencing based on host genetic context, severity, and metabolic phenotype.

If you’ve spent years being told you have multiple unrelated conditions and that nothing more can be done — you are not crazy, you are not unlucky, and you are not out of options. You have been working with a model that doesn’t see the connection. The connection is real. The mechanism is published. The path forward is built on it.

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If this resonated with your experience and you’d like to discuss whether the Host Capacity framework applies to your case, I work with a small number of clients privately. Inquiries: biomelogic@outlook.com.

— Mohammed Attallah