The Keto HDAC Myth – How One Paper Misled Millions for a Decade

For the past decade, the ketogenic diet community has promoted a compelling narrative: that entering ketosis produces beta-hydroxybutyrate (BHB), which acts as a powerful histone deacetylase (HDAC) inhibitor, unlocking profound epigenetic benefits that explain many of the diet’s purported health advantages.

This story has been repeated by researchers, health influencers, and keto advocates worldwide, including prominent figures like Dr. Dominic D’Agostino from the University of South Florida, whose work on ketogenic diets and exogenous ketones has been featured on countless podcasts and media outlets. The epigenetic narrative became central to explaining why ketosis seemed to help with everything from inflammation to neurodegeneration to cancer. There’s just one problem: it appears to be wrong.

The Paper That Started It All

In December 2012, a landmark paper was published in the prestigious journal Science by Shimazu and colleagues. The study, titled “Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor,” made a bold claim: the ketone body d-β-hydroxybutyrate (BHB) is an endogenous and specific inhibitor of class I histone deacetylases.

The paper reported that BHB inhibited HDAC1, HDAC3, and HDAC4 in a dose-dependent manner, with IC50 values in the low millimolar range — concentrations achievable during fasting or ketosis. The researchers showed that administration of BHB, fasting, or calorie restriction all increased global histone acetylation in mouse tissues, and that this was associated with increased expression of oxidative stress resistance genes like FOXO3A and MT2.

This was exactly the mechanistic explanation the keto community needed. HDAC inhibitors are a well-established class of drugs with anticancer, anti-inflammatory, and neuroprotective properties. If BHB was a natural HDAC inhibitor produced during ketosis, it would explain why the ketogenic diet seemed to have such wide-ranging benefits.

The paper was cited over 2,000 times and became foundational to how keto advocates explained the diet’s benefits. Prominent researchers began incorporating the HDAC inhibitor narrative into their lectures, papers, and media appearances. The story was simple and compelling: ketosis → BHB production → HDAC inhibition → epigenetic benefits → better health outcomes.

The 2019 Reckoning — When Scientists Actually Compared the Two Molecules

The problem is that butyrate — a short-chain fatty acid produced by gut bacteria when they ferment dietary fiber — is also an HDAC inhibitor. In fact, butyrate is a well-established HDAC inhibitor that has been studied for decades. And structurally, butyrate and BHB are remarkably similar, differing only by a hydroxyl group.

This similarity led researchers to wonder: when you actually compare the two molecules head-to-head using the same assays, do they perform equally?

In January 2019, a team of researchers published a study in Scientific Reports titled “Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule.” Their findings were devastating to the BHB-as-HDAC-inhibitor narrative.

The researchers conducted a systematic comparison, evaluating histone acetylation levels, transcriptional regulation of metabolic and inflammatory genes, and cytokine secretion profiles across multiple cell types. Their conclusion was stark:

“We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-β-hydroxybutyrate in vivo nor in vitro.”

Even more concerning, the study found that while butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes in endothelial cells, BHB actually “acted as a slightly pro-inflammatory molecule.” This was the opposite of what the keto community had been claiming.

What the Head-to-Head Comparison Revealed

The 2019 study tested BHB at concentrations significantly higher than butyrate — yet BHB still failed to promote histone acetylation. The researchers used multiple forms of BHB (the R-enantiomer, S-enantiomer, and racemic mixture) to ensure they weren’t missing any activity. None showed HDAC inhibition.

In contrast, butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1α, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial antioxidative genes SOD2 and catalase. These are exactly the kinds of metabolic improvements that people attribute to ketosis — yet butyrate, not BHB, was driving them.

The researchers explicitly called for “a reassessment of R-β-hydroxybutyrate function as HDAC inhibitor and anti-inflammatory molecule.” This wasn’t a minor quibble — it was a direct challenge to the foundational claim of the ketogenic diet’s epigenetic benefits.

Before examining the head-to-head comparison, it’s essential to understand one of the most important differences between these two molecules: their effects on regulatory T cells, or Tregs. These specialized immune cells function as the body’s master peacekeepers, actively suppressing excessive immune responses and preventing your immune system from attacking your own tissues.

Without adequate Treg function, inflammation runs unchecked, autoimmune diseases develop, and the body exists in a state of chronic immune activation that accelerates aging and tissue destruction.

Tregs exert their calming influence by secreting anti-inflammatory cytokines like IL-10 and TGF-β, and by directly suppressing the activity of pro-inflammatory immune cells. The transcription factor Foxp3 is the master regulator that defines Treg identity, when Foxp3 is expressed, a T cell commits to the regulatory lineage and gains its inflammation-suppressing capabilities.

This is why the ability to induce Foxp3 expression and promote Treg differentiation is considered one of the most powerful anti-inflammatory mechanisms known to medicine. Pharmaceutical companies have spent billions trying to develop drugs that can enhance Treg function. As you’ll see in the comparison below, butyrate does this naturally through direct epigenetic modification of the Foxp3 gene — while BHB has no such capability whatsoever.

The Honest Comparison — BHB vs. Butyrate

The Cruel Irony — Keto Diets May Actually Reduce Your HDAC Inhibitor Levels

If the HDAC inhibitor story weren’t damaging enough, there’s an even more troubling irony: ketogenic diets may actually reduce your body’s production of the real HDAC inhibitor — butyrate.

Butyrate is produced in your colon when beneficial gut bacteria ferment dietary fiber. This requires two things: adequate fiber intake and a healthy population of butyrate-producing bacteria like Faecalibacterium prausnitzii, Roseburia, and Eubacterium rectale. Ketogenic diets directly undermine both of these requirements.

A systematic review published in 2023 in Advances in Nutrition found that ketogenic diets consistently decrease Bifidobacterium abundance and reduce fecal short-chain fatty acids including butyrate. The review noted that “colonic health was the main concern raised by the included studies relating to the KD’s microbial impacts, primarily ascribed to the negative impact on SCFA production.”

Another 2024 study in women with overweight and obesity found that a 6-week ketogenic diet significantly reduced fecal butyrate, propionate, acetate, and total SCFA levels. The researchers also observed decreased abundance of butyrate-producing bacteria including Roseburia and Bifidobacterium species.

Perhaps most damning, research has demonstrated that BHB itself directly inhibits Bifidobacterium growth. So not only does the low-fiber nature of keto diets starve butyrate-producing bacteria, but the very ketone bodies produced by the diet may further suppress beneficial bacterial populations.

This creates a bitter paradox: people following strict ketogenic diets to obtain “HDAC inhibitor benefits” from BHB may actually be depleting their levels of butyrate — the molecule that actually provides robust HDAC inhibition.

Where BHB Still Has Legitimate Value

This isn’t to say that BHB or ketogenic diets are worthless. There are legitimate, well-documented benefits that don’t require HDAC inhibition:

Dr. D’Agostino’s work on exogenous ketones for Navy SEAL oxygen toxicity prevention, seizure disorders, and performance optimization is still valid. These applications don’t require HDAC inhibition to work. But the broader narrative that “BHB is an epigenetic wonder molecule” needs serious revision.

The Oral Butyrate Problem — Why Supplements Don’t Work

If butyrate is the real HDAC inhibitor and keto diets reduce its production, can you simply take butyrate supplements?

Unfortunately, this approach faces a significant pharmacokinetic problem: orally administered butyrate is absorbed almost entirely in the small intestine, before it can reach the colon where it’s actually needed. Research indicates that only about 2% to 5% of orally administered butyrate reaches systemic circulation — and virtually none reaches the colon in meaningful concentrations.

As one research review noted: “orally administered free butyrate is taken up almost entirely by enterocytes in the proximal intestine and may not reach the colon.” This means conventional butyrate supplements, despite their marketing claims, largely fail to deliver butyrate to the colonocytes that need it.

Various strategies have been attempted to solve this problem, including enteric-coated tablets, tributyrin (butyrate esterified to glycerol), and butyrylated starches. Some of these show modest improvements in colonic delivery, but no commercially available product has been shown to reliably deliver therapeutic levels of butyrate to the colon.

This represents a significant gap in the supplement market. The molecule that actually provides the HDAC inhibition benefits that people seek from ketosis currently has no effective oral delivery mechanism available to consumers.

What This Means for the Keto Community

To be fair to Dr. D’Agostino and other keto researchers, the original 2013 Shimazu paper was published in Science — one of the world’s most prestigious journals. It’s not unreasonable that researchers and advocates built upon its claims. The paper appeared to provide a compelling mechanistic explanation for ketosis benefits.

But science is supposed to be self-correcting. The 2019 Chriett study in Scientific Reports directly challenged the foundational claim with side-by-side experimental evidence. Other studies, including a 2021 paper in Life Science Alliance, have similarly failed to confirm BHB’s HDAC inhibitory activity, noting that “recent studies have since been unable to confirm a HDAC inhibitory activity for βOHB in various cell types.”

Yet the “BHB is an HDAC inhibitor” narrative continues to be promoted in podcasts, articles, and presentations. Searches for keto diet benefits still return claims about epigenetic regulation through HDAC inhibition. This represents a significant failure of scientific communication.

The ketogenic diet community owes it to the millions of people following their advice to update the narrative. Continuing to promote claims that have been experimentally refuted doesn’t serve anyone’s health — it only undermines trust in scientific guidance.

The Bottom Line

The story that ketosis provides epigenetic benefits through BHB’s HDAC inhibition appears to be built on a foundation that has crumbled under experimental scrutiny. The actual HDAC inhibitor your body produces is butyrate — a molecule made by gut bacteria from dietary fiber, not from fat metabolism.

Ironically, strict ketogenic diets that eliminate fiber may actually deplete butyrate production, causing the very harm that people thought they were preventing by entering ketosis.

This doesn’t mean ketogenic diets are without merit. But it does mean that the mechanistic story needs to be updated. Health claims should be based on the best available evidence — and when that evidence changes, the claims should change too.

For those seeking the true HDAC inhibition benefits that were attributed to BHB, the answer lies not in reducing carbohydrates, but in optimizing colonic butyrate levels. The challenge is that oral butyrate supplements don’t effectively reach the colon — a problem that represents a significant opportunity for future research and product development. A colon-targeted butyrate delivery system, particularly when combined with glycine for synergistic anti-inflammatory effects, would address something that:

The scientific record is now clear. It’s time for the keto community to update its story.

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