The Real Science Behind Ketones, Butyrate, and Epigenetic Health (2026)

Introduction

Ketogenic diets and fasting raise levels of β-hydroxybutyrate (BHB), a ketone body often linked to health benefits. Early studies suggested BHB could act as a histone deacetylase (HDAC) inhibitor, changing gene activity in ways that support metabolism and anti-aging.

Newer research shows this claim is oversimplified. While BHB has important signaling roles, the gut-derived molecule butyrate is a more potent HDAC inhibitor, driving many of the epigenetic benefits once attributed solely to ketones.

Therefore, while BHB has epigenetic and signaling roles, the mechanistic narrative behind ketogenic diet benefits requires refinement based on evolving evidence.

This guide explains the science and provides practical tips for a balanced, gut-friendly ketogenic diet.

What Are HDACs and Why Do They Matter?

• Histone deacetylases (HDACs) remove acetyl groups from histones, tightening DNA and reducing gene activity.

• HDAC inhibition relaxes DNA, activating genes linked to metabolism, stress resistance, and inflammation control.

• Certain compounds, like butyrate, are strong HDAC inhibitors and influence gene expression in humans.

The BHB “HDAC Myth”

• Initial studies suggested BHB might inhibit HDACs and explain keto’s epigenetic benefits.

• Follow-up studies found BHB’s HDAC effects are weak and context-dependent.

• BHB does affect gene activity, but through β-hydroxybutyrylation, a different histone modification, not classical HDAC inhibition.

Key point: BHB contributes to health, but it is not the main HDAC driver.

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.

Butyrate: The True HDAC Powerhouse

• Produced when gut bacteria ferment dietary fiber.

• Strongly inhibits HDACs, activating beneficial genes related to metabolism, mitochondria, and inflammation control.

• Research shows butyrate’s HDAC inhibition is far stronger than BHB, especially in vascular and muscle cells. (PMC6346118)

Implication: Low-fiber ketogenic diets may reduce butyrate production, limiting this key epigenetic benefit.

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.

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.

BHB vs. Butyrate

Research shows that while BHB has some signaling and metabolic roles, butyrate, produced by gut bacteria from fiber, is much more potent in driving HDAC-related epigenetic benefits. Here’s a direct comparison:

1. HDAC Inhibition

• BHB (Ketone): Weak or undetectable

• Butyrate (Fiber-Derived): Strong and well-documented

2. Anti-Inflammatory Effects

• BHB: Mixed; may be pro-inflammatory in some contexts

• Butyrate: Robust anti-inflammatory effects

3. GPR109A Agonist Activity

• BHB: Yes

• Butyrate: Yes

4. Alternative Fuel Source

• BHB: Yes, for brain, heart, and muscle

• Butyrate: Yes, primarily for colonocytes

5. Regulatory T Cell (Treg) Induction

• BHB: No

• Butyrate: Yes — directly induces Foxp3+ Tregs via epigenetic mechanisms

6. IL-10 (Anti-Inflammatory Cytokine) Effects

• BHB: Unknown

• Butyrate: Upregulates IL-10, a master anti-inflammatory cytokine

7. Practical Delivery

• BHB: Ketogenic diet, exogenous ketones, fasting

• Butyrate: Produced via fiber fermentation; oral supplements are poorly absorbed (~5%)

How Ketones Affect Gene Regulation

1. β-Hydroxybutyrylation

   • BHB attaches to histones via β-hydroxybutyrylation, subtly influencing gene activity.

2. Indirect epigenetic effects

   • Ketosis alters metabolic cofactors affecting DNA and histone methylation.

3. Signaling pathways

   • BHB activates receptors like GPR109A, reducing inflammation and supporting metabolism.

Bottom line: BHB has meaningful roles, just not the robust HDAC inhibition originally claimed.

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. 

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.

Practical Tips for a Balanced Keto Diet

1. Eat Fiber-Rich, Low-Carb Vegetables

• Spinach, kale, broccoli, cauliflower, zucchini, and peppers.

• Supports gut bacteria to produce butyrate, enhancing HDAC-related benefits.

2. Moderate Protein Intake

• Excess protein can reduce ketone production.

• Aim for a sustainable amount to maintain ketosis while preserving gut health.

3. Stay Hydrated and Maintain Electrolytes

• Ketosis increases water and mineral excretion.

• Ensure sufficient hydration and electrolytes to support metabolism.

4. Rotate High-Fiber Low-Carb Foods

• Diverse vegetables feed different gut bacteria.

• Maximizes butyrate production and overall microbiome diversity.

5. Consider Intermittent Fasting

• Naturally raises BHB levels.

• Can complement ketogenic diets for metabolic and signaling benefits.

6. Track Ketone Levels (Optional)

• Blood BHB meters help monitor nutritional ketosis.

• Remember, fiber-derived butyrate also contributes to health, independent of BHB.

FAQ: Ketones, Butyrate, and Epigenetics

Q1: Does BHB provide epigenetic benefits?
Yes, through β-hydroxybutyrylation, but its HDAC inhibition is weak compared to butyrate.

Q2: What is butyrate’s role?
It’s a gut-produced short-chain fatty acid and a strong HDAC inhibitor, regulating metabolism and inflammation.

Q3: Can keto reduce butyrate production?
Yes, if fiber intake is too low.

Q4: Can I get benefits from both BHB and butyrate?
Yes, include low-carb, fiber-rich vegetables while maintaining moderate ketosis.

Q5: Should I stop keto to get epigenetic benefits?
No. Balance ketosis with fiber intake for optimal metabolic and gut health.

Q6: Is beta-hydroxybutyrate (BHB) a meaningful HDAC inhibitor?
Early research suggested BHB acted as a histone deacetylase (HDAC) inhibitor, which fueled claims that ketosis delivered powerful epigenetic benefits. Later head-to-head studies failed to confirm this. Direct comparisons show BHB does not significantly inhibit HDACs in cells or living systems.

Q7: What molecule actually provides strong HDAC inhibition in the body?
Butyrate, a short-chain fatty acid produced by gut bacteria when they ferment dietary fiber, is a well-established and potent HDAC inhibitor. It increases histone acetylation, regulates gene expression, and reduces inflammation across multiple tissues.

Q8: How did the original BHB-HDAC theory gain traction?
A highly cited 2012 paper in Science reported that BHB inhibited class I HDACs at concentrations seen during fasting or ketosis. The paper shaped a decade of keto-related messaging. Subsequent studies using improved methods failed to reproduce those findings.

Q9: How do ketogenic diets affect butyrate production?
Ketogenic diets often reduce fiber intake and suppress beneficial gut bacteria that produce butyrate. Reviews and clinical studies show ketogenic diets lower fecal butyrate and other short-chain fatty acids, raising concerns about colonic and immune health.

Q10: Does BHB still provide real benefits?
BHB serves as an alternative fuel for the brain, heart, and muscles, activates the GPR109A receptor, and supports seizure control in epilepsy. It also participates in histone β-hydroxybutyrylation, a distinct process from HDAC inhibition. These benefits do not rely on HDAC suppression.

Conclusion

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 (low carb high fat) 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:

• Ketogenic diets cannot provide (and may actually impair)
• Oral butyrate supplements miss (absorbed in small intestine)
• Standard fiber supplements do inefficiently (dependent on microbiome composition)

References:

1. PMC6346118 – Butyrate vs BHB HDAC comparison

2. Shimazu et al., 2013 – BHB inhibits HDACs

3. β-hydroxybutyrylation and epigenetic regulation

4. https://articles.mercola.com/sites/articles/archive/2026/01/14/keto-bhb-hdac-myth.aspx

5. Ketogenic Diet Alters the Epigenetic and Immune Landscape of Prostate Cancer to Overcome Resistance to Immune Checkpoint Blockade Therapy (Cancer Research 2024)