Gene Regulation
Butyrate Reversed Gene Chaos in Kabuki Cells
Butyrate, a compound made when bacteria digest dietary fiber, restored normal gene activity patterns in blood cells from children with Kabuki syndrome—offering a potential path toward simple dietary or supplement-based therapy
Kabuki is called a 'chromatin-related' disorder. What does that mean?
Chromatin is how our DNA is packaged inside cells. In Kabuki, a change in the gene KMT2D disrupts this packaging, which changes how other genes get switched on and off.
Does this only affect the brain?
No. The KMT2D gene is active in most cells, including the immune system. So researchers can study its effects using a simple blood sample.
What did they find in the blood of Kabuki kids?
Compared to healthy children, their immune cells showed a shared pattern: disrupted ribosomal pathways and disrupted immune pathways. This same signature appeared across several different neurodevelopmental disorders.
Is there anything that could help?
They tested butyrate, a natural substance from fibre digestion, on the cells in the lab. It largely reversed these abnormal patterns, calming the immune activity and restoring normal function.
A new study suggests that a natural substance produced in the gut—called butyrate—may reverse some of the disrupted gene activity seen in children with Kabuki syndrome and related neurodevelopmental disorders.
The findings offer a potential path toward a therapy that targets the underlying biology of these conditions, rather than just managing symptoms.
Butyrate is a short-chain fatty acid, not a ketone. Despite its similar-sounding name, it is chemically distinct from the ketone bodies produced by the ketogenic diet. This means butyrate represents a different supplement pathway than the keto drinks or diets some families may have encountered.
What the study looked at
Researchers in Australia examined blood cells from children with four types of neurodevelopmental disorders: Kabuki syndrome, CHARGE syndrome, Rett syndrome, and a group of children with complex developmental disabilities who did not have a single identifiable genetic cause.
They sequenced the RNA—the molecular messages that cells use to read their genes—from the blood cells of 19 children with these conditions and 21 healthy age- and sex-matched controls.
Their goal was to see whether these different conditions share a common pattern of disrupted gene activity, and whether butyrate could shift that pattern back toward normal.
A shared disruption
At the start of the study, before any treatment, the researchers found something striking. All four groups of children—regardless of which gene caused their condition—showed similar disruptions in their blood cells' gene activity.
Specifically, the children's cells showed reduced activity in ribosomal pathways—the cellular machinery that builds proteins. At the same time, their immune pathways were overactive.
This pattern appeared not only in the children with known genetic syndromes like Kabuki, but also in the group without a single identified genetic cause, suggesting that chromatin dysfunction—problems with how DNA is packaged and read—may be a common thread across many neurodevelopmental disorders.
What butyrate did
The researchers then took immune cells from one child in each group, plus two healthy controls, and treated these cells in a lab dish with butyrate.
They used single-cell RNA sequencing—a powerful technique that can measure gene activity in tens of thousands of individual cells at once—to see what happened.
The results were clear: butyrate largely reversed the disrupted gene activity, normalizing both the ribosomal and immune pathways in the treated cells.
Specifically, butyrate increased the activity of genes involved in building proteins (ribosomes), cellular energy production (mitochondria), and cell structure (cytoskeleton). It decreased the activity of overactive immune and epigenetic pathways.
Why this matters for Kabuki families
Kabuki syndrome is caused by changes in genes that help control how DNA is packaged in the cell's nucleus—a process called chromatin regulation. The most common gene involved is KMT2D, which provides instructions for a protein that adds chemical marks to histones, the spools around which DNA is wound.
When these marks are missing, cells can't read their genes properly. This study suggests that this disruption leads to a specific signature of ribosomal and immune problems that butyrate can partially correct.
The study used butyrate at a dose of 5 mM, which was chosen based on the blood levels of ketone bodies seen in children on the ketogenic diet for epilepsy. But butyrate itself is not a ketone—it is a different molecule with its own properties.
Important caveats
This work is early-stage, and the researchers are careful to note its limitations. The study used blood cells, not brain tissue, because it is not possible to take brain samples from living children. Chromatin is found in most cell types throughout the body, so blood cells can serve as a useful window into these broader processes.
The sample sizes were small—only one child from each group was used for the butyrate experiments—meaning the results need confirmation in larger studies.
What comes next
The researchers call for larger studies, both in the lab and eventually in clinical trials, to evaluate the safety and effectiveness of butyrate and related compounds in children with neurodevelopmental disorders.
They also note that more detailed testing is needed to confirm whether butyrate actually improves immune function in these children, and to understand how it affects the brain.
For now, this study provides a clear scientific rationale for investigating butyrate as a potential therapy. It suggests that a simple, naturally occurring substance might help reset some of the disrupted gene activity that lies at the heart of Kabuki syndrome and related conditions.
Deeper concepts
These ideas from the paper require more specialized vocabulary than fits the main article:
• Butyrate acts as a histone deacetylase (HDAC) inhibitor, which means it can change how tightly DNA is wound around its packaging proteins, making genes more or less accessible to be read by the cell.
• The researchers identified a common ribosomal-immune RNA signature across the conditions they studied, characterized by downregulated ribonucleoprotein complex biogenesis and upregulated immune pathways.
• GTPase activity and cytoskeleton organization pathways, which were affected by butyrate treatment, are important mechanisms of chromatin remodeling—the process by which cells reorganize their DNA packaging to control gene activity.
• The study used both bulk RNA sequencing of whole blood and single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs), which includes T cells, B cells, monocytes, and other immune cell types.
• T cells were the largest individual cell population across samples, representing 52–83% of cells, and were analyzed separately as well as in the overall bulk analysis.
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