I have been working with mast-cell stabilizers now for nearly a decade.
When I was diagnosed with histamine intolerance and mast cell activation, I could not tolerate any of the prescription mast-cell stabilizers.
That led me to research the list of 21 anti-histamine foods that fight inflammation and stabilize mast cells nearly seven years ago.
Many of that list contribute to butyrate production and highlight butyrate as a proven mast-cell stabilizer.
Since then, I have come to understand the paramount importance of butyrate.
It is a critical anti-inflammatory that helps regulate auto-immunity and signals our cells to repair themselves.
The immune system is compromised if butyrate levels are low in the microbiome.
What Is Butyrate?
Butyrate is a type of short-chain fatty acid (SCFA) or postbiotic.
SCFAs are the building blocks of fats that our cells need for energy. Without sufficient SCFAs, our cells do not have the energy to function.
Butyrate is produced mainly by our microbiome, where it provides the energy for the cells lining our intestines to function.
Around 5 – 10% of butyrate enters the bloodstream, where it circulates throughout the body to maintain energy for vital functions.
Butyrate is a postbioitic as it is produced mainly by our microbiota.
Butyrate is produced indirectly through:
The presence of butyrate-producing bacteria
Feeding on prebiotic fibers (and intestinal mucus)
Cross-feeding and interacting with the whole microbiota.
Butyrate-producing bacteria typically belong to the firmicutes phylum. A detailed list of known butyrate-producing bacteria follows:
Of these, Faecalbacterium prausnitzii are significant butyrate-producers and amongst the most abundant bacteria in a healthy microbiome.
Interestingly, in an animal study, butyrate supplementation also directly altered the gut microbiota by increasing SCFA-producing bacteria and decreasing histamine-releasing bacteria.
Butyrate production will therefore be hampered without sufficient butyrate-producing bacteria, the fiber in the diet, or a diverse and abundant microbiota.
Our microbiome regulates the cells lining our intestines.
Butyrate provides the energy to the large intestine to grow, maintain, and protect the intestinal barrier.
Certain butyrate-producing bacteria, including Rosburia intestinalis and Eubacterium rectale, feed on the intestinal lining to produce butyrate.
Therefore, a healthy intestinal lining is crucial to some butyrate-producing bacteria colonizing and feeding on it.
Without sufficient butyrate, a leaky gut is inevitable.
Mast-Cell and Immune Function
Butyrate supports the gut barrier and regulates mast cells and the immune system.
The gut immune system must mount immune responses to pathogens while maintaining immune tolerance to commensal bacteria and foods.
Butyrate levels determine whether these two seemingly competing needs can be achieved.
High levels of butyrate:
Assist the immune cells in mounting a response to bacteria, viruses, and even cancer,
Improve oral tolerance of foods,
Increase the number of immune cells that suppress inflammation and allergic responses,
Enhance the anti-bacterial activity of macrophages to restrict pathogen growth,
Suppress mast-cell activation, and
Coordinate the mast-cell and immune system to both promotes immunity and immune tolerance.
Th2 dominance, autoimmunity, and mast-cell activation are inevitable without sufficient butyrate.
Butyrate is vital to optimal energy production.
Specifically, butyrate is:
The primary energy source of the intestines (which consume up to 95% of butyrate)
An important backup source of energy to the brain (when glucose is not available – for example, when we are sleeping),
The mitochondria regulate energy production (the cells that convert food into energy – if levels are low, butyrate signals slow down energy production).
High levels of butyrate also result in metabolic programming. Butyrate;
Prevents obesity by increasing energy expenditure,
Improves blood glucose and insulin,
Regulates appetite and leptin,
Prevents fatty liver, and
Improves mitochondrial function.
Interestingly, besides being produced by bacterial fermentation, butyrate can also be produced in smaller amounts by our cells.
Without sufficient butyrate, energy homeostasis is impossible, resulting in obesity, metabolic syndrome, fatty liver, and mitochondrial issues.
Indeed, a recent 2023 study, found that the relative number of Faecalibacterium prausnitzii (the predominant producer of butyrate in a health microbiome) directly correlated with fatigue in myalgic encephalomyelitis/chronic fatigue syndrome.
The brain is a site of immense energy demands.
While our body can operate on three fuels (amino acids, glucose, and essential fatty acids), our brain cannot. Our brain’s preferred fuel source is glucose and butyrate as backup fuel.
Butyrate not only crosses the blood-brain barrier but there are SCFA transporters and receptors in the brain.
While research is still emerging, studies to date all point to butyrate playing a significant role in both the brain and the gut-brain axis.
High levels of butyrate;
Maintain the blood-brain-barrier – similar to the intestinal barrier,
Have an anti-inflammatory effect on the brain,
Facilitates neuronal plasticity by transforming short-term memory into long-term memory,
Restore neuronal plasticity as a result of illicit drug use (including cocaine or amphetamines), and I suspect pharmaceutical drug-acquired brain injuries,
Increase GABA (an important inhibitory neurotransmitter that puts the brakes on histamine in the brain),
Regulate the hypothalamic-pituitary-adrenal (HPA) by reducing cortisol in response to acute psychological stress, and
Stimulate colonic motility by stimulating serotonin secretion from the gut cells through activation of the vagus nerve.
All of these points to butyrate play an essential role in providing the energy the brain needs to maintain homeostasis in the brain and communicate with the gut-brain axis.
Mechanism of Action
The mechanism of action of butyrate is still emerging.
However, the degree of the interface between butyrate and the body is truly astounding.
Fundamental mechanisms of action include:
Microbiome homeostasis – Butyrate is vital in regulating the gut biome, producing many essential vitamins and neurotransmitters for health.
Histone activation – Butyrate activates the HDAC genes that promote survival, plasticity, and cell regeneration and protect cells from oxidative stress. This accounts for much of its mast-cell stabilizing properties.
G protein-coupled receptors (GPCR) – Butyrate regulates energy homeostasis via GPCRs. GPCRs bind extracellular signals such as light, hormones, and neurotransmitters that influence cell function. GPCRs are critical to homeostasis, the immune system, the autonomic nervous system, and energy production.
Mitochondrial activity – Butyrate regulates energy homeostasis in the mitochondria. Mitochondria are responsible for generating the energy (ATP) needed to power the cell’s biochemical reactions.
Simply put, butyrate levels regulate most, if not all, genes, cells, and functions.
How To Increase Butyrate
Fortunately, there are many ways to increase butyrate levels with foods, fibers, probiotics, and direct supplementation.
Foods high in butyrate – Butyrate is also produced in an animal’s gut and transferred via milk. Butyrate occurs naturally in whole cow’s milk, butter, ghee, cheese (especially goat’s cheese), and human breast milk.
Foods that feed butyrate-producing bacteria – To some extent, most whole grains, fruit, and vegetables have prebiotic fibers. However, foods that mainly feed butyrate-producing bacteria include:
Pumpkin seeds (pepitas)
When our microbiome is diverse and rich in butyrate-producing bacteria, feeding our microbiome a wide variety of prebiotic fibers should suffice.
However, where our diet is limited, we have a low number of butyrate producers, or gut dysbiosis then supplementation can be extremely useful to prime the gut.
Where butyrate-producing bacteria are low, prebiotic supplementation can be extremely helpful.
Prebiotics are food supplements that produce butyrate in the gut through microbial fermentation. Hyper producers of butyrate are:
Fructose Oligosaccharides (FOS)
Galactose Oligosaccharides (GOS)
Potato Starch (and RS2)
The products with butyrate-producing prebiotics are:
Zinobiotic – this is my preferred prebiotic, which tests extremely well. It can be purchased individually or at a heavily discounted price on a subscription.
MegaPre – this is my second preference.
Actilax (this is available in Australia without a prescription).
I use all three and rotate them as they feed different bacteria. These prebiotic products may be unsuitable if there is a small intestinal overgrowth where partially hydrogenized guar gum is preferable.
There has been limited research into probiotics that cross-feed with butyrate-producing bacteria.
As MegaSporeBiotic is a quorum-sensing probiotic that restores homeostasis to the microbiome, it is my preferred probiotic for increasing butyrate.
While the overall goal is to raise butyrate levels through our diet, prebiotic fibers, and probiotics, butyrate supplementation can be needed when overall butyrate levels are low.
Most studies that supplement butyrate directly use sodium butyrate.
A plethora of new types of butyrate supplements has come onto the market. Most marketing materials quote improved bioavailability.
It is important to emphasize that sodium butyrate supplementation will not directly raise butyrate-producing gut bacteria levels. It will simply protect cells from the impact of low butyrate production by the microbiome.
The dosages of sodium butyrate used in the studies vary widely.
Studies use doses of between 100 – 1200 mg/kg. Studies also use them via enemas direct to the colon. Pessaries can also likely be used. The dosage will vary if you use other forms with higher bioavailability.
It is important to note that high doses can activate the HPA axis, becoming a stressor, such that it is best to titrate any supplementation. Developing brains both while pregnant and in children also not be exposed.
Pure Encapsulations Sunbutyrate has been available in the USA for some time and is not available in Australia.
It is actively being used for irritable bowel syndrome by gastroenterologists in the USA with profound effects.
In conclusion, SCFA receptors are important mast-cell and immune function regulators, including neuroinflammation, energy metabolism, and homeostasis.
There is no commercially available way of measuring butyrate levels.
However, butyrate-producing bacteria, and the firmicutes family, are measured by most complete microbiome mapping tests.
Generally, butyrate producers should be 25% or more of the microbiome. The higher the inflammation in the body, the higher we want butyrate producers.
While demand for butyrate can be inferred from a range of standard blood panel markers, including metabolic markers (such as blood glucose, insulin, and triglycerides) and inflammation (raised CRP).
In my experience, butyrate levels are the most critical health markers and the ultimate mast-cell stabilizer.
Wang, Chun Chun, et al. “Sodium butyrate enhances intestinal integrity, inhibits mast cell activation, inflammatory mediator production and JNK signaling pathway in weaned pigs.” Innate immunity 24.1 (2018): 40-46.
Mortensen, Frank V., et al. “Short-chain fatty acids stimulate mucosal cell proliferation in the closed human rectum after Hartmann’s procedure.” International journal of colorectal disease 14.3 (1999): 150-154.
Hague, A., B. Singh, and C. Paraskeva. “Butyrate acts as a survival factor for colonic epithelial cells: further fuel for the in vivo versus in vitro debate.” Gastroenterology 112.3 (1997): 1036-1040.
Canani, Roberto Berni, et al. “Effect of Lactobacillus GG on tolerance acquisition in infants with cow’s milk allergy: a randomized trial.” Journal of allergy and clinical immunology 129.2 (2012): 580-582.
Duysburgh, Cindy, et al. “A synbiotic concept containing spore-forming Bacillus strains and a prebiotic fiber blend consistently enhanced metabolic activity by modulation of the gut microbiome in vitro.” International journal of pharmaceutics: X 1 (2019): 100021.
Henagan, Tara M., et al. “Sodium butyrate epigenetically modulates high‐fat diet‐induced skeletal muscle mitochondrial adaptation, obesity, and insulin resistance through nucleosome positioning.” British journal of pharmacology 172.11 (2015): 2782-2798.
Canfora, Emanuel E., et al. “Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial.” Scientific reports 7.1 (2017): 1-12.
Khan, Sabbir, and Gopabandhu Jena. “Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: a comparative study with metformin.” Chemico-biological interactions 254 (2016): 124-134.
Li, Robert W., and Cong-Jun Li. “Enhancing butyrate biosynthesis in the gut for health benefits.” Butyrate: Food sources, functions and health benefits Hauppauge, NY, USA nova science publishers (2014): 1-23.
Savignac, Helene M., et al. “Prebiotic feeding elevates central brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunits, and D-serine.” Neurochemistry international 63.8 (2013): 756-764.
Kao, Amy Chia-Ching, et al. “Prebiotic reduction of brain histone deacetylase (HDAC) activity and olanzapine-mediated weight gain in rats, are acetate independent.” Neuropharmacology 150 (2019): 184-191.
Mika, Agnieszka, et al. “Feeding the developing brain: Juvenile rats fed a diet rich in prebiotics and bioactive milk fractions exhibit reduced anxiety-related behavior and modified gene expression in emotion circuits.” Neuroscience Letters 677 (2018): 103-109.
Burokas, Aurelijus, et al. “Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice.” Biological Psychiatry 82.7 (2017): 472-487.
van den Berg, Jolice P., et al. “Neurodevelopment of preterm infants at 24 months after neonatal supplementation of a prebiotic mix: A randomized trial.” Journal of pediatric gastroenterology and nutrition 63.2 (2016): 270-276.
Yang, Tao, et al. “Impaired butyrate absorption in the proximal colon, low serum butyrate and diminished central effects of butyrate on blood pressure in spontaneously hypertensive rats.” Acta Physiologica 226.2 (2019): e13256.
Val‐Laillet, David, et al. “Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.” The FASEB Journal 32.4 (2018): 2160-2171.
Byrne, Claire S., et al. “Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.” The American journal of clinical nutrition 104.1 (2016): 5-14.
Mitchell, Ryan W., et al. “Fatty acid transport protein expression in the human brain and potential role in fatty acid transport across human brain microvessel endothelial cells.” Journal of neurochemistry 117.4 (2011): 735-746.
Lattal, K. Matthew, Ruth M. Barrett, and Marcelo A. Wood. “Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction.” Behavioral neuroscience 121.5 (2007): 1125.
Fehlbaum, Sophie, et al. “In vitro fermentation of selected prebiotics and their effects on the composition and activity of the adult gut microbiota.” International journal of molecular sciences 19.10 (2018): 3097.
Kratsman, Neta, Dmitriy Getselter, and Evan Elliott. “Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model.” Neuropharmacology 102 (2016): 136-145.
Guo, Cheng, et al. “Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS.” Cell Host & Microbe 31.2 (2023): 288-304.