Butyrate — The Gut-Brain Axis Connector That Influences Mood and Cognition

Butyrate, a short-chain fatty acid (SCFA) produced in your colon through the bacterial fermentation of dietary fiber, is a metabolite byproduct that nourishes your colonocytes (i.e., the cells lining your colon). Interestingly, it’s also an important signaling molecule within the complex communication network between your gut and your brain, known as the gut-brain axis. As explained in a paper published in Nutrients,¹ the gut-brain axis is a bidirectional communication system involves a dynamic interplay of neural, hormonal, immune, and metabolic pathways, enabling constant information exchange between your gastrointestinal tract and your central nervous system.

The exchange of information between your gut and brain affects a multitude of functions, from stress and pain tolerance to immunity,² brain function and even mood.

Butyrate’s Role in Combatting Neuroinflammation

When inflammation within the brain (neuroinflammation) becomes chronic, it creates neuronal damage, synaptic dysfunction, and ultimately, cognitive decline.

Neuroinflammation is widely recognized as a key factor in the development and progression of a wide range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Within this context, researchers sought to understand how butyrate, which originates from the gut, promotes brain health.

• Butyrate boosts mitochondrial function in brain cells — In a meta-analysis published in Neuroscience Letters,³ researchers hypothesized that butyrate is able to promote brain health because of its diverse modes of action that influence the gut-brain axis. Notably, they proposed that the butyrate produced through fermentation of dietary fiber boosts the health of mitochondria located in the brain.

“While the metabolic events in the colon may appear disconnected from that of the brain, it’s important to consider the immense energy demands of the brain and the energy dyshomeostasis that occurs in the brain in many neurological diseases. Perhaps the best cited example is the reduced glucose utilization in the Alzheimer’s brain, which occurs at the earliest stages of the disease and well before memory loss …

However, we hypothesize that if sufficient butyrate levels could be reached in the brain, butyrate could stand in as an energy substrate, as in the colon, and restore energy homeostasis,” the researchers said.⁴

• The dangers of reduced glucose availability in the brain — The study authors highlighted this problem, which “is believed to contribute to mitochondrial dysfunction in acute and chronic neurological diseases.”⁵ These findings reinforce what I’ve written about before, which is the health dangers of following a low-carb diet, as your body actually needs carbs to function at an optimal state.
• Butyrate lowers the risk of colon cancer — Based on the evidence reviewed by the researchers, butyrate activates GPR109a (a G protein-coupled receptor found on the surface of cells), which belongs to the larger family of G protein-coupled receptors (GPCRs). This receptor is present in colonocytes (cells lining the colon) and T cells (immune cells), and when this particular protein is expressed, it triggers programmed cell death (apoptosis) in human colon cancer cells.

A Deeper Dive Into Butyrate’s Ability to Inhibit Neuroinflammation

Butyrate also inhibits proinflammatory signaling pathways, such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, a master regulator of inflammation. As explained in the Neuroscience Letter paper:⁶

“Treatment with β-hydroxybutyrate induced anti-inflammatory effects in both in vitro and in vivo models of Parkinson’s disease through GPR109a activation and down regulating NF-κB activation. The neurons were also protected from LPSinduced [editor’s note: endotoxin-induced] injury and improved behavioral outcomes in the animal models.”

By inhibiting NF-κB activation, butyrate curtails the production of inflammatory mediators like cytokines,⁷ which promote synaptic dysfunction that contributes to worsening brain health.⁸

• Butyrate inhibits histone deacetylases (HDACs) —⁹ These enzymes modify histones, proteins around which DNA is wrapped, thereby influencing gene expression.
• HDAC inhibition manages brain inflammation — By inhibiting HDACs, butyrate induces epigenetic modifications that alter gene expression in brain cells,¹⁰ thereby decreasing the production of proinflammatory substances while simultaneously increasing the production of anti-inflammatory molecules, effectively dampening the inflammatory response in the brain. Going deeper, a study published in Frontiers in Neuroscience provides a more nuanced look at butyrate’s HDAC-limiting capabilities to help fight neuroinflammation associated with ischaemic stroke:¹¹

“In addition to its role as an antitumor agent, butyrate partially achieves its anti-inflammatory effects by inhibiting HDAC.

For example, butyrate reduced neuroinflammation caused by microglia in IS [ischaemic stroke] mice by inhibiting HDAC, thereby altering the gene initiation of histone-3-lysine 9-acetylation (H3K9ac) in microglia. In conclusion, butyrate modulates microglia in the brain to attenuate neuroinflammation in IS through multiple mechanisms.”

• Butyrate lowers the risk of Alzheimer’s disease — Another study, which used animal test models of Alzheimer’s disease, demonstrated that butyrate reduces the accumulation of amyloid-beta plaques, a pathological hallmark of the disease, and concurrently improves cognitive function. In fact, it was able to reduce amyloid-beta plaques by as much as 40%.¹²
• GLP-1 stimulation by butyrate helps fight against Parkinson’s disease — Animal models have shown butyrate to have protective effects by stimulating glucagon-like peptide-1 (GLP-1).¹³ GLP-1 and GLP-1 receptor agonists (medications that mimic GLP-1) are being actively studied as potential treatments for Parkinson’s disease because they appear to have neuroprotective effects. In addition to reducing brain inflammation, research has shown that GLP-1 protects dopamine-producing neurons, which are damaged in Parkinson’s disease, by reducing oxidative stress and improving mitochondrial function. GLP-1 also:

• Enhances autophagy — The cell’s natural cleaning process that removes damaged proteins and cellular components. This is particularly important because Parkinson’s disease involves the accumulation of misfolded proteins (especially alpha-synuclein).^14,15
• Boosts metabolic function — Improves insulin sensitivity and cellular energy metabolism in the brain,¹⁶ which is often impaired in Parkinson’s disease. Better energy metabolism helps neurons function more effectively and resist damage.

The Role of Butyrate in Neurotransmitter Function and Mood

Neurotransmitters are chemical messengers that transmit signals between nerve cells (neurons) in the brain, orchestrating a vast array of brain functions, including mood, behavior, cognition, sleep and appetite. And based on published evidence, butyrate (as well as other SCFAs) influences the production, release and signaling of several key neurotransmitters, including GABA (gamma-aminobutyric acid) and dopamine.¹⁷

• GABA is the primary inhibitory neurotransmitter in your brain — It acts as a natural calming agent by reducing neuronal excitability, promoting relaxation, and alleviating anxiety.¹⁸

Butyrate and other SCFAs have been shown to enhance GABA production in the gut, and remarkably, research has shown that GABA helps modulate abdominal pain and bowel disorders, showcasing the symbiotic relationship of the gut-brain axis.¹⁹

• Dopamine controls your reward responses — A neurotransmitter associated with motivation, movement and pleasure, dopamine is also modulated by butyrate. Butyrate crosses the blood-brain barrier to enhance its production, as well as microglial function and development.²⁰

By modulating these vital neurotransmitter systems, butyrate exerts a significant influence on mood disorders such as anxiety and depression. Research has shown a link between altered gut microbiota composition, reduced butyrate production and the development of these conditions.²¹

Butyrate and Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors, which are essential for the survival, growth, differentiation, and maintenance of neurons. BDNF plays a vital role in neuronal plasticity, the brain’s ability to change and adapt its structure and function in response to external stimuli, which is fundamental for learning and memory formation.^22,23

• BDNF production and expression is increased — Research shows butyrate boosts BDNF production, targeting brain regions essential for learning and memory, such as the hippocampus, by inhibiting HDACs.²⁴ This increase in BDNF promotes neurogenesis (the birth of new neurons),²⁵ strengthens existing neuronal connections (synapses),²⁶ and protects neurons from inflammatory damage.²⁷
• Deficiency increases your risk of neurological conditions — Reduced BDNF levels have been consistently implicated in the pathophysiology of various neurological and psychiatric conditions, including depression²⁸ and Alzheimer’s disease.²⁹ By enhancing butyrate production, the resulting rise in BDNF levels protects against these debilitating conditions and promotes cognitive resilience.

Butyrate’s Role in Vagus Nerve Crosstalk

The vagus nerve, often referred to as the “wandering nerve” due to its extensive network throughout the body, is the longest cranial nerve and serves as a major communication highway between the gut and the brain.³⁰

• The vagus nerve allows your gut and brain to communicate — Essentially, the vagus nerve functions as the information highway of the gut-brain axis, affecting a widearray of neural/digestive functions, including mood regulation, stress response, appetite control, and immune function.
• Butyrate travels along the vagus nerve — Sensory information arising from the gut, including signals related to the presence and concentration of butyrate, travel along the vagus nerve to reach various brain regions, influencing their activity and function.
• Butyrate directly stimulates nerve endings located in the gut lining — This process triggers the transmission of electrical and chemical signals to the brain via the vagus nerve.³¹

Integrating Gut Health and Brain Health

Dietary fiber is the fuel that is responsible for the production of butyrate and other SCFAs in your gut. From there, butyrate works its metabolic magic on the gut-brain axis, helping promote cognitive function. But how do you effectively increase butyrate production? While the obvious answer is increasing your fiber intake, there are caveats to this approach.

• Start with healthy carbs — If you have only moderate gut issues, you’ll be able to start with options like white rice and ripe, whole fruits right away.
• Severe gut issues require a different approach — If your gut health is severely compromised, it’s important to build it from the ground up again. I recommend sipping on dextrose water throughout the day as a transitional solution until you’re able to eat fruits and rice. Unlike complex carbohydrates, dextrose is metabolized in the small intestine and doesn’t feed the bad bacteria in your colon.
• Add more dietary fiber in the long run — As your gut begins to improve, you’ll be able to move on to more fiber-rich veggies and starches without creating digestive problems. But dietary fiber isn’t the only aspect that’s emphasized when optimizing overall gut health. It’s also wise to add more fermented foods to your diet. This approach helps restore a balanced gut microbiome, meaning your good bacteria keep pathogenic bacteria in check.

Here are additional recommendations that will help optimize your gut-brain connection further:

1. 1. Make your own fermented foods at home — Creating fermented foods at home ensures you receive fresh, potent probiotics. Homemade options like yogurt, kefir and sauerkraut contain a diverse array of beneficial bacteria essential for a healthy gut microbiome. Plus, making your own fermented foods is cost-effective and allows you to control the ingredients, avoiding unnecessary additives, genetically modified ingredients and refined sugars found in mass-produced probiotic goods.
   2. Avoid pasteurized commercial fermented foods — Commercially available fermented foods are often pasteurized to extend shelf life, which kills the live bacteria necessary for gut health. If you’re unable to make fermented vegetables at home, opt for traditionally fermented, unpasteurized products sourced from reputable businesses. But again, a better solution is preparing them yourself to maximize the health benefits.
   3. Incorporate various fermented foods into your diet — Diversity is key when it comes to fermented foods. Different types offer unique strains of probiotics that work synergistically to enhance your gut microbiome’s resilience. Include a range of options such as kimchi, natto, homemade yogurt and homemade fermented vegetables in your daily meals. Variety helps ensure a robust and balanced microbiome, which is essential for optimal gut-brain communication.
   4. Maintain consistent consumption — Regularly consuming fermented foods is essential for sustaining a healthy gut microbiome and reaping long-term mental health benefits. That’s because the modern Western diet is filled with ingredients that consistently destroy beneficial gut bacteria. Therefore, reseeding your gut with probiotics is important. Make it a habit to include fermented foods in your everyday diet, whether through meals or snacks. Consistency helps maintain gut microbiota diversity, reduces inflammation and supports stable neurotransmitter levels, all of which contribute to improved mood and cognitive function.

Frequently Asked Questions About Butyrate’s Role in the GutBrain Axis

Q: What is butyrate and why is it important?

A: Butyrate is a short-chain fatty acid produced when beneficial bacteria in your colon ferment dietary fiber. Beyond nourishing cells in your colon, butyrate also serves as a crucial signaling molecule along the gut-brain axis, helping regulate inflammation, mood, and energy metabolism.

Q: How does butyrate combat neuroinflammation and support brain health?

A: Research shows that butyrate inhibits inflammatory pathways, particularly the NF-κB pathway, and even boost mitochondrial function in brain cells. By reducing brain inflammation and oxidative stress, it helps protect neurons, which helps lower the risk of neurodegenerative diseases like Alzheimer’s, Parkinson’s, and multiple sclerosis.

Q: What role does butyrate play in preventing colon cancer?

A: Consuming adequate dietary fiber (especially from starches, fruits, and vegetables) is key to boosting butyrate production. Fermented foods like homemade yogurt, kefir, and sauerkraut further enrich your gut microbiome, enhancing natural butyrate production. If you have severe gut issues, starting with easily digestible carbs (like dextrose water) and gradually increasing fiber intake is recommended to rebuild your gut health over time.

Analysis by Dr. Joseph Mercola

Sources and References

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²Cleveland Clinic, September 20, 2023, The Gut-Brain Connection
^{3 4 5 6} Neuroscience Letters, Volume 625, June 20, 2016, Pages 56-63
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⁸ Molecular Brain, Volume 17, Article number: 4 (2024), Abstract
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¹¹Front Neurosci. 2024 Feb 29;18:1304906, Discussion
¹² Journal of Alzheimer’s Disease. 2020;74(1):91-99, Abstract
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¹⁸ Cleveland Clinic, April 25, 2022, Gamma-Aminobutyric Acid (GABA)
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²³ The University of Queensland, What Is Synaptic Plasticity?
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³⁰ Massachusetts General Hospital, October 16, 2024
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