Metabolite of the Month: Short-Chain Fatty Acids - Butyrate

Metabolite of the Month: Short-Chain Fatty Acids - Butyrate

By Andrea McBeth, ND

Welcome back to our Metabolite of the Month series. This month, I will discuss the most popular postbiotic: butyrate. Its rise to fame began as early research highlighted its connections to the gut-brain, gut-immune, gut-metabolism, and gut-cancer axes. On paper, butyrate looked like the missing link between gut dysbiosis and chronic disease. However, as supplement companies and researchers started touting it as a panacea, its momentum waned. It turned out that butyrate was more complicated than we originally thought

Complications aside, butyrate is fascinating in its mechanisms and serves as a great model to understand the tip of the metabolite (postbiotic) iceberg and the importance of maintaining an appropriate balance within a healthy gut ecosystem. Butyrate exemplifies the complex interplay between a healthy gut and overall health, and it is also illustrative of the pitfalls of trying to oversimplify the complex systems within our microbiome as they relate to health. 

I hope you enjoy this month’s journey through the inspiring and sometimes confusing world of science as we explore all the amazing things butyrate does and ponder why 6 grams per day of supplemented sodium butyrate does not, in fact, keep the doctor away.

Starting with the Basics: Short-Chain Fatty Acids (SCFAs)

SCFAs are fatty acids with fewer than six carbon atoms, primarily produced in the gut through the fermentation of dietary fibers by anaerobic bacteria (bacteria that do not live or grow where oxygen is present). The most prevalent SCFAs are acetate, propionate, and butyrate, typically found in a ratio of 60:20:20, respectively. SCFAs are rapidly absorbed and utilized by colonocytes, the cells lining the colon. Butyrate, in particular, serves as a primary energy source for these cells, supporting their function and integrity.  But it does more than just that, and below is an overview of the roles we now have evidence it plays and some mechanistic insights into how butyrate impacts health.

Butyrate’s Many Roles

  1. Energy Source for Colonocytes: Butyrate is the preferred energy source for the cells lining the colon, colonocytes. It helps maintain the integrity of the gut lining and supports overall gut health by producing ATP, crucial for cell function and proliferation.
  2. Anti-Inflammatory Effects: Butyrate has potent anti-inflammatory properties, promoting the differentiation of regulatory T cells (Tregs) in the gut-associated lymphoid tissue (GALT), thereby maintaining immune balance and suppressing inflammatory responses.
  3. Histone Deacetylase Inhibition: Butyrate acts as a histone deacetylase (HDAC) inhibitor, influencing gene expression by altering chromatin structure. This property has implications for cancer prevention and treatment, as well as for reducing inflammation. By inhibiting HDAC, butyrate promotes the acetylation of histones, enhancing the transcription of tumor suppressor genes and anti-inflammatory genes.
  4. Barrier Function: Butyrate enhances the gut barrier function, preventing the translocation of harmful bacteria and toxins into the bloodstream. It strengthens the tight junctions between epithelial cells, reducing intestinal permeability and protecting against conditions like leaky gut syndrome.
  5. G Protein-Coupled Receptors (GPCRs) Binding: Butyrate binds to GPCRs such as GPR41 and GPR43, impacting downstream cellular gene expression and signaling pathways. This binding influences various physiological processes, including inflammation, metabolism, and gut motility, highlighting the complex interplay between diet, microbiota, and host health.

Butyrate’s Mechanistic Insights

Oxidative Stress:

Pre-treatment with butyrate improves oxidative stress tolerance and increases lifespan and healthspan in model organisms like Caenorhabditis elegans. Butyrate enhances resistance to oxidative stress by upregulating genes involved in oxidative stress response and modulating mitochondrial function.

Gut-Brain Axis:

Butyrate influences brain function by modulating the gut-brain axis. It can reduce symptoms of anxiety and depression, enhancing brain-derived neurotrophic factor (BDNF) levels in the hippocampus, which is critical for mood regulation and cognitive function.

Metabolic Health:

Butyrate improves insulin sensitivity and reduces systemic inflammation, making it a promising metabolite for managing metabolic disorders. It activates AMP-activated protein kinase (AMPK) and upregulates peroxisome proliferator-activated receptor gamma (PPARγ), playing essential roles in regulating glucose and lipid metabolism.

If butyrate is so influential, then why wouldn’t supplementing with butyrate solve all our problems?

Endogenous Production vs. Supplementation: 

While butyrate supplementation can provide some benefits, it often falls short of the comprehensive health effects observed when butyrate is produced endogenously (within us) by a healthy gut microbiota. This discrepancy can be attributed to several factors:

  • Microbial Ecosystem Synergy: The gut microbiota produces a diverse array of metabolites, including butyrate, acetate, propionate, and numerous other small molecules. These metabolites work synergistically to promote gut health and systemic effects. For example, acetate and propionate also contribute to metabolic health by influencing lipid metabolism and gluconeogenesis in the liver​​​​.
  • Metabolite Ratios and Interaction: The relative abundance and ratio of SCFAs to other metabolites are crucial. A balanced production of these metabolites ensures optimal cell signaling and receptor activation in enterocytes and immune cells​​ .
  • Receptor Binding and Signaling: SCFAs interact with various G-protein-coupled receptors (GPCRs) on the surface of gut cells and immune cells. These interactions trigger a cascade of signaling pathways that regulate inflammation, gut barrier function, and even brain function via the gut-brain axis​​​​.

Systemic Absorption and Effects: 

For butyrate to exert effects beyond the gut, it must be absorbed into the bloodstream. However, this process is not straightforward:

  • Butyrate Transport Mechanisms: Butyrate is primarily utilized by colonocytes, but some of it can enter the portal circulation and reach the liver. From the liver, butyrate can potentially influence systemic metabolism and immune responses. However, the efficiency of this transport and its subsequent impact on distant organs depend on various factors, including the presence of other SCFAs and metabolites​​.
  • Systemic Health Implications: Studies have shown that butyrate and other SCFAs can modulate systemic inflammation, metabolic health, and even neurological functions by influencing immune cell activity and crossing the blood-brain barrier.

Theoretical Considerations: 

Several theories and emerging concepts in microbiome research support the multifaceted roles of SCFAs:

  • Metabolite Cross-Feeding: Different microbial species in the gut engage in cross-feeding, where the metabolic by-products of one species serve as substrates for another. This metabolic interdependence enhances the production of beneficial metabolites, including butyrate​​​​.
  • Microbiome-Gut-Brain Axis: The gut microbiome influences brain health through the production of SCFAs and other metabolites that can modulate neurotransmitter synthesis and inflammatory responses in the brain. Butyrate, in particular, has been shown to enhance the production of brain-derived neurotrophic factor (BDNF), which supports cognitive function and resilience against stress.

Thaena’s Early Days

Our early work at Thaena focused on butyrate and SCFAs. We theorized that if we could create a supplement containing SCFAs—specifically butyrate—from sterilized, freeze-dried stool, we could provide a meaningful health boost, piggybacking on butyrate’s early mechanistic discoveries. There was a problem, though. We wanted to freeze-dry our sterilized stool, but the prevailing belief was that freeze-drying would volatilize (lose in the air) all the SCFAs. Hence, my first pitch for repurposing the very stinky ice that condensed in our freeze-drying machine as a skincare treatment. But I digress. 

At the time, a brilliant student working with us was determined to solve this problem. After discovering some 1990s research on freeze-dried milk, we applied similar principles and adjusted the pH of the stool slurry to be basic (higher pH) before freeze-drying. We ran a series of metabolomics experiments and, after a long fight with an analytics company, proved that the SCFAs were indeed retained in the powder at the higher pH. Our early work focused on this class of molecules, and we thought it would be the star of our story. 

However, we soon realized that the concentrations in our daily 100mg pill (we're talking microgram quantities) were insignificant compared to the 5-20 grams of butyrate, propionate, and acetate that a healthy gut produces each day from a fiber-rich diet. This discrepancy made it clear that our understanding had to be more complex—shocking, I know.

Over the years, I have learned that while butyrate is present in ThaenaBiotic® and is a fascinating part of our early research, it is not the sole reason ThaenaBiotic® helps people. It turns out that the mechanisms behind ThaenaBiotic® are far more complex than a single super molecule. Like much of herbal medicine and microbiome science, the effects are multifactorial and likely co-regulatory. Overall, SCFAs will always be important to the gut microbiome, and I hope that learning about butyrate will further intrigue you and help you understand both the complexity of our systems and the importance of gut health to our overall well-being.


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