March 30, 2022 6 min read
Thousands of bioactive molecules in our bodies are made not by our human cells but by the bacteria in and on us. The gut, specifically the colon, is the most densely populated region, with upwards of 100 trillion resident bacteria.
These microbes power their metabolisms by consuming molecules that we eat (e.g., fiber), molecules made by human cells (e.g., complex sugars within mucus proteins), and/or molecules made by other bacteria.
In turn, these microbes produce essential nutrients for our body (e.g. vitamin B12 and K).
The gut bacteria also secrete metabolites that interact with our tissues and modulate their function. One such metabolite is butyrate.
Butyrate is a 4-carbon short chain fatty acid. Short chain fatty acids, like all fatty acids, are molecules with a backbone composed of carbon and hydrogen. Specifically, short chain fatty acids have a backbone that is between one and five carbons in length.
There are four primary bacteria in the gut that produce butyrate from indigestible carbohydrates:
All of these species are from the phylum Firmicutes. Additionally, other bacteria also produce butyrate:
The Bifidobacterium probiotics generate butyrate from lactate (a product of glucose metabolism) and acetate (a two-carbon short chain fatty acid).
All of the primary butyrate-producing bacteria are anaerobes, meaning that they can only grow in low-oxygen environments. Because oxygen levels in a healthy colon are extremely low, these organisms thrive in this ecosystem.
Butyrate produced in the colon is taken up and metabolized by colonocytes (colon cells), where it serves as the major energy source for these cells. Additionally, because cells must consume oxygen in order to burn butyrate, the colonocyte butyrate oxidation further drives down oxygen levels and promotes the growth of anaerobic bacteria.
In addition to supporting energy metabolism in colonocytes, butyrate also exerts anti-tumor effects and can protect individuals against the development of colorectal cancer. Specifically, butyrate can inhibit cell proliferation, promote apoptosis (i.e. programmed cell death) in tumor cells, and reduce the ability of tumor cells to invade neighboring healthy tissue.
Butyrate also enters the immune cell niche within the gut, where it is taken up by resident macrophages. In these cells, butyrate directly modulates gene expression to decrease the production of inflammatory mediators and increase the production of anti-inflammatory factors.
In the setting of gut inflammation, the transporters that mediate the uptake of butyrate into colonocytes and resident immune cells become down-regulated. This results in colonocytes being unable to burn butyrate, which subsequently drives up oxygen levels in the gut, facilitating the growth of pathogenic, aerobic (i.e., oxygen-loving) bacteria, and preventing the growth of our friendly anaerobes.
Moreover, due to lack of transport into macrophages, butyrate is unable to inhibit the release of inflammatory factors and up-regulate the release of anti-inflammatory factors.
In this way, inflammation in the gut drives a vicious cycle that actively prevents itself from being extinguished. Indeed, aberrations in butyrate metabolism have been observed in irritable bowel diseases including Crohn’s disease and ulcerative colitis.
To heal an inflamed gut, it is important to begin by spinning down inflammation. Otherwise, attempts to up-regulate butyrate consumption and production through diet and supplementation will fail due to the transport bottleneck and inhibition of anaerobe growth.
To this end, the use of exogenous antioxidants and molecules that up-regulate our natural anti-inflammatory processes is key.
For example, the phenolic compound hesperidin, found in high levels in orange juice, has been shown to ameliorate colitis through up-regulation of cellular antioxidant pathways. This results in the increased production of enzymes involved in neutralizing reactive oxygen species (ROS; also known as free radicals). Furthermore, hesperidin has been shown to upregulate proteins involved in maintaining the integrity of the tight junctions between cells in the gut. The failure of these tight junctions is what leads to the condition known as leaky gut.
Another helpful intervention is supplementation with the molecule N-acetyl cysteine (NAC). NAC is the precursor to glutathione: the most abundant antioxidant molecule in the body. Glutathione is synthesized by cells and neutralizes ROS.
Finally, the introduction of polyphenol rich foods into the diet (e.g., highly pigmented fruits like berries and pomegranate) will not only feed friendly microbes in the gut, but the polyphenols can also directly scavenge free radicals and exert anti-inflammatory effects in the gut.
In a non-inflamed gut, butyrate status can be optimized through both diet and supplementation.
Anaerobes in the colon use indigestible carbohydrates and polyphenols as the substrate for butyrate production.
Accordingly, consumption of foods containing these compounds will preferentially feed these bacteria and support butyrate levels.
These foods include resistant starches such as those found in:
Eating butter or taking butyrate supplements like sodium/calcium butyrate isn’t going help increase the butyrate levels in the long run. Scientific research shows that feeding the butyrate-producing bacteria is the key to increase butyrate levels in the colon. If those bacteria are fed with the right food – prebiotic fibers, they stay and thrive.
Prebiotics are indigestible molecules that reach to the colon where they serve as a food source for commensal bacteria. Supplementation with prebiotics, like human milk oligosaccharides (HMOs), feeds key bacteria in the gut, which in turn support the growth of butyrogenic bacteria.
HMOs are indigestible carbohydrates discovered in human breast milk. Their function is to establish the gut microbiome in newborns by feeding Bifidobacteria in the infant gut. In adults, the consumption of HMOs, like 2’-fucosyllactose, bolsters Bifidobacteriacommunities and helps to boost butyrate production which goes on to support the maintenance of gut barrier integrity, favorable modulation of the immune system, and prevention or treatment or inflammatory bowel diseases.
In recent years, scientists have developed Human identical Milk Oligosaccharides (HiMOs), which created via a fermentation process. They do not contain any human milk but are molecularly identical to the HMO found in real human milk. These HiMOs are available in supplement form.
Other prebiotics like fructo-oligosaccaharides (FOS) and galacto-oligosaccharides (GOS) can also support the growth and maintenance of a healthy microbiome and a healthy gut.
Specifically, Bifidobacteria, as well as butyrate-producing bacteria from the genus Clostridium, enjoy feasting on both FOS and GOS.
Butyrate is an essential molecule for not only maintenance of colon function but also for immune modulation and the prevention and treatment of inflammatory bowel diseases.
In an inflamed gut, butyrate status should not be optimized until inflammation has been tamped down, which can be accomplished using a combination of dietary and nutraceutical approaches.
In the absence of inflammation, optimization of butyrate production and consumption can be achieved through the consumption of foods rich in resistant starch and polyphenols, as well as through supplementation with key prebiotics.
Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.
Follow Dr. Cowan on Instagram: @dralexisjazmyn
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Davani-Davari D, Negahdaripour M, Karimzadeh I, Seifan M, Mohkam M, Masoumi SJ, Berenjian A, Ghasemi Y. Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods. 2019 Mar 9;8(3):92. doi: 10.3390/foods8030092. PMID: 30857316; PMCID: PMC6463098.
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