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Butyrate: a New Health Biomarker

How to increase butyrate levels and achieve health effects beyond the gut!

Our gut or the gastrointestinal tract (GIT) is a fascinating microcosm, busy generating a complex and diverse set of chemicals that greatly impact our overall health and wellness. Besides the common duties of elimination and absorption, our GIT also helps metabolize or break down and change existing molecules whilst generating new ones, which can be both friend and foe.

Whilst the small intestine is largely responsible for digestion and absorption, the large intestine or the colon, is the epicenter of generating these chemicals. This is because the colon houses hundreds of billions of microbes, including a large range of bacteria, jostling for location and anchor sites in the colon. Real estate in the colon is highly prized, and competitive, where the bacteria live next to each other and frenzied metabolic activity is constantly taking place. These manufacturing sites act as miniature independent fermenters.

Colonies of bacteria, abut each other in tight compact spaces and compete for resources, while generating their produce that have huge implications on our overall health far beyond the gut, including but not limited to: cognitive health, diabetes, obesity, liver health, cholesterol, kidney function, systemic anti-inflammatory effect, anti-cancer effects and immune health.

Our diet greatly influences what chemicals these microbes produce. One group of chemicals are the short chain fatty acids (SFCA’s).

What are SCFA’s?

We are all familiar with omega-3 fatty acids like EPA and DHA from marine sources, or oleic acid from olive oil or linoleic acid from flax, and other vegetable oils we regularly consume. They all have common chemical structure between 18 to 22 carbon chain length with a carboxylic acid- COOH head. SFCA’s are similar in structure to their cousins except they are shorter chain length.

The three most common SFCA’s are acetate, propionate and butyrate with two, three and four carbon length chain respectively.  Butyrate is the most widely studied and is the primary food source for the cells lining the colon or the enterocytes, much like glucose is the energy source for cells in the rest of the body. Energy is essential and without energy, the cells cannot survive or even perform their daily duties in maintaining their integrity and functions. Butyrate is a key energy molecule in the colon.

What then are the benefits of butyrate?

Cancer and chemoprevention

Butyrate acts on the genes of the cells modifying them, in some cases increasing the activity (over expressing) of the beneficial genes while silencing or inhibiting the activity of harmful genes, like oncogenes) in others. In this regard, butyrate acts to reduce the incidence of cancer. Animal studies have confirmed the benefits of butyrate intake and the reduced number of cancer and pre-cancerous polyps incidence.

High intake of various types of fibre like resistant starches, soluble and insoluble fibres and natural gums is associated with raised butyrate levels in the GIT. Raised levels of butyrate are protective against various cancers including colorectal cancer.

Diabetes, insulin resistance and obesity

Several studies have shown that when butyrate levels are increased, there is a reduction in the incidence of diabetes, obesity and insulin resistance. Insulin resistance occurs when the hormone insulin becomes less effective because the hormone no longer recognizes the insulin receptor and/or the interaction between insulin and its receptor is not as strong. In such cases, diabetes is the likely outcome along with accompanying obesity. Butyrate is a well-known, AMPK enzyme activator, which essentially improves insulin sensitivity and receptor interaction thereby reducing the related metabolic syndrome of diabetes, obesity, high cholesterol and raised blood pressure.

Anti-inflammatory effects

Persistent ongoing inflammation may well be the basis of most diseases. Nuclear factor Kappa B (NFkB), is a molecule that plays a key role in inflammation. Normally, NFkB is handcuffed and prevented from being released, however, when NFkB becomes unchained and free, it quickly moves to the nucleus activating a number of inflammatory genes. Various stressors like improper diet, localized gastric stress like ulcers, carcinogens, bacterial toxins etc. readily “unchain” NFkB. Butyrate keeps the NFkB chained, and thereby reducing inflammation.

Inflammation is particularly evident in the GIT in cases of ulcerative colitis (UC) or inflammatory bowel disease (IBD), conditions that cause significant pain, loss of quality of life, activity and work for the sufferer. Human clinical studies have shown that when sodium butyrate is given orally along with the prescription drug 5-aminosalicylic acid (5-ASA), there is significant relief when compared to 5-ASA used alone. Other studies have shown that when a high fibre diet was prescribed to sufferers of UC, there was a significant improvement in the symptoms of the UC group. This was directly correlated to high levels of butyrate that the fibre generated due to the fermentation action of the microbes in the colon.

Immune Health

Butyrate has been shown to regulate the immune system not only locally in the GIT but throughout the whole body. Butyrate helps the immune system to mature, as well as priming the key immune players to become more alert and be ready to face off invaders. In this way, butyrate improves the ability of immune cells to fight the invaders more effectively. A recent study showed that various SCFA’s stimulated the primary gatekeepers to entry of pathogens in the gut called the macrophages. These are specific white blood cells that have the sole function of fighting off any and all incoming invaders. However, macrophages first have to be readied or primed, and this butyrate does very effectively, by inhibiting a series of enzymes that usually keep the macrophages subdued. By inhibiting these enzymes, macrophages are empowered to be more effective anti-microbials and immune surveillance cells.

Another research paper showed that when macrophages were incubated with various SCFA’s, butyrate was the most effective in activating the macrophages far more than acetate and propionate.

Autism spectrum disorder

Autism spectrum disorder (ASD) affects approximately 2% of children in the United States. The cause of ASD is unknown but environmental factors may play a key role. Mitochondrial dysfunction may be a critical factor.

Mitochondria are the key energy generating centers within the cell. Mitochondria not performing properly or efficiently may be a contributing factor in ASD. In animal models of ASD, butyrate has been found to support optimal mitochondrial function, whereby more energy is generated and with less amount of reactive oxygen species being generated which are largely responsible for mitochondrial dysfunction and related behavioural issues. In effect, butyrate rescues the mitochondria from various stressors resulting in diseases like ASD. In another study, when mitochondria from boys with ASD, and matching controls without ASD, were incubated with butyrate, more energy was generated in the form of molecules like ATP, and there was improved efficiency of the mitochondria. In addition, butyrate seemed to be protecting the mitochondria against various toxic insults.

 Reducing systemic dysbiosis

Our GIT is being exposed to everyday stressors in the form of toxic nutrients, foods, pathogens, carcinogens, heavy metals, solvents etc. Maintaining the gut integrity and local defence systems is critical. Mucus is a thick layer that acts as a first line in the defensive barrier preventing invasion by pathogenic bacteria like E coli, Staphylococcus, Clostridia, Salmonella etc. and preventing colonies of these pathogens from getting a foothold in the colon. Studies show butyrate helps regenerate the mucin by stimulating Paneth cells, the main cells responsible for their production. More mucin equates to greater protection.

Furthermore, butyrate also prevents entry of any colonic bacteria into the blood circulation. In conditions like “leaky gut syndrome”, our enterocytes become more permeable allowing entry of colonic bacteria and their toxins. One way these invaders get entry is via tight-junctions, which are tiny pores or entry channels, which lie between neighbouring enterocytes that become “wider” in many cases of gut dysbiosis allowing unwarranted entry of toxins. These toxins once in the circulatory system cause systemic inflammation. Butyrate is able to close down the tight junctions thus preventing entry. A further benefit of increased butyrtae levels is that it helps increases the number of bacteria that have been positively associated with health including Akkermansia muciniphila, Faecalibacterium prausnitzi, and others.

Neuroprotective effects

Cerebral ischemia is a sudden loss or reduced blood flow to the brain, which is the major cause of stroke. In different animal models of stroke, butyrate was shown to protect nerve cells from damage, improve their maturation and increase production of brain derived neurotrophic factor a key protein that helps protect the nerve cells against a host of stressors. Other animal studies have shown that butyrate may help in a number of neuro-degenerative diseases.

In summary, butyrate is an excellent protective molecule throughout the body and helps against a host of diseases. One of the best ways of increasing butyrate levels is by improving intake of fibre but also by using bacteria that helps produce butyrate naturally. Probiotic-3 is a probiotic, which is a mixture of three unique strains of bacteria that act as pre-biotic, symbiotic and probiotic producing significant levels of butyrate in the colon. Probiotic-3 contains Clostridium butyricum, which is a strain that helps raise butyrate levels naturally and safely and is the only approved butyrate producing strain by Health Canada.

Probiotic-3 has been on the market since the early 1960’s and has over 60 clinical studies on the product attesting to its safety and efficacy. In large part, this is due to the unique butyrate producing strain in the formula.

References:

Deehan, EC et-al, “Precision Microbiome modulation with discrete fiber structures directs short chain fatty acid production” 2020, Cell Host Microbe, 27: 389-404

Gao, Z et-al, “Butyrate improves insulin sensitivity and increases energy expenditure in mice” 2009, Diabetes: 58: 1509-1517

Cani R B, et-al, “The epigenetic effects of butyrate: potential therapeutic implications for clinical practice” 2012, Clinical Epigenetics, 2012, 4: 4-11

Scheppach W and Weiler F, “The butyrate story: old wine in new bottles” 2004, Curr Opin Clin Nutr Metab Care, 7: 563-567

Zhou Q et-al, “Gut bacteria Akkermansia is associated with reduced risk of obesity: evidence from the American Gut Project”2020, Nutr Metab, 17: 90-99

Silva JPB et-al, “Protective mechanisms of butyrate on inflammatory Disease” 2018, Curr Pharm Design, 24:1-13

Peng L et-al, “Butyrate enhances the intestinal barrier by facilitating tight junctions in the human cancer colon cell line” 2009, J Nutr 139: 1619-1625

Zihni, C et-al, “Tight junctions: from simple barriers to multifunctional molecular gates” 2016, Nat Rev Mol Cell Biol, 17: 564-580

Luhrs H et-al, “Butyrate inhibits NFkB activation in lamina propria macrophages of patients with ulcerative colitis”, 2002, 37: 458-466 Rose S et-al, “Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism”, 2018, Translational Psychiatry; 8: 42-59

About The Author

Dr. Traj Nibber is the Director of AOR, he has a degree in Pharmacy, a Masters in Toxicology and a PhD in Pathology. Dr. Nibber founded AOR to clear the misdirection prevalent in the nutraceutical world, and provide people with highly effective, research backed products.

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