by Gabi Giacomin
A significant number of children with Down Syndrome (DS) are on grain free diets. This is due to the fact that grains such as rye, barley and oats and even rice are well known triggers of celiac disease, a condition strongly associated with DS. Grains are some of the best sources of dietary fibre which aid digestion, improve bowel function and clean the colon. Current research reveals that Short Chain Fatty Acids (SCFA) such as Butyrate are produced by bacterial fermentation of fibre in the colon and can improve brain health. How can we give our children the benefits associated with a high fibre diet, without giving them grains?
RELATIONSHIP BETWEEN THE GUT AND BRAIN
Ninety percent of cells in the human body are microbes, most of which reside in the gut lumen. The human body relies on diversity of microbial species in order to maintain homeostasis. Increasingly, research shows that microbes balance the immune system, alter epigenetics, produce food for gut microbes, improve energy levels and produce neurotransmitters such as GABA and serotonin. The use of dietary interventions to restore microbial balance and neurology is a new approach currently being investigated.
Butyrate is a short chain fatty acid (SCFA) produced by bacteria in the colon. Its role as a potential therapy for neurological diseases has been the focus of recent research. Butyrate has a wide range of biological functions including inhibition of histone deacetylase (HDAC), an energy source for ATP production and an activator of G protein-coupled receptor (GPCR).
Butyrate has a positive effect on the brain and can improve neurodegenerative as well as psychological disorders. The species of bacteria involved in the production of butyrate are Clostridium, Eubacterium, Fusobacterium, Butyrivibrio, Megasphaera elsdenii, Mitsuokella multiacida, Roseburia intestinalis, Faecalibacterium prausnitzii and Eubacterium hallii. In addition, butyrate directly suppresses the growth of Escherichia coli, Campylobacter, Salmonella and Shigella. Butyrate is the primary source of energy for colonocytes as well as being used by gut microbes. Butyrate forming bacteria thrive on a diet of high fibre foods including non-starch polysaccharides, resistant starch, oligosaccharides (inulin and oligofructose), disaccharides(lactose) and sugar alcohols (sorbitol and mannitol). Resistant starch is particularly good at increasing levels of butyrate. It is found naturally in partially milled seeds and grains, uncooked potatoes, green bananas and various vegetables.
BUTYRATE IN THE DIET
Following 2 weeks of a high FOS diet, an increase in butyrate was observed in the large intestine of mice, without changing the number of anaerobic bacteria. This increase wasn’t observed in a wheat bran diet. Different sources of fibre produce different levels of butyrate and should be carefully selected. Butter contains the richest dietary source of butyrate. People on low fibre diets such as a low-carbohydrate Atkins-type diets have both low faecal ammonia and butyrate levels. Mouse studies show that large bowel levels of ammonia are positively associated with butyrate levels. People with DS produce high levels of ammonia due to the over expressed CBS enzyme and could benefit from butyrate supplementation.
Highly processed diets rich in sugar result in low butyrate production. Butyric acid prevents the loss of electrolytes such as sodium, chlorine and potassium also absorbing water in the colon and making it an effective treatment for diarrhoea. Pure butyric acid has an extremely pungent smell, which makes it very difficult to handle. It is quickly absorbed in the upper part of the gastrointestinal tract, which reduces its positive effects in the colon. These characteristics limit the clinical utility of pure butyric acid. Recently, a new range of products has been developed, in which butyric acid is encapsulated in a triglyceride matrix, resulting in slow release during its transport through the intestinal tract.
BUTYRATE IS A HISTONE DEACETYLASE INHIBITOR (HDAC)
Neurodegenerative diseases are characterised by reduced histone acetylation and transcriptional dysfunction. Histone deacetylase inhibitors (HDAC) such as butyrate have become popular due to their ability to increase histone acetylation and promote plasticity, survival and regenerative expression of genes. Butyrate resists oxidative stress, increasing HDAC inhibition via a protective mechanism, preventing neuronal cell death and extending the lifespan of mice. Butyrate has a profound effect on learning and memory particularly in toxicity or disease induced dementia.
In mouse models of Alzheimer’s Disease (AD), butyrate restored histone acetylation and expression of genes associated with learning. Contextual memory improved in the mouse model even at late stages of AD. Improvements in memory and learning have also been observed following impairment from metal toxicity, neurological infection and traumatic brain injury. Butyrate has the ability to increase the activity of BDNF, GDNF and NGF and other genes involved in plasticity. Butyrate is capable of upregulating genes that improve regeneration, plasticity and survival.
BUTYRATE IS A LIGAND FOR FOR A SUBSET OF G PROTEIN-COUPLED RECEPTORS
G-Protein-coupled receptors (GPCR) are a large, diverse family of transmembrane proteins. They bind extracellular signals such as hormones, growth factors, neurotransmitters, light-sensitive compounds and activate signalling pathways inside cells including cAMP. Critical for many physiological functions they regulate the immune system, autonomic nervous system, sensory function and maintain energy equilibrium. Dysfunction of GPCR’s is associated with a number of diseases. Butyrate signals through GPR109a, which is widely found in the colon and T cells, but also found in microglia. Butyrate activates these receptors in the colon protecting colon tissue through its anti inflammatory actions.
BUTYRATE IS AN ENERGY METABOLITE
Butyrate is an energy metabolite. Colonocytes use butyrate as their main source of energy producing 70% of the bodies ATP. Butyrate was able to restore ATP levels, diminished mitochondrial respiration and NADH/NAD+ ratio in germ free mice, who lacked a microbiome. The brain has an enormous requirement for energy. Glucose utilisation is reduced in the Alzheimer’s brain which has prompted researchers to look for alternative sources to satisfy the brains energy demands. It is suggested that butyrate could represent this energy source, to restore energy homeostasis in the brain as it does in the colon, but the exact amount needed to affect the brain remains unknown.
The reduced availability of glucose in the brain, contributes to mitochondrial dysfunction in neurological disease and could be enhanced by butyrate’s effects on energy metabolism. Butyrate can 1) act as a substrate for beta-oxidation 2) up regulate genes involved in mitochondrial biogenesis 3) is involved in acetylation for a large number of proteins including this associated with gluconeogenesis, the TCA cycle, glycogen metabolism and fatty acid metabolism. Butyrate is capable of increasing mitochondrial activity to reduce disease associated mitochondrial dysfunction in the brain.
HIGH FIBRE AND THE BRAIN
High fibre diets have many health benefits such as reducing type 2 diabetes, cardiovascular disease, obesity, colon cancer and stroke making it a recommended part of the diet. The ability of the microbiome to produce SCFA’s like butyrate is associated the reported benefits. When germ free mice were colonised with butyrate producing bacteria such as Clostridium, BBB permeability was restored to healthy levels, while also increasing histone acetylation in the brain. This study proved the strong link between the brain, microbiota and butyrate. Mice fed a soluble fibre diet recovered faster from endotoxin-induced sickness. The diet increased all SCFA’s in the colon as well as reducing neurological inflammation. Mice showed an increase in IL-1RA which inhibits pro-inflammatory IL-1B in the brain, LPS and decreased IL-1B and TNF-a. Elevated dietary butyrate contributes to the immune response.
THE MICROBIOME AND COGNITION
Children on a high fibre diet have better cognitive control than children on a low fibre diet. Butyrate enhancing probiotics lowered psychological stress in human trials and reduced anxiety in chronic fatigue patients. Seventy percent of children with autism suffer from gastrointestinal symptoms. Studies have found evidence of decreases in Bifidobacteria, Prevotella and increases of Lactobacillus, Sutterella and Firmicutes. Many of these altered bacteria are important in the fermentation process that produce SCFA’s like butyrate.
Adults with DS show signs of immunosenescence and higher levels of local inflammation similar to much older non-DS populations, including alterations of B and T cell populations. Ageing and immunosenescence are associated with a deterioration of homeostasis in the gut microbiome. Key butyrate producing microbes such as Clostridium are reduced in ageing, increasing an overall proinflammatory environment leading to immunosenescence. SCFA’s such as butyrate are immune system modulators via there ability to facilitate communication between the microbiome and host immune system. Butyrate is crucial for differentiation of T reg cells. SCFA’s from polysaccharides can possibly counteract the proinflammatory immune imbalances which drive immunosenescence.
In addition, supplementation with butyrate stimulated elongation of the villi in the ileum and crypt depth in the caecum. Diet control in people with DS is extremely relevant to support a healthy gut micro biome. According to Biagi et al. the addition of fibre to the diet which supports the growth of Clostridium clusters IV and XIV should be encouraged in people with DS.
Butyrate has many benefits for the brain, in both supplement or dietary form. Its action in the body is diverse and offers a simple and low risk approach to improve brain health. Using dietary options such as a high fibre diet or one rich in butyrate rich foods is an easy way to integrate this treatment. The association between the gut and the brain can no longer be ignored, neither the use of nutrition in disease treatment.
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