Title: The Gut-Brain Axis In Human Disease
Key words: radio immunoassay, immunohistochemistry, peptides, neurotransmitters, neuromodulators, hormones, dietary precursors, essential amino acids, dopamine, noradrenaline, gut hormones, satiety, sulphate, neuroexcitatory amines, autism, migraine
Date: Aug 2000
Category: 8. The Gut
Author: Dr Van Rhijn
The Gut-Brain Axis In Human Disease
Demonstrations with radioimmunoassay and immunohistochemistry techniques have given rise to the concept of the gut-brain axis, as many peptides (neurotransmitter, neuromodulator and hormonal) activities are common to both gut and brain cells1,2. Several studies suggest that brain function, including cognitive processing, responds to changes in nutrients. Neurotransmitters are synthesised from dietary compounds such as essential amino acids, although serum elevation from dietary precursors does not necessarily elevate transmitter brain concentrations3. Many behaviour disturbances and diseases are thought to have their origin in a metabolic dysfunction due to consumption and absorption of certain food products and their metabolites. Almost any product may be a provocative culprit (allergy or intolerance) and this paper will focus on the role of the gut and its interaction with neuromodulatory metabolites in common central nervous system related disorders.
The Gut as a Barrier
Numerous foods contain amino acids (cysteic acid, glutamine, glycine) and neurotransmitter phenols & amines (dopamine, serotonin [banana], tyramine [cheese], phenylethylamine [chocolate]) that may have excitatory neurotransmitter effects in the CNS. They are normally metabolised into non-toxic, readily extractable metabolites via conjugation with glucuronic acid or sulphate (sulphotransferase enzymes [ST]) 4 and by monoamine oxidase activity in the gut, liver and brain. The sulphation pathway (platelet [p] and gut mucosa [m] form) appears to be more significant than the glucuronic pathway in humans. Phenolsuplhotransferase (PST) and mono-amine-sulphotransferases (MST) use phenols and neurotransmitter amines as substrates respectively.
Aberrant biochemical inactivation of these neurotransmitters, due to inadequate sulphation conjugation, secondary to a deficit of ST activity, may cause a cerebral increase of catecholamines that can be further metabolised to neurotoxic compounds. The gastrointestinal tract also acts as a protective barrier (sulphated glycoprotein containing mucin), inhibiting absorption of these compounds into the circulation. This function is compromised by low sulphate levels (sulpho-transferase5), resulting in a leaky gut, allowing proteins and peptides through into the circulation, causing neuronal over stimulation and contributing to various conditions and illnesses.
Chronic dysbacteriosis and candidiasis (enhanced by inadequate sulphation) may compromise this barrier function, allowing metabolite absorption from these organisms (tartaric acid & arabinose)6 into the circulation, resulting in cross linking in the brain and blockages in the Kreb’s Cycle. It is now possible to measure these metabolites in the urine7. Clostridia infections give rise to a toxic DHPPA compound, associated with an alteration in the HVA/VMA ratio, suggesting an inhibition of the conversion of dopamine to noradrenaline, which could explain the repetitive, stereotypical and hyperactive behaviour seen in autistic children.
Gut hormones such as gastrin, which stimulate cholecystokinin (CCK) and pepsin, to release secretin and other pancreatic enzymes for protein metabolism (peptides to AA), so regulating neuro-endocrine metabolism, satiety, dopamine action, memory and anxiety, are also sulphur dependent. Inorganic sulphate can be obtained from sulphate-rich foods (dried fruits) that are readily absorbed, and may help to restore the gut barrier to prevent free entry of potentially toxic compounds and neuroexcitatory amines.
Parents and support groups have reported that autistic behaviour (hyperactivity, attention deficit) is exacerbated when children eat certain food products, especially dairy products8, wheat, corn, sugar, bananas, sweets and chocolate. Studies have postulated that the behaviour of autistic children could partly be explained by an inability to effectively metabolise certain compounds, particularly phenolic amines (reduced sulphation capacity), resulting in an increased absorption of neuro-active peptides, which are potentially toxic to the CNS9. Autistic children appear to lack serum inorganic sulphate ions (10 fold) and have abnormally increased urinary sulphate10, sulphite, thiosulphate and taurine excretion11, resulting in low sulphotransferase levels12 and hence, reduced inorganic sulphate conjugate synthesis. Urinary thiocyanate levels are not raised, suggesting a reduction in rhodanase activity required to detoxify cyanide ions that may become neurotoxic and inhibit oxidative phosphorylation processes. Reduced sulphation of the mucous proteins that regulate gastrointestinal tract function may lead to protein leakage13 and increased intestinal peptide absorption14, which was confirmed by raised levels of peptides excreted in the urine15. Autistic children have increased IAG levels, a urinary metabolite of 3-(indol-3-yl) acrylic acid (IacrA), a product of disturbed tryptophan metabolism associated with damaged gut function, membrane leakage and the uptake of excessive amounts of opioid peptides16, gliadomorphins and casein, derived from wheat (gluten) and milk proteins. The elevated opiate peptides on exposure to dietary gluten17 and casein may also be mediated via reduced zinc levels and zinc dependent peptidase activity, resulting in partial metabolism of these neuro-active peptides. Detecting urinary IAG levels may be used as a diagnostic test for autism18. Supplementation with B vitamins and molybdenum, essential for the enzyme sulphate oxidase, helps the conversion of sulphite (neurotoxin) to sulphate (improves sulphate/cysteine ratio) and reduces sulphate excretion in some patients. All these mechanisms may play a role in the distinctive presentation and behaviour of autistic children.
ST activity may be reduced in migraine patients, making them susceptible to dietary triggers (cheese, banana, chocolate), suggesting that excess amines enter the blood stream unconjugated. Studies found elevated endogenous neurotransmitter amines (adrenaline19 & dopamine20) and reduced PST activity21 (which can be inactivated by flavonoids 22) that may contribute synergistically to the catecholamine imbalance and sympathetic dysfunction in migraine. Other contributory factors such as high concentrations of neuroexcitatory amino acids (glutamic acid, glutamine, glycine cysteic acid and homocysteic acid) were also found in migraine sufferers23, confirming raised levels of glutamate found in previous studies24,25, which act as an agonist at the NMDA sub-type receptor. Migraine sufferers have a genetic fault in processing amino acids resulting in raised serum excitatory amino acids even between attacks. Stress situations increase the permeability of the BBB26 with a rapid increase in levels of brain neuroexcitatory amino acids during an attack.
The concept of the gut-brain axis demonstrates the intimate relations between endocrinology and neuroendocrinology, and emphasise that dietary reactions are not ‘all in the mind’. Although a cause-effect relationship is not necessary involved, as most conditions are heterogeneous, consumption of foods containing high quantities of phenolic amines may accentuate the metabolic dysfunction and exacerbate CNS symptoms.
Dietary modulation by eliminating provoking foods (gluten, casein, chocolate, bananas, citrus fruit), and supplementation with sulphate (MgSO4) and molybdenum, zinc and Vit B6 may prove useful in treating autism. Providing pancreatic enzymes and correcting gut dysbiosis with probiotics (Lactobacillus acidophilus) helps to improve gut barrier function and may synergistically reduce exposure to neuroexcitatory substances and metabolites. L-glutamine supplementation may help to restore gut integrity27, stimulate pancreatic enzymes and neutralise the toxic effects of IGA 28.
Elimination of provoking foods and instigating a low protein diet may benefit migraine sufferers. Further research is required to increase understanding of these complex interactions in order to provide patients with evidence based nutritional support and treatment.
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