Title: Gut-Brain Axis In Human Disease (Two)
Key words: peptides, opioid excess hypothesis, autism, coeliac disease, epilepsy, sulphate metabolism, cysteine, methionine, molybedenum, cyanide, cytokines, free radicals, inflammation, mucin proteins, candidiasis, cholestokinin, migraine, sulphotransferase, flavinoids, catecholamines, tryptophan,
Date: Jan 2001
Category: The Gut
Author: Kate Neil (NS3)
Gut-Brain Axis In Human Disease
The concept of a gut-brain axis arose in the early 1970’s as a result of the observation that many of the peptides originally isolated in the gut are also found in the brain, and vice versa1. The gut has been described as ‘the second brain’2.
The 3-mm epithelial cell lining that separates the contents of the lumen of the gut from the systemic circulation is responsible for the absorption of nutrients and exclusion of unwanted substances3. Hyper-permeability of this barrier may play a primary role in the aetiology of many systemic disorders3. Intact proteins and other large molecules can cross the intestinal lining, even in healthy individuals4. In the newborn, this is an advantage as it helps to confer immunity via breast-milk5.
Autism, ME-CFS, multiple chemical sensitivity, fibromyalgia, restless leg and Gulf war syndrome, pesticide poisoning, irritable bowel and bladder syndromes, migraines, temporal mandibular joint syndrome6, coeliac related schizophrenia7, epilepsy8, post-partum psychosis9, have all been implicated in the opioid-excess theory6.
The opioid-excess hypothesis suggests that autism is the consequence of the incomplete breakdown and excessive absorption of peptides with opioid activity (dietary gluten and casein), causing disruption to biochemical and neuroregulatory processes10. Abnormally porous intestinal membranes increase the passage of peptides through to the CNS, disrupting various systems within the CNS10. These peptides may be responsible for the social withdrawal, insensitivity to pain and altered responses to sensory stimuli seen in autism11.
Opioids have been found to play a major role in the extensive bi-directional signalling between the brain, endocrine and immune systems6. The opioid theory provides a holistic understanding of opioid-induced changes that affect stress responses, the peripheral, autonomic and central nervous systems, the immune system, the pineal gland, sleep, circadian and diurnal rhythms6.
Long-term dietary exclusion of gluten and casein is associated with improvements in the behaviour of some children with autism10. Regression has been noted on suspension of the diet10. Increased levels of urinary peptides have been shown in people with autism10, which could have toxic effects on the CNS12.
IAG (trans-3-(indol-3-yl)-acroylglycine) a urinary metabolite of 3-(indol-3-yl)acrylic acid (IAcrA)6, is a product of disturbed tryptophan metabolism and could be derived from the host and/or microbial metabolism in the gut13 particularly disordered microbial activity2. Unpublished research has shown that this metabolite is capable of disrupting biological membranes6 leading to increased opioid uptake2.
Psychiatric symptoms are prominent in the majority of children and in many adults with coeliac disease7. Researchers have demonstrated up to 15 opioid sequences in the gluten molecule7.
Gluten-free diets have been shown to benefit the course of epilepsy14.
Disordered Sulphate Metabolism
Migraine15, autism15, ME-CFS6, MCS6 and GWS6 show disordered sulphate metabolism.
Most sulphate is reduced to hydrogen sulphide by the gut bacteria15. Little is absorbed15. Oxidation of cysteine and methionine are the primary sources of sulphate2,15. About one-third of autistic children demonstrate inefficient activity of sulphite oxidase, a molybdenum dependent enzyme, that converts sulphite into sulphate2,11. Molybdenum supplementation helps around one-third2,15. High levels of sulphites are neurotoxic2,11. Mutations in this enzyme or inhibition of its activity may be part of the aetiology of autism11. This enzyme detoxifies cyanide ions. Cyanide ions inhibit oxidative phosphorylation and cellular oxidation reducing ATP supply in vivo, leading to cell damage and death11.
Conversion problems at the step of cysteine-dioxygenase, is associated with rheumatoid arthritis and allergy, which are common in their family history11.
Both enzymes appear inhibited by cytokines, particularly TNF-alpha, indicating an inflammatory response in the body15, increasing susceptibility to free radical generated pathological disorders.
Importance of Sulphation
Reduced sulphation of mucin proteins has been associated with inflammation and gut dysfunction, coupled with a breakdown in the protective properties of the mucins and an increase in permeability11. Defective sulphation of mucins increases susceptibility of colonisation of Candida albicans in the gut15. Normally, negatively charged sulphated gut-wall proteins will repel Candida, as it is also negatively charged minimising colonisation15. Systemic Candidiasis is associated with neurological symptoms. Virus particles are also negatively charged and tend to reside on a non-sulphated gut-wall, which may help explain reactions to vaccines in susceptible children15.
The combination of sulphated cholecystokinin and secretin stimulates pancreatic digestive enzymes release11. Insufficient sulphur for the sulphation of gastrin and cholecystokinin and achlorhydria leads to unbalanced bowel flora16 and proteins and peptides gaining entry across a ‘leaky’ gut and ‘leaky’ blood/brain barrier15.
Cholecystokinin is an important neuropeptide involved in neuroendocrine function, modulation of dopamine action, and is involved in learning, memory and mood15. As cholecystokinin is essentially activated in its sulphated form, a lack of sulphur will inhibit function15. The precise role of cholecystokinin as a transmitter involved in anxiety is unknown but it is one of the very few agents that elicit genuine panic-like attacks in humans17. Excess dopamine found in autism is associated with stereotyped behaviour15.
A disturbance of neurotransmitter amines is thought to underly the aetiology of migraine15. Neurotransmitters are inactivated by monoamine oxidase enzymes or by the addition of a sulphate group15.
The body's capacity to sulphate compounds is not high, as only small quantities of 3’-phosphoadenosine-5’-phosphosulphate (PAPS) are available to transfer a sulphate group to a target molecule18. Migraine sufferers appear to have less active sulphotransferase enzymes15. Dietary compounds may modulate sulphotransferase detoxification either by interacting directly with enzymes or by competing for sulphation with toxins thus exhausting PAPS supplies before dietary compounds have been metabolised18.
It may be that the M-form sulphotransferase in the gut is overwhelmed due to a large dietary intake of amines15 such as serotonin in bananas, phenylethylamine in chocolate and tyramine in cheese11. Migraine patients have particularly low levels of the P-form sulphotransferase and consequently have reduced ability to inactivate dietary phenols and amines15. Autism sufferers often have a family history of migraine or suffer with abdominal migraine and often improve when chocolate, bananas, orange juice, vanillin and food colourants are removed from their diet11. A combination of low enzyme activity and low sulphate availability greatly reduces their capacity to detoxify endogenous and exogenous amines and phenols11.
Flavonoids found in citrus, red wine and many fruits and vegetables inhibit phenylsulphurtransferases in vitro, particularly the P-form15. In vivo conditions may be different as generally flavonoids have low oral bioavailability and are degraded by gut bacteria19. Low P-form give rise to raised levels of catecholamines in the CNS, which are believed to be a major factor in headache19,20.
Patients with migraine may benefit from a low protein diet15. Waring and others reviewed a three-generation family that had migraine and were able to show that gut amino acid levels were a good predictor of who would develop migraine15. Neuroexcitatory amino acids: glutamic acid, glutamine, glycine, cysteic and homocysteic acid have been shown to be elevated in migraine sufferers21. Migraine without aura sufferers have also shown raised tryptophan levels21. Increases in neurotransmitter amino acids during an attack could magnify the clinical dysfunction and lengthen its duration21.
It is probable that a number of dysfunctional pathways contribute to a high endogenous CNS excitability, which is readily triggered by a variety of exogenous factors including stress21. Stress can profoundly disrupt digestive processes3, undermine the integrity of the gut-wall3 and recent work has shown that stress situations greatly increase the permeability of the blood-brain barrier21.
Homocysteic and cysteic acid are excitotoxins. Homocysteinemia is a risk factor for cerebrovascular disease and likely toxic to vascular endothelium21. Low basal levels of cysteine, with levels rising during an attack, is a likely response to oxidative stress21. Oxidative stress is implicated in most degenerative disorders.
Protein and carbohydrate ingestion can modify the formation of tryptophan and catecholamines, because the brain levels of tryptophan and tyrosine influence the rate at which they are converted to their respective neurotransmitters22. Research is controversial, though gaining in strength, regarding their effects on controlling mood, sleep and carbohydrate cravings22.
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Basic Clinical Endocrinology, Ch 17, Regulatory Peptides of the Gut, 5th Edn, Appleton and Lange, London 1997
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Shattock P et al, Role of Neuropeptides in Autism and Their Relationship with Classical Neurotransmitters, Brain Dysfunct 1990; 3:328-345
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Wakefield A et al, Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children, The Lancet, Vol 351 Feb 28, 1998
McSoreley S and Garside P, Vaccination by inducing oral tolerance? Immunology Today, Dec 1999, Vol.20 No 12 555-560
Roderick I et al, Gastrointestinal Microbial Ecology, Science and Medicine, Nov/Dec 1999 18-27