Gluten-related pathologies range from immune-mediated conditions, such as coeliac disease (CD) and wheat allergy (WA), to non-coeliac gluten sensitivity (NCGS). In either instance, symptoms can range from localised to systemic and may easily be misdiagnosed as seemingly unrelated to their underlying cause: gluten intolerance.
Gluten is the main structural protein complex of wheat and features the potentially toxic protein fraction gliadin. Gluten is also present in several other grains including oats, barley and rye.
Both WA and CD are mediated by the adaptive immune system and involve T cell activation in the gastrointestinal mucosa in response to gluten ingestion. NCGS is characterised by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing foods in individuals that are not affected with either CD or WA.
(a) Healthy villi of the small intestine; (b) Damaged villi of a person with untreated coeliac disease
Coeliac disease (CD)
CD develops from an autoimmune response to dietary gluten and manifests as chronic inflammation of the gastrointestinal tract, particularly the small intestine and jejunum, resulting in atrophy of the absorbent villi apparatus and consequent malabsorption of nutrients.
While 30% of the population carry the genes (HLA DQ2 and HLA DQ8) responsible for CD, only 1 in 30 of these carriers will develop the disease.
Diagnosis is based on the clinical presentation of symptoms, which may include diarrhoea, fatty stools, and abdominal bloating and cramping as well as the presence of specific autoantibodies against tissue transglutaminase and endomysium. Small bowel biopsy can assess the severity of tissue damage.
According to Coeliac Australia, the disease affects approximately 1 in 70 individuals, but about 80% currently remain undiagnosed. This means that approximately 330,000 Australians have CD but are not aware that this may be the underlying cause of their ongoing health concerns.
People with CD remain sensitive to gluten for life. However, as long as dietary gluten abstinence is strictly adhered to, problems arising from the disease should not recur.
On the other hand, long term consequences of untreated CD are numerous and can be severe. Conditions that may be associated with CD are summarised in Table 1. The reasons for these comorbidities include:
- Genetic factors – the genetic predisposition to CD may also make sufferers susceptible to a range of other autoimmune conditions, including type 1 diabetes.
- Chronic inflammation – inflammation caused by CD in the gastrointestinal tract may also present in a variety of other organs and systems, including the skin, joints, bones, liver, pancreas, thyroid gland, nervous system and reproductive tract.
- Intestinal damage – damage due to chronic inflammation of the small intestine results in poor absorption of nutrients and may lead to problems related to deficiency states, including anaemia and osteoporosis.
Moreover, patients with CD experience intestinal barrier dysfunction (“leaky gut”) in response to gluten consumption. Pathogenically increased intestinal permeability predisposes the individual to diffusion of antigenic food molecules and translocation of bacteria and yeast from the gut to extraintestinal sites.
Leaky gut has been linked to a wide range of problems including fatigue, irritability, lethargy, mood swings, muscle or joint pain, poor concentration, memory difficulties, sleep disturbances, food hypersensitivities and environmental intolerances.
Non-coeliac gluten sensitivity (NCGS)
Differentiating between NCGS and other gluten-related disorders is often challenging. According to a study conducted at the Center for Coeliac Research at the University of Maryland, the most frequently reported symptoms of NCGS are: abdominal pain (68%); eczema and/or rash (40%); headache (35%); “foggy mind” (34%); fatigue (33%); diarrhoea (33%); depression (22%); anaemia (20%); numbness in the legs, arms or fingers (20%); and joint pain (11%).
The prevalence of NCGS in the general population is unknown, largely because many patients are self-diagnosed and follow a gluten-free diet (GFD) without medical consultation. Incidence reported in the literature ranges between 0.5-6%.
NCGS and autism – is there a link?
Several studies also suggest a relationship between NCGS and neuropsychiatric disorders such as autism and schizophrenia.
It has been suggested that some symptoms of autism spectrum disorder (ASD) may be caused by opioid peptides formed from the incomplete breakdown of gluten and casein (milk protein).
Increased intestinal permeability in ASD is thought to be part of the chain of events that allows these peptides to enter the bloodstream and cross the blood-brain-barrier, affecting the endogenous opiate system and neurotransmission within the nervous system. The resulting excess of opioids is believed to lead to behaviours noted in ASD.
A two-stage, randomised, controlled study of a gluten-and-casein-free diet in children with ASD has shown significant group improvements in core autistic and related behaviours after 8 and 12 months on the diet.
Clinical support for gluten intolerant patients
After diagnosis of gluten intolerance, a GFD must be implemented and repair of the gastrointestinal mucosa should be initiated. Individuals with CD are also more susceptible to dysbiosis, pancreatic insufficiency, lactase insufficiency, as well as malnutrition.
Healing the gastrointestinal tract
Numerous botanicals and nutrients can assist in the repair of the gastrointestinal mucosa; one that stands out is the amino acid glutamine. Glutamine aids the proliferation and repair of intestinal cells and is the preferred respiratory fuel for enterocytes. Glutamine is presently the best known compound for reducing intestinal permeability.
Re-establishing a healthy luminal microenvironment is also therapeutically significant. The introduction of lactobacilllus species will facilitate this modification while also promoting increased secretary IgA (sIgA) secretion which is often reduced in these patients. Saccharomyces boulardii is also a sIgA promoter. Moreover, faecal samples of CD patients (treated and untreated) have shown lower bifidobacterium levels compared to controls.
As a GFD does not appear to normalise microflora levels, pre- and probiotic supplementation may be beneficial to modify the intestinal microflora in CD patients, reduce inflammatory responses and increase positive clinical outcomes.
Digestive support – digestive enzymes
Postprandial hormone secretion signals the pancreas to secrete hormones that assist in the digestion of partially digested food materials in the upper intestines. The primary hormonal signal for pancreatic enzyme secretion is cholecystokinin (CCK). The cells responsible for CCK secretion are found in the crypts and villi of the duodenum and jejunum. Therefore, any condition that causes tissue damage to these structures can contribute to a reduction in pancreatic enzyme secretion.
Evaluating faecal elastase-1 (E1: marker of exocrine pancreatic function) values in several malabsorption syndromes, researchers found that 56% of coeliac patients had abnormal values indicating insufficient exocrine pancreatic function. However, E1 was normalised in all CD subjects after one year on a GFD.
In a group of CD patients with persistent diarrhoea, even though they were following a GFD, the use of pancreatic enzymes significantly reduced diarrhoea frequency, suggesting that exocrine pancreatic insufficiency may cause persisting symptoms despite gluten avoidance.
Lactase, the enzyme responsible for the digestion of the milk sugar lactose, is naturally secreted from cells located in the brush border of the upper intestinal tract. For this reason, a person with CD is at increased risk of being lactose intolerant.
Nutritional support – vitamins and minerals
Nutritional deficiencies are frequent in CD. A recent study from the Netherlands reported that almost 90% of newly diagnosed CD patients had one or more nutritional deficiencies. Commonly noted deficiencies include vitamins B6 and B12, folic acid, the fat soluble vitamins A, D and E, and minerals iron, selenium and zinc.[8,11,14]
A standard comprehensive multivitamin/mineral supplement (100-300% of RDA) should be considered for every newly diagnosed CD patient. Continuation time for supplementation has yet to be determined, since patients have been found to be at risk for deficiencies even after 10 years on a GFD.
- Gasbarrini GB, Mangiola F. Wheat-related disorders: A broad spectrum of ‘evolving’ diseases. United European Gastroenterol J 2014;2(4):254-262. [Full text]
- Coeliac disease. Coeliac Australia 2015. Viewed 15 September 2015, http://www.coeliac.org.au/coeliac-disease/
- Juuti-Uusitalo K, Lindfors K, Maki M, et al. Inhibition of epithelial growth factor receptor signalling does not preserve epithelial barrier function after in vitro gliadin insult. Scand J Gastroenterol 2009;44(7):820-825. [Abstract]
- Miller AL. The pathogenesis, clinical implications, and treatment of intestinal hyperpermeability. Altern Med Rev 1997;2(5):330-345.
- Lyon MR, Laurell GC. Is your child’s brain starving? Food not drugs for life and learning. Canada: Mind Publishing Inc, 2002.
- Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 2012;10:13. [Full text]
- Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: The new frontier of gluten related disorders. Nutrients 2013;5(10):3839-3853. [Full text]
- Malterre T. Digestive and nutritional considerations in celiac disease: Could supplementation help? Altern Med Rev 2009;14(3):247-257. [PDF]
- Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev 1999;4(4):239-248. [PDF]
- Rapin JR, Wiernsperger N. Possible links between intestinal permeability and food processing: a potential therapeutic niche for glutamine. Clinics (San Paulo) 2010;65(6):635-643. [Full text]
- Helms S. Celiac disease and gluten-associated diseases. Altern Med Rev 2005;10(3):172-192. [PDF]
- Walkowiak J, Herzig KH. Fecal elastase-1 is decreased in villous atrophy regardless of the underlying disease. Eur J Clin Invest 2001;31(5):425-430. [Abstract]
- Leeds JS, Hopper AD, Hurlstone DP, et al. Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms? Aliment Pharmacol Ther 2007;25(3):265-271. [Full text]
- Wierdsma NJ, van Bokhorst-de van der Schueren MAE, Berkenpas M, et al. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients 2013;5(10):3975-3992. [Full text]
- Hallert C, Grant C, Grehn S, et al. Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years. Ailment Pharmacol Ther 2002;16:1333-1339. [Full text]