A paper published in the journal CNS Neurology Disorders Drug Targets highlights some of the areas of dysfunction liked to adverse exposure to gluten and subsequent effects on functionality.[1]
The non-celiac gluten sensitivity (NCGS) is a chronic functional gastrointestinal disorder which is very common world-wide.
The human gut harbours microbiota which has a wide variety of microbial organisms; they are mainly symbiotic and important for well-being. However, “dysbiosis” – i.e. an alteration in normal commensal gut microbiome with an increase in pathogenic microbes, impacts homeostasis/health.
Dysbiosis in NCGS causes gut inflammation, diarrhoea, constipation, visceral hypersensitivity, abdominal pain, dysfunctional metabolic state, and peripheral immune and neuro-immune communication. Thus, immune-mediated gut and extra-gut dysfunctions, due to gluten sensitivity with comorbid diarrhoea, may last for decades.
A significant proportion of NCGS patients may chronically consume alcohol, non-steroidal anti-inflammatory drugs, and fatty diet, as well as suffer from various comorbid disorders. The above pathophysiological substrate and dysbiosis are underpinned by dysfunctional bidirectional “Gut-Brain Axis” pathway.
Pathogenic gut microbiota is known to upregulate gut- and systemic inflammation (due to lipopolysaccharide from pathogenic bacteria and synthesis of pro-inflammatory cytokines); they enhance energy harvest, cause obesity, insulin resistance, and dysfunctional vago-vagal gut-brain axis.
Conceivably, the above cascade of pathology may promote various pathophysiological mechanisms, neuroinflammation, and cognitive dysfunction. Hence, dysbiosis, gut inflammation, and chronic dyshomeostasis are of great clinical relevance.
It is argued here that we need to be aware of NCGS and its chronic pathophysiological impact. Therapeutic measures including probiotics, vagus nerve stimulation, antioxidants, alpha 7 nicotinic receptor agonists, and corticotropin-releasing factor receptor 1 antagonist may ameliorate neuroinflammation and oxidative stress in NCGS; they may therefore, prevent cognitive dysfunction and vulnerability to Alzheimer’s disease.
Comment
Whilst some people continue to raise questions about the existence of NCGS others are increasingly willing to explore its effects and suggest approaches to its resolution, apart from avoidance that is.
Definitions
Since 2010, the definition of NCGS has been discussed at 3 consensus conferences, which led to 3 publications.[2],[3],[4] Given the uncertainties about this clinical entity and the lack of diagnostic biomarkers, all 3 reports concluded that NCGS should be defined by the following exclusionary criteria:
The following very useful information is extracted from an article in Gastroenterology “Nonceliac Gluten Sensitivity”.[5]
A clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that resolve once the gluten-containing foodstuff is eliminated from the diet, and when celiac disease and wheat allergy have been ruled out.
One of the most controversial and highly debated discussions concerns the role of gluten in causing NCGS. Recent reports have indicated that gluten might not be the cause of NCGS, and some investigators still question whether NCGS as a real clinical entity.
Therefore, to avoid further confusion, it is important to clearly define the difference between food sensitivity and food intolerance.
According to the US National Institute of Allergy and Infectious Diseases,[6] food intolerance occurs when the body lacks a particular enzyme to digest nutrients, nutrients are too abundant to be digested completely, or a particular nutrient cannot be digested properly. Therefore, symptoms are exclusively GI and mostly secondary to sugar fermentation by the intestinal microbiota, leading to the production of gas, which causes abdominal distention, abdominal pain, and irregular bowel movements. Common examples include lactose intolerance, or intolerance to excess fermentable oligo- and disacchararides, monosaccharides and polyols (FODMAPs) or lactulose.
Food sensitivities are immune-mediated reactions to some nutrients; these reactions (intestinal and extraintestinal) do not always occur in the same way when people ingest that particular nutrient. NCGS is an example of food sensitivity. There have been reports that FODMAPs, rather than gluten, induce the abdominal symptoms attributed to NCGS. These findings indicate that NCGS might not be a separate entity from irritable bowel syndrome (IBS),[7],[8] but rather a subgroup of IBS.
However, keeping in mind the difference between the definition of food intolerance (GI symptoms secondary to fermentation of sugars by the colonic microbiota) and food sensitivity (an immune response to nutrient-derived antigens that causes GI and extra-GI symptoms), as well as the definition of NCGS (characterized by intestinal and/or extraintestinal symptoms, after ingestion of gluten-containing grains, that resolve upon elimination of these grains from the diet), it should be clear that IBS and NCGS are distinct entities with some overlapping features. Moreover, although FODMAPs can cause GI symptoms such as bloating, they inhibit, rather than cause, intestinal inflammation, inducing beneficial alterations to intestinal microbiota and generation of short-chain fatty acids.[9]
ATI: amylase trypsin inhibitors.
ATIs are plant-derived proteins that inhibit enzymes of common parasites, such as mealworms and mealbugs, in wheat. ATIs also have an important role in metabolic processes that occur during seed development, and vary among cultivars. These variations affect their protein expression, accessibility, and extractability.[10]In vitro and in vivo studies have suggested that wheat ATIs induce innate immune responses that involve monocytes, macrophages, and dendritic cells activation of the TLR4 complex.[11]
Therefore, ATIs could be the long-sought inducers of innate immunity in patients with celiac disease or NCGS. Importantly, ATIs are present in commercial gluten and resist proteolytic digestion, such as by the gastric and enteric proteases pepsin and trypsin, maintaining the ability to activate TLR4 throughout oral ingestion and intestinal passage. ATIs account for approximately 2%−4% of the total protein in modern wheat (with gluten accounting for 80%–90%).[12]
References
[1] Daulatzai MA. Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia. CNS Neurol Disord Drug Targets. 2015;14(1):110-31. View Abstract
[2] A. Sapone, J.C. Bai, C. Ciacci, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification BMC Med, 10 (2012), p. 13 View Full Paper
[3] C. Catassi, J.C. Bai, B. Bonaz, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders Nutrients, 5 (2013), pp. 3839–3853 View Full Paper
[4] J.F. Ludvigsson, D.A. Leffler, J.C. Bai, et al. The Oslo definitions for coeliac disease and related terms Gut, 62 (2013), pp. 43–52 View Full Paper
[5] Fasano A, Sapone A, Zevallos V, Schuppan D. Nonceliac gluten sensitivity. Gastroenterology. 2015 May;148(6):1195-204. View Abstract
[6] J.A. Boyce, A. Assa’ad, A.W. Burks, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel J Allergy Clin Immunol, 126 (2010), pp. S1–S58 View Full Paper
[7] J.R. Biesiekierski, S.L. Peters, E.D. Newnham, et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates Gastroenterology, 145 (2013), pp. 320–328 View Abstract
[8] Vanga R, Leffler DA. Gluten sensitivity: not celiac and not certain. Gastroenterology. 2013 Aug;145(2):276-9
[9] Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015 Jan;64(1):93-100 View Abstract
[10] C. Finnie, S. Melchior, P. Roepstorff, et al. Proteome analysis of grain filling and seed maturation in barley Plant Physiol, 129 (2002), pp. 1308–1319 View Full Paper
[11] Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, Zevallos V, Libermann TA, Dillon S, Freitag TL, Kelly CP, Schuppan D. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012 Dec 17;209(13):2395-408 View Full Paper
[12] Altenbach SB, Vensel WH, Dupont FM. The spectrum of low molecular weight alpha-amylase/protease inhibitor genes expressed in the US bread wheat cultivar Butte 86. BMC Res Notes. 2011 Jul 20;4:242. View Full Paper
