It’s been a while since my last post as I have been quite busy with school, work, new house stuff, and unfortunately a recent compromise of my site. Luckily I was able to have the site fully cleaned and didn’t lose any material in the process. There are some remaining error pages that may show in a Google search but they are slowly being cleared by Google. I apologize if this impacted you in any way. Onto non-celiac gluten sensitivity (NCGS), you may know that I have written about gluten before (here, here, and here), but this is a lengthy, very informative post adapted from a recent school paper I wrote, be patient.
With celiac disease (CD) rising in prevalence in Western countries from 0.2% of the population in the mid-1970s to at least 1% in 2014, the awareness of gluten and its negative impacts on human health have received a large amount of attention over recent decades (1). During this time health experts and the media have also put a focus on the negative impacts of gluten, with experts advising for a gluten-free diet for the treatment of medical conditions, non-specific health symptoms, and improving general health. Subsequently, sales of gluten free foods have risen 6 fold from 2006 to 2015, the estimated percentage of the United States population (non-celiac) adhering to a gluten free diet has risen from approximately 0.52% in 2009 to 1.69% in 2014, and approximately 1/3 of the population express a willingness to try a gluten free diet (2, 3). However, the use of a gluten free diet in the non-celiac population is a point of major controversy in the media, public, medical disciplines, and scientific literature. Thus, the question stands: is adherence to a gluten free diet beneficial for those without CD?
Gluten Related Disorder Spectrum
There is an acknowledged spectrum of gluten related disorders including wheat allergy, CD, gluten ataxia, and dermatitis herpetiformis (4, 5). Those with wheat allergy experience an IgE immune reaction to wheat ingestion (6), while CD, gluten ataxia and dermatitis herpetiformis are considered autoimmune diseases with elevated levels of specific tissue anti-transglutaminase (anti-TG) antibodies:
- Dermatitis Herpetiformis is characterized by a rash typically on the elbows, forearms, buttocks, knees, and scalp along with elevated anti-TG3 (found preferentially in the skin versus TG2 in the gut) (7).
- Gluten Ataxia is characterized by neurological symptoms including dizziness, clumsiness, loss of coordination, fatigue, difficulty speaking, difficulty swallowing, muscular tremors, abnormal gait or difficulty walking, nausea, and vomiting as well as the presence of anti-TG6 (found preferentially in nervous tissue versus anti-TG2 in the gut and anti-TG3 in skin) (8).
- CD is characterized by elevated anti-TG2 and IgA endomysial antibodies with small bowl biopsy showing villus atrophy, epithelial damage, and elevated immune markers (9; 10; 11).
Gastrointestinal symptoms are not always present in these conditions, even CD.
With the recent popularity of the gluten free diet there has been a rediscovery of another clinical entity on the gluten disorder spectrum known as NCGS, and it is receiving growing attention in scientific literature and clinical practice.
What is NCGS
NCGS is a syndrome characterized by intestinal and extra-intestinal symptoms caused by the ingestion of gluten in individuals who do not have CD, wheat allergy, gluten ataxia, or dermatitis herpetiformis (12). Evidence for NCGS dates back to the 1970s; however, it has gained increasing attention since a 2010 paper (13) that described altered intestinal immune function in NCGS patients distinct from what is seen in CD (14). Since then, increasing scientific evidence indicates that NCGS is a bona fide condition falling on the gluten related disorder spectrum. However, controversy remains since no consistent diagnostic measures have been identified and other dietary factors (FODMAPS and ATIs) sometimes play a role in symptom presentation (15; 16, 17, 18, 19, 20, 21).
While there isn’t much evidence for the prevalence of NCGS, some estimates are as high as 10% of the Western population and others as low as 2% (22). However, many functional medical practitioners believe the rate to be much higher based on their clinical experience (https://chriskresser.com/when-gluten-free-is-not-a-fad/, https://avivaromm.com/is-a-gluten-free-diet-right-for-you/).
NCGS symptoms are non-specific and can manifest in both intestinal and extra-intestinal ways:
- Intestinal: IBS like symptoms such as diarrhea, abdominal discomfort/pain, bloating, flatulence, etc.
- Extra-intestinal: Headache, lethargy, brain fog, chronic fatigue, attention-deficit/hyperactivity disorder, schizophrenia, skin manifestations, recurrent oral ulceration, autism-like symptoms, etc.
NCGS Pathophysiology (A.K.A. pathological changes that happen in the body)
Given the infancy of NCGS research, some suggest that our current knowledge of NCGS is comparable to what was known about CD 20 years ago (23). With that in mind, the current literature on NCGS provides evidence that the following may be involved in the pathophysiology of NCGS but there is no consistent consensus:
- Innate Immune Response: Contrary to CD, which is an adaptive immune response (ex. autoimmune), NCGS commonly presents with dysregulated innate immune markers (increased intestinal eosinophils, Toll-like receptor-2 and 4, α and β intraepithelial lymphocytes, and reduced numbers of T-regulatory cells) (24; 25, 26, 27, 28)
- Adaptive Immune Response: Some evidence supports the possible presence of an adaptive immune response. Anti-Gliadin (AGA) antibodies IgA and IgG are elevated in some celiac patients although it has been determined that they are not sensitive or specific enough to diagnosis celiac disease; however, some NCGS cases also present with elevated AGAs after exclusion of CD via intestinal biopsy. This indicates the presence of an adaptive immune response to gliadin (29). Additional evidence indicates that increased adaptive immune cytokine production and elevated basophils can occur in NCGS, further supporting adaptive immune involvement (30).
- Gut Microbiome Dysbiosis: Homeostasis of intestinal bacteria is well known to impact our intestinal and systemic health. Gut dysbiosis has been linked to virtually all chronic diseases (31, 32). There is also evidence of gut dysbiosis in cases of NCGS with some researchers indicating that differences in the bacterial content of the gut may actually drive some patients towards overt CD and others towards NCGS (33, 34). However, it is not fully known whether gut dysbiosis causes NCGS or whether exposure to wheat/gluten causes gut dysbiosis.
- Increased Intestinal Permeability: A great deal of evidence indicates that increased intestinal permeability is present in NCGS and is proposed as an explanation for extra-intestinal NCGS symptoms. Increased intestinal permeability would allow foreign antigens and immune molecules to enter the body, negatively impacting systemic immune regulation (35). It is also not clear whether increased intestinal permeability causes gluten spectrum disorders; in fact, intestinal inflammation and gluten’s direct interaction with zonulin (controls intestinal cell tight junctions) are more likely to cause increased permeability and associated extra-intestinal symptoms (36, 37, 38, 39).
A common theme occurs with the above points in the form of dysregulation of the intestinal immune system in the form of elevated inflammation and/or an autoimmune response causing gastrointestinal symptoms and increased intestinal permeability, the former causing extra-intestinal symptoms.
NCGS Etiology (A.K.A what is the cause?)
The cause of NCGS has been put under great scrutiny in the scientific literature with multiple studies indicating non-gluten factors and an equal number of studies indicating gluten as the cause. Subsequently, all of the following have been identified as possible underlying causes/factors of NCGS.
- Genetics: 2 Genotypes have been linked to the gluten disorder spectrum, HLA-DQ2 and HLA-DQ8. One of these genotypes is present in 90-100% of those with CD and up to 30% in the general population. These genotypes are also present in up to 50% of those diagnosed with NCGS, higher than the general population but lower than the CD population. Therefore, HLA-DQ2 and DQ8 are not sufficient to contract CD or NCGS; however, they do increase the risk (40, 41, 42).
- Gluten: Gluten ingestion is one of the core underlying causes of NCGS and removal of it from the diet addresses symptoms in most cases; however, as noted above, differences in the gut microbiome may directly impact symptom severity and possibly even disease onset.
- Modern Wheat: Some research suggests that the rise in gluten related disorders and NCGS may be due to the higher gluten composition and greater immune system impact of modern wheat strains versus their wild/heritage counterparts (43, 44). This change has occurred through basic and complex selective breeding processes since the start of modern agriculture.
- Irritable Bowel Syndrome (IBS): There is significant cross-over between the reported symptoms of NCGS and IBS, leading to the belief that NCGS may actually be a form of IBS or vice versa (45, 46). Diarrhea prominent IBS patients positive for HLA-DQ2/DQ8 tend to experience symptom resolution on a gluten free diet, supporting the NCGS-IBS connection (Makharia et al., 2015). However, other research suggests that while a gluten free diet may be ideal for all NCGS and some IBS patients, it does not mean that they should be considered part of the same disease (47).
- Amylase-Trypsin Inhibitors (ATIs): ATIs are a defensive molecules present in many plants where their purpose is to inhibit the actions of parasitic enzymes from worms and bugs (48). In humans, ATIs have been shown to increase the release of innate immune system cytokines in celiac and non-celiac patients (49). Out of the common cereal grains, wheat, rye, and barley show the most active ATIs and are also the gluten containing grains (50). Such a combination simply adds to the confusion about NCGS with some evidence suggesting that ATIs may be the dietary irritant in NCGS, not gluten (51, 52, 53).
- Fermentable Oligosaccharides, Disaccharides, monosaccharides and Polyols (FODMAPS): FODMAPS are short chain carbohydrates and alcohol sugars found naturally in food but poorly digested, leaving them intact for bacteria in the large intestine to metabolise (i.e. ferment). FODMAPS are well known to cause symptoms in IBS and Inflammatory Bowel Disorder due to colonic fermentation and osmotic properties (attract excess water causing diarrhea). In the past few years, FODMAPS have also been identified as another possible trigger for NCGS. However, these studies were criticized by some as the control/placebo food contained other common gut irritants such as milk proteins, there was no consideration for extra-intestinal symptoms, and they were not longer than 3 weeks in duration. Furthermore, wheat, rye, and barley can only be considered minor FODMAP sources when consumed in normal daily quantities (54, 55, 56).
Do You Have NCGS?
If you have a general physician who is a bit progressive and stays current on the literature and if you have any of the above noted symptoms, you may be tested for CD with an anti-TG2 blood test. If this is negative there will likely be no further investigation into a gluten related disorder. If you believe you have NCGS and wish to confirm this with clinical testing, you will likely have to find a functional medical practitioner. They are more likely to fully investigate gluten related disorders (and other conditions for that matter). Here is a sample diagnostic workup for NCGS:
- Rule Out CD: Comprehensive investigation for CD prior to further NCGS testing. CD testing can include:
- Serum and intestinal anti-TG2
- Serum and intestinal AGA IgA and IgG
- Intestinal anti-endomysium antibodies
- Small intestinal biopsy
- Genetic testing
- Rule Out Gluten Allergy, Ataxia, and Dermatitis Herpetiformis: The following investigations for these conditions should also take place prior to further NCGS testing:
- Serum anti-TG3 and anti-TG6
- Skin prick testing (allergy)
- Serum IgE gluten antibodies (allergy)
- Genetic Testing: Testing for HLA-DQ2/DQ8 mutations is standard practice for CD diagnosis; however, the presence of these mutations should also be an indication of possible NCGS if CD has been ruled out.
- Serum and/or Intestinal AGA IgG: AGA IgG antibodies can be absent or present in both CD and NCGS; however, once celiac has been ruled out, the presence of these antibodies is an indication of NCGS.
- Other Intestinal Adaptive and Innate Immune Markers: Dysregulation in multiple immune markers has been identified in NCGS which can be measured with fecal testing. The following should be considered for NCGS fecal testing, indicating NCGS:
- Increased α and β Intraepithelial Lymphocytes (EILs)
- Increased Interferon gamma (IFNγ)
- Increased Toll-like receptor-2 (TLR2) and Toll-like receptor-4 (TLR4)
- Reduced numbers of T-regulatory cells
- Increased Eosinophil Cationic Protein (ECP)
- Increased Intestinal Permeability: Altered intestinal permeability has been identified in both CD and NCGS; therefore, once CD has been ruled out, testing for increased intestinal permeability can help in the diagnosis of NCGS.
- Blind Gluten Challenge: While all the above have been identified as possible markers to assist in the diagnosis of NCGS there is no consistent consensus for a fully accurate diagnostic criteria. As such, the gold standard for diagnosis of NCGS is the Blind Gluten Challenge test. This test involves 3 weeks as follows:
- Patient has already been following a strict gluten free diet with little to no symptoms.
- Week 1: A blind challenge with a gluten or non-gluten containing food eaten daily. The food is provided by the medical clinic and the 2 foods must be indistinguishable from each other by the patient (otherwise the patient will know what food has gluten, skewing results via bias).
- Week 2: A washout period of following a strict gluten free diet (or until any symptoms from week 1 resolve)
- Week 3: A blind challenge with a gluten or non-gluten containing food eaten daily. The food is provided by the medical clinical and the 2 foods must be indistinguishable from each other by the patient (otherwise the patient will know what food has gluten, skewing results via bias). *The food provided in week 3 must be the opposite from week 1.*
- If symptoms are apparent during the gluten challenge week and not during the gluten-free challenge week, it is a strong indication of NCG. If symptoms are the same for the non-washout weeks, then NCGS may not be present and the practitioner can explore other diagnoses such as FODMAP intolerance, IBS, etc.
That being said, the above can be pricey if you don’t have comprehensive paramedical insurance coverage. However, a free alternative is to complete the gluten challenge test on your own. You could even get someone else to give you the food so you don’t know if it’s gluten or not. Otherwise, you can do the test in a non-blind manner. Simply follow a gluten-free diet until your symptoms resolve, then eat gluten for 1-2 weeks and make a food/symptoms journal during those weeks. If your symptoms return, go back to the gluten free diet until symptoms resolve. Basically, if symptoms return when eating gluten and resolve without it, it is a strong indication that you have some level of NCGS. If you really want to make certain of NCGS, repeat your gluten challenge a few more times. Another trick for this test is for the first few days you start eating gluten, eat a larger than normal amount (ex. in every meal), which will more quickly induce symptoms in sensitive individuals.
What if You Don’t Have NCGS
So, now we know that NCGS is a bona fide medical condition and how to confirm if you have it or not, but a bigger question still remains…Should anyone eat gluten, even those without NCGS or a gluten spectrum disorder?
This question is exactly what my next will address, Stay Tuned!
The Barefoot Golfer