Gluten sensivity does not necessarily involve the gut and intestines only. There are a number of diseases and disorders related to gluten sensitivity that are just recently being addressed. These are a few articles related to non-celiac gluten related disorders that we found interesting.

Gluten sensitivity: from gut to brain.
Hadjivassiliou M1, Sanders DS, Grünewald RA, Woodroofe N, Boscolo S, Aeschlimann D.

Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.

2010 Elsevier Ltd. All rights reserved.

PMID: 20170845

Non-Celiac Gluten Sensitivity and related disorders

Gluten-related neurologic dysfunction.
Hadjivassiliou M1, Duker AP2, Sanders DS3.

The term gluten-related disorders (GRD) encompasses a spectrum of systemic autoimmune diseases with diverse manifestations. GRD are characterized by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Celiac disease (CD) or gluten-sensitive enteropathy is only one of a number of GRD. Extraintestinal manifestations include dermatitis herpetiformis (DH) and neurologic dysfunction. Furthermore it is only recently that the concept of extraintestinal manifestations without enteropathy has become accepted. In this chapter we review the spectrum of neurologic manifestations in GRD, discuss recent advances in their diagnosis, and look at their possible pathophysiologic mechanisms.

© 2014 Elsevier B.V. All rights reserved.


KEYWORDS:Gluten ataxia; antigliadin antibodies; celiac disease; gluten enteropathy; gluten neuropathy; transglutaminase antibodies

PMID: 24365341 [PubMed - indexed for MEDLINE]

Spectrum of gluten-related disorders: consensus on new nomenclature and classification
Anna Sapone, Julio C Bai, [...], and Alessio Fasano

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns.

This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.

BMC Med. 2012; 10: 13.

Published online Feb 7, 2012. doi:  10.1186/1741-7015-10-13

PMCID: PMC3292448

Gluten-free diet in nonceliac disease.
El-Chammas K1, Danner E.

A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies, and future research may better define the benefits of a GFD for those conditions with weak existing evidence.

PMID: 21586414


Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad.
Pietzak M. University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.


As the gluten-free diet (GFD) gains in popularity with the general public, health practitioners are beginning to question its real health benefits. For those patients with celiac disease (CD), the GFD is considered medical nutrition therapy, as well as the only proven treatment that results in improvements in symptomatology and small bowel histology. Those with wheat allergy also benefit from the GFD, although these patients often do not need to restrict rye, barley, and oats from their diet. Gluten sensitivity is a controversial subject, where patients who have neither CD nor wheat allergy have varying degrees of symptomatic improvement on the GFD. Conditions in this category include dermatitis herpetiformis (DH), irritable bowel syndrome (IBS), and neurologic diseases such as gluten-sensitive ataxia and autism. It is important for patients and healthcare practitioners to understand the differences between these conditions, even though they may all respond to a GFD. Patients with CD can experience comorbid nutrition deficiencies and are at higher risk for the development of cancers and other autoimmune conditions. Those with wheat allergy and gluten sensitivity are thought not to be at higher risk for these complications. Defining the symptoms and biochemical markers for gluten-sensitive conditions is an important area for future investigations, and high-quality, large-scale randomized trials are needed to prove the true benefits of the GFD in this evolving field.

PMID: 22237879


Intestinal antibody pattern of celiac disease: occurrence in patients with normal jejunal biopsy histology
Arranz E1, Ferguson A.

BACKGROUND:Patients with celiac disease have immunoglobulin (Ig) M antibodies and IgA antigliadin antibody in gut secretions; this pattern of intestinal immunity may be a marker of latent celiac disease. Its frequency in patients referred for jejunal biopsy has been examined.


Serum IgG and IgA antigliadin antibody, jejunal fluid IgA and IgM antibodies to gliadin, ovalbumin and beta lactoglobulin, and jejunal fluid IgA and IgM concentrations were measured by enzyme-linked immunosorbent assay.


Seventeen of 19 celiac patients on normal diet and 16 of 23 on gluten-free diet had the celiac-like antibody pattern, as did 41 of 217 other patients. Jejunal biopsy histology had been classified as normal in 38 of these, with minor abnormalities in 3; however, intraepithelial lymphocyte (IEL) counts were high in 13 cases. Trial of a gluten-free diet produced clinical improvement in 6 of 7 antibody-positive patients. After extra dietary gluten, one developed subtotal villous atrophy.


The celiaclike intestinal antibody pattern and a high IEL count may be markers of latent gluten-sensitive enteropathy; some of these patients are clinically gluten sensitive in the absence of enteropathy.

PMID: 8482440


Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.
Biesiekierski JR1, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR.


Despite increased prescription of a gluten-free diet for gastrointestinal symptoms in individuals who do not have celiac disease, there is minimal evidence that suggests that gluten is a trigger. The aims of this study were to determine whether gluten ingestion can induce symptoms in non-celiac individuals and to examine the mechanism.


A double-blind, randomized, placebo-controlled rechallenge trial was undertaken in patients with irritable bowel syndrome in whom celiac disease was excluded and who were symptomatically controlled on a gluten-free diet. Participants received either gluten or placebo in the form of two bread slices plus one muffin per day with a gluten-free diet for up to 6 weeks. Symptoms were evaluated using a visual analog scale and markers of intestinal inflammation, injury, and immune activation were monitored.


A total of 34 patients (aged 29-59 years, 4 men) completed the study as per protocol. Overall, 56% had human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8. Adherence to diet and supplements was very high. Of 19 patients (68%) in the gluten group, 13 reported that symptoms were not adequately controlled compared with 6 of 15 (40%) on placebo (P=0.0001; generalized estimating equation). On a visual analog scale, patients were significantly worse with gluten within 1 week for overall symptoms (P=0.047), pain (P=0.016), bloating (P=0.031), satisfaction with stool consistency (P=0.024), and tiredness (P=0.001). Anti-gliadin antibodies were not induced. There were no significant changes in fecal lactoferrin, levels of celiac antibodies, highly sensitive C-reactive protein, or intestinal permeability. There were no differences in any end point in individuals with or without DQ2/DQ8.

CONCLUSIONS:"Non-celiac gluten intolerance" may exist, but no clues to the mechanism were elucidated.

PMID: 21224837


Gluten-sensitive diarrhea without evidence of celiac disease.
Cooper BT, Holmes GK, Ferguson R, Thompson RA, Allan RN, Cooke WT.


Eight adult female patients suffering from abdominal pain and chronic diarrhea which was often incapacitating and frequently nocturnal, had dramatic relief on a gluten-free diet and return of symptoms after gluten challenge. Previous nonspecific measures and a milk-free diet were ineffective. Multiple jejunal biopsies showed minor, but significant changes in cellularity which returned to normal on the gluten-free diet. Apart from a slight increase in jejunal cellularity, no immunological abnormalities were found after gluten challenge. Steatorrhea or other biochemical defects, common in celiac disease, were not found.

It was concluded that these patients had a gluten-sensitive diarrhea, but had no evidence of celiac disease.

PMID: 7419003


Markers of Celiac Disease and Gluten Sensitivity in Children with Autism.
Lau NM1, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky BE, Higgins JJ, Rajadhyaksha AM, Alaedini A.



Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease.


Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n=37), their unaffected siblings (n=27), and age-matched healthy controls (n=76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles.


Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed.


A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.


PMCID: PMC3688832 Free PMC Article

Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity.
Caio G, Volta U1, Tovoli F, De Giorgio R.



Non-celiac gluten sensitivity is a syndrome characterized by gastrointestinal and extra-intestinal symptoms occurring in a few hours/days after gluten and/or other wheat protein ingestion and rapidly improving after exclusion of potential dietary triggers. There are no established laboratory markers for non-celiac gluten sensitivity, although a high prevalence of first generation anti-gliadin antibodies of IgG class has been reported in this condition. This study was designed to characterize the effect of the gluten-free diet on anti-gliadin antibodies of IgG class in patients with non-celiac gluten sensitivity.


Anti-gliadin antibodies of both IgG and IgA classes were assayed by ELISA in 44 non-celiac gluten sensitivity and 40 celiac disease patients after 6 months of gluten-free diet.


The majority of non-celiac gluten sensitivity patients (93.2%) showed the disappearance of anti-gliadin antibodies of IgG class after 6 months of gluten-free diet; in contrast, 16/40 (40%) of celiac patients displayed the persistence of these antibodies after gluten withdrawal. In non-celiac gluten sensitivity patients anti-gliadin antibodies IgG persistence after gluten withdrawal was significantly correlated with the low compliance to gluten-free diet and a mild clinical response.


Anti-gliadin antibodies of the IgG class disappear in patients with non-celiac gluten sensitivity reflecting a strict compliance to the gluten-free diet and a good clinical response to gluten withdrawal.


PMID:24524388 [PubMed - in process] PMCID:PMC3926852 Free PMC Article

Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism.
Vojdani A1, O'Bryan T, Green JA, Mccandless J, Woeller KN, Vojdani E, Nourian AA, Cooper EL.

The mechanisms behind autoimmune reaction to nervous system antigens in autism are not understood. We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously. For examining cross-reaction between dietary proteins and cerebellar antigens, antibodies were prepared in rabbits, and binding of rabbit anti-gliadin, anti-cerebellar peptides, anti-MBP, anti-milk, anti-egg, anti-soy and anti-corn to either gliadin- or cerebellar-antigen-coated wells was measured. In comparison to anti-gliadin peptide binding to gliadin peptide at 100%, the reaction of anti-cerebellar peptide to gliadin peptide was 22%, whereas the binding of anti-myelin basic protein (MBP), anti-milk, anti-egg and anti-soy to gliadin was less than 10%. Further examination of rabbit anti-gliadin (EQVPLVQQ) and anti-cerebellar (EDVPLLED) 8 amino acid (AA) peptides with human serum albumin (HSA) and an unrelated peptide showed no binding, but the reaction of these antibodies with both the cerebellar and gliadin peptides was greater than 60%. This cross-reaction was further confirmed by DOT-immunoblot and inhibition studies. We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.


PMID:15526989[PubMed - indexed for MEDLINE]