In any case, it is reassuring to know that researchers now have scientific evidence to disprove the belief (held by many medical professionals) that non-celiac gluten sensitivity simply doesn't exist.
http://newsroom.cumc.columbia.edu/blog/ ... itivity-2/
Columbia Researchers Find Biological Explanation for Wheat Sensitivity
Weakened Intestinal Barrier, Systemic Immune Activation May Explain Symptoms in People Without Celiac Disease
July 26, 2016
NEW YORK, NY (July 26, 2016)—A new study may explain why people who do not have celiac disease or wheat allergy nevertheless experience a variety of gastrointestinal and extra-intestinal symptoms after ingesting wheat and related cereals. The findings suggest that these individuals have a weakened intestinal barrier, which leads to a body-wide inflammatory immune response.
Findings from the study, which was led by researchers from Columbia University Medical Center (CUMC), were reported in the journal Gut.
“Our study shows that the symptoms reported by individuals with this condition are not imagined, as some people have suggested,” said study co-author Peter H. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at CUMC and director of the Celiac Disease Center. “It demonstrates that there is a biological basis for these symptoms in a significant number of these patients.”
Celiac disease is an autoimmune disorder in which the immune system mistakenly attacks the lining of the small intestine after someone who is genetically susceptible to the disorder ingests gluten from wheat, rye, or barley. This leads to a range of gastrointestinal symptoms, including abdominal pain, diarrhea, and bloating.
Researchers have struggled to determine why some people, who lack the characteristic blood, tissue, or genetic markers of celiac disease, experience celiac-like GI symptoms, as well as certain extra-intestinal symptoms, such as fatigue, cognitive difficulties, or mood disturbance, after ingesting foods that contain wheat, rye, or barley. One explanation for this condition, known as non-celiac gluten or wheat sensitivity (NCWS), is that exposure to the offending grains somehow triggers acute systemic immune activation, rather than a strictly localized intestinal immune response. Because there are no biomarkers for NCWS, accurate figures for its prevalence are not available, but it is estimated to affect about 1 percent of the population, or 3 million Americans, roughly the same prevalence as celiac disease.
In the new study, the CUMC team examined 80 individuals with NCWS, 40 individuals with celiac disease, and 40 healthy controls. Despite the extensive intestinal damage associated with celiac disease, blood markers of innate systemic immune activation were not elevated in the celiac disease group. This suggests that the intestinal immune response in celiac patients is able to neutralize microbes or microbial components that may pass through the damaged intestinal barrier, thereby preventing a systemic inflammatory response against highly immunostimulatory molecules.
The NCWS group was markedly different. They did not have the intestinal cytotoxic T cells seen in celiac patients, but they did have a marker of intestinal cellular damage that correlated with serologic markers of acute systemic immune activation. The results suggest that the identified systemic immune activation in NCWS is linked to increased translocation of microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier.
“A systemic immune activation model would be consistent with the generally rapid onset of the reported symptoms in people with non-celiac wheat sensitivity,” said study leader Armin Alaedini, PhD, assistant professor of medicine at Columbia. He also holds an appointment in Columbia’sInstitute of Human Nutrition and is a member of the Celiac Disease Center.
NCWS patients who followed a diet that excluded wheat and related cereals for six months were able to normalize their levels of immune activation and intestinal cell damage markers, the researchers also found. These changes were associated with significant improvement in both intestinal and non-intestinal symptoms, as reported by the patients in detailed questionnaires.
Dr. Alaedini added, “The data suggest that, in the future, we may be able to use a combination of biomarkers to identify patients with non-celiac wheat sensitivity, and to monitor their response to treatment.”
The study involved an international collaboration between researchers at CUMC and the University of Bologna in Italy. “These results shift the paradigm in our recognition and understanding of non-celiac wheat sensitivity and will likely have important implications for diagnosis and treatment,” said co-author Umberto Volta, MD, professor of internal medicine at the University of Bologna. “Considering the large number of people affected by the condition and its significant negative health impact on patients, this is an important area of research that deserves much more attention and funding.”
In future studies of NCWS, Dr. Alaedini and his team plan to investigate the mechanisms responsible for triggering the intestinal damage and breach of the epithelial barrier and to further characterize the immune cell responses.
http://gut.bmj.com/content/early/2016/0 ... 11964.full
Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease
Melanie Uhde1, Mary Ajamian1, Giacomo Caio2, Roberto De Giorgio2, Alyssa Indart1,Peter H Green1,3, Elizabeth C Verna1, Umberto Volta2, Armin Alaedini1,3,4
1 Department of Medicine, Columbia University Medical Center, New York, New York, USA
2 Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital,Bologna, Italy
3 Celiac Disease Center, Columbia University Medical Center, New York, New York, USA
4 Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA
Dr Armin Alaedini, Department of Medicine, Columbia University Medical Center, 1130 Saint Nicholas Ave., Room 937; New York, NY 10032, USA; email@example.com
Received 31 March 2016
Revised 9 June 2016
Accepted 20 June 2016
Published Online First 25 July 2016
Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.
Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.
Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.
These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.
Significance of this study
What is already known on this subject?
Some individuals experience a range of symptoms in response to the ingestion of wheat and related cereals, yet lack the characteristic serological or histological markers of coeliac disease.
Accurate figures for the population prevalence of this sensitivity are not available, although estimates that put the number at similar to or greater than for coeliac disease are often cited.
Despite the increasing interest from the medical community and the general public, the aetiology and mechanism of the associated symptoms are largely unknown and no biomarkers have been identified.
What are the new findings?
Reported sensitivity to wheat in the absence of coeliac disease is associated with significantly increased levels of soluble CD14 and lipopolysaccharide-binding protein, as well as antibody reactivity to microbial antigens, indicating systemic immune activation.
Affected individuals have significantly elevated levels of fatty acid-binding protein 2 that correlates with the markers of systemic immune activation, suggesting compromised intestinal epithelial barrier integrity.
How might it impact on clinical practice in the foreseeable future?
The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.
The data offer a platform for additional research directed at assessing the use of the examined markers for identifying affected individuals and/or monitoring the response to treatment, investigating the underlying mechanism and molecular triggers responsible for the breach of the epithelial barrier, and evaluating novel treatment strategies in affected individuals.
From the Open Access article:
B-cell response to microbial antigens
When compared with the healthy control and coeliac disease cohorts, the NCWS group had significantly higher levels of EndoCAb IgM (p<0.0001 and p=0.028, respectively) (figure 2D), but not IgG or IgA (see figure 2C and online supplementary figure S2A). In contrast to the NCWS cohort, the coeliac disease group had higher levels of EndoCAb IgA when compared with the NCWS and healthy control groups (p=0.021 and p=0.032, respectively) (see onlinesupplementary figure S2A), but not IgG or IgM (figure 2C, D).
Furthermore, the levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort when compared with the healthy control group (p=0.001 and p=0.009, respectively) (figure 2E, F). These antibodies were not significantly elevated in the coeliac disease cohort, although there was a trend towards higher IgA reactivity to flagellin when compared with healthy controls (p=0.059) (see online supplementary figure S2B). The increased IgM antibody response to flagellin correlated with the elevated EndoCAb IgM in the NCWS cohort (r=0.386, p<0.0001) (see online supplementary figure S3).
As expected, the cohort of individuals with sensitivity to wheat in the absence of coeliac disease did not exhibit significantly elevated antibody responses to TG2 or deamidated gliadin sequences. This indicates that in contrast to coeliac disease, the observed humoral immune response to gluten in NCWS is independent of TG2 enzymatic activity and HLA-DQ2/DQ8, and is likely to target certain epitopes that are distinct from those in coeliac disease. We hypothesised that the enhanced antibody response to native gliadin in NCWS individuals, particularly IgG and IgM isotypes, may be a consequence of ongoing intestinal epithelial barrier defects. If so, such defects might also give rise to an inadequate regulation of the interaction between the gut microbiota and systemic circulation, resulting in peripheral immune activation. To examine this, we measured the levels of LBP and sCD14 as indicators of the translocation of microbial products, particularly LPS, across the epithelial barrier. Translocated circulating LPS can result in the rapid secretion of LBP by GI and hepatic epithelial cells, as well as sCD14 by CD14+ monocytes/macrophages.19 sCD14 binds LPS in the presence of LBP to activate TLR4.27 We found significantly elevated serum levels of both LBP and sCD14 in individuals with NCWS in comparison with patients with coeliac disease and healthy controls. The high degree of correlation between serum LBP and sCD14 suggested that these molecules are concurrently expressed in response to the stimulus in NCWS individuals.
We also quantified serum levels of antibody to LPS core oligosaccharide, or EndoCAb, which is known to modulate in response to bacterial endotoxin in circulation.28 As they are involved in the neutralisation of circulating endotoxin, EndoCAb immunoglobulins are typically depleted in response to an acute LPS exposure, but eventually rise due to the B-cell anamnestic response.19 Individuals in the NCWS cohort exhibited increased levels of EndoCAb IgM. To demonstrate that the systemic immune response in individuals identified as having NCWS would not be limited to only LPS if driven by translocated microbial products, we also measured serum levels of antibody to flagellin, the principal substituent protein of the flagellum in Gram-positive and negative bacteria. We found that levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort. Considering that no individuals in this study had evidence of infection, these observations are suggestive of a translocation of microbial products from the GI tract that contributes to the observed innate and adaptive immune activation in the NCWS cohort.
Circulating bacterial components, such as LPS and flagellin, bind to their respective TLRs on various cells, including macrophages and dendritic cells, which results in signalling through the myeloid differentiation factor 88 (MyD88) adaptor protein.27 Ultimately, MyD88 signalling leads to the activation of transcription factor nuclear factor-κB and increased expression of various proinflammatory cytokines that can exert deleterious systemic effects.19 ,29 A systemic innate immune activation model would be consistent with the generally rapid onset of reported symptoms in NCWS.6 In addition, circulating microbial products can bind to TLRs on other cells to trigger a more localised inflammatory response. For example, LPS binds directly to TLR4 on the luminal surface of brain blood vessels, resulting in local cytokine secretion in the brain that has been shown to activate the microglia to displace inhibitory synapses.30 In HIV infection, where the presence of microbial translocation is linked to intestinal epithelial damage, increased systemic immune activation in response to bacterial antigens is associated with cognitive deficits.31 Such a pathway might contribute to some of the neurocognitive symptoms experienced by NCWS individuals.
On the other hand, despite the established extensive villous damage associated with coeliac disease, neither LBP nor sCD14 levels were found to be significantly elevated in the coeliac disease group, thus standing in stark contrast to the NCWS cohort. In addition, among the immunoglobulin responses to microbial antigens, only IgA antibodies appeared to be increased in coeliac disease. These data suggest that there is an effective mechanism for the neutralisation of microbial products that may cross into the lamina propria in most cases of coeliac disease, possibly in part via the localised IgA response and mucosal phagocytic cells. These mechanisms are known to be essential for the immune surveillance of luminal antigens and the elimination of microbial products that cross the epithelial barrier, thereby reducing the likelihood of their translocation into the submucosa and access to blood vessels.19 Such mucosal immune responses may be lacking or inadequate in individuals with NCWS. Instead, what we observed were enhanced IgM responses to gliadin, LPS and flagellin in the NCWS cohort, which clearly contrasted with the coeliac disease group.
The hallmark of NCWS is the onset of intestinal and/or extraintestinal symptoms on ingestion of gluten-containing foods, that is, wheat, rye and barley, and the alleviation of symptoms on their withdrawal from diet. To determine whether the patient-reported symptom resolution on the elimination of these foods would be associated with the amelioration of intestinal epithelial cell damage and a reduction in microbial translocation and systemic immune activation, we examined the above markers in a subset of NCWS subjects before and after a diet that excluded wheat and related cereals. The results indicated a significant decline in the markers of immune activation and gut epithelial cell damage, in conjunction with the improvement of symptoms. However, the magnitude of change in the measured biological markers did not correlate significantly with that for the symptom scores. This appears to be similar to observations in patients with coeliac disease, where symptoms are known to be a poor predictor of disease activity and associated biomarkers.46 ,47 A limitation of this portion of the study was the absence of a healthy control group to assess the potential impact of the dietary restriction in unaffected individuals.
In summary, the results of this study on individuals with sensitivity to wheat in the absence of coeliac disease demonstrate (1) significantly increased serum levels of sCD14 and LBP, as well as antibody reactivity to microbial antigens, indicating systemic immune activation; (2) an elevated expression of FABP2 that correlates with the systemic immune responses to bacterial products, suggesting compromised intestinal epithelial barrier integrity and increased microbial translocation; and (3) a significant change towards normalisation in the levels of the immune activation markers, as well as FABP2 expression, in response to the restrictive diet, which is associated with improvement in symptoms. Our data establish the presence of objective markers of systemic immune activation and epithelial cell damage in the affected individuals. The results of the multivariate data analysis suggest that a selected panel of these may have use for identifying patients with NCWS or patient subsets in the future. It is important to emphasise that this study does not address the potential mechanism or molecular trigger(s) responsible for driving the presumed loss of epithelial barrier integrity and microbial translocation. Further research is needed to investigate the mechanism responsible for the intestinal damage and breach of the epithelial barrier, assess the potential use of the identified immune markers for the diagnosis of affected individuals and/or monitoring the response to specific treatment strategies, and examine potential therapies to counter epithelial cell damage and systemic immune activation in affected individuals.