-
1.
The Differences between Gluten Sensitivity, Intestinal Biomarkers and Immune Biomarkers in Patients with First-Episode and Chronic Schizophrenia.
Dzikowski, M, Juchnowicz, D, Dzikowska, I, Rog, J, Próchnicki, M, Kozioł, M, Karakula-Juchnowicz, H
Journal of clinical medicine. 2020;9(11)
-
-
-
Free full text
Plain language summary
Schizophrenia is a heterogeneous neuroimmune disorder with unknown mechanisms and aetiology. The goal of this clinical study was to compare and evaluate IgG and IgA sensitivity, inflammation, and gut integrity between 52 first episode Schizophrenia patients, 50 chronic Schizophrenia patients, and 60 healthy controls to explain whether there were any associations between these markers. Study results show that antigliadin IgG and IgA antibodies, as well as inflammatory markers such as hs-CRP and IL-6, were significantly higher in the first episodes of schizophrenia and chronic schizophrenia patients when compared to the healthy controls. Schizophrenia risk was 4-7% higher among those with elevated Antigliadin IgG and IgA antibody levels. In addition, smoking cigarettes has been shown to increase the risk of developing schizophrenia. Patients with chronic schizophrenia showed elevated levels of anti-Saccharomyces cerevisiae antibody and soluble CD14, indicating bacterial translocation and immune activation. To understand the mechanisms behind chronic Schizophrenia, which link inflammation, immune responses, and the gut-brain axis, further robust larger studies are necessary. The results of this study can be used by healthcare professionals to understand the relationship between intestinal permeability, inflammation, and food hypersensitivity.
Abstract
Schizophrenia is a heterogeneous disorder without a fully elucidated etiology and mechanisms. One likely explanation for the development of schizophrenia is low-grade inflammation, possibly caused by processes in the gastrointestinal tract related to gluten sensitivity. The aims of this study were to: (1) compare levels of markers of gluten sensitivity, inflammation and gut permeability, and (2) determine associations between gluten sensitivity, inflammation, and intestinal permeability in patients with first-episode/chronic (FS/CS) schizophrenia and healthy individuals (HC). The total sample comprised 162 individuals (52 FS; 50 CS, and 60 HC). The examination included clinical variables, nutritional assessment, and serum concentrations of: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), anti-Saccharomyces cerevisiae antibody (ASCA), antigliadin antibodies (AGA) IgA/IgG, antibodies against tissue transglutaminase 2 (anti-tTG) IgA, anti-deamidated gliadin peptides (anti-DGP) IgG. A significant difference between groups was found in sCD14, ASCA, hs-CRP, IL-6 and AGA IgA levels. AGA IgG/IgA levels were higher in the FS (11.54%; 30.77%) and CS (26%; 20%) groups compared to HC. The association between intestinal permeability and inflammation in the schizophrenic patients only was noted. The risk for developing schizophrenia was odds ratio (OR) = 4.35 (95% confidence interval (CI 1.23-15.39) for AGA IgA and 3.08 (95% CI 1.19-7.99) for positive AGA IgG. Inflammation and food hypersensitivity reactions initiated by increased intestinal permeability may contribute to the pathophysiology of schizophrenia. The immune response to gluten in FS differs from that found in CS.
-
2.
Multifactorial Etiology of Anemia in Celiac Disease and Effect of Gluten-Free Diet: A Comprehensive Review.
Martín-Masot, R, Nestares, MT, Diaz-Castro, J, López-Aliaga, I, Alférez, MJM, Moreno-Fernandez, J, Maldonado, J
Nutrients. 2019;11(11)
-
-
-
Free full text
Plain language summary
Anaemia is a common clinical expression of Celiac Disease (CD) alongside vitamin B12, iron and folate deficiencies. This review looks at the latest evidence and effects of a gluten free diet, the mainstay of treatment for CD. Typically, symptoms subside whilst adhering to a GF diet however in 20% of people anaemia and nutrient deficiencies can persist. Some of this is attributed to lack of adherence to the diet, oftentimes accidental given the wide range of foods containing gluten. This in turn leads to further damage of the intestine and can be difficult to detect and monitor effectively. Inflammation of the gastrointestinal tract, and malabsorption, are the main reasons for nutrient deficiencies leading to anaemia in CD. Iron is a critical nutrient which can easily be affected by damage to the intestinal villi, common in CD, and over time lead to iron deficiency anaemia as the body is unable to absorb dietary iron and the body’s iron stores are depleted. Likewise, absorption of vitamins B12 and B9 (folate) are also impaired by damaged villi and vitamin B12 is further affected by small intestine injuries including decreased gastric acid production, bacterial overgrowth and reduced intrinsic factor efficiency. Deficiencies of these two nutrients can lead to macrocytic anaemia with low blood cell volumes. Overall a gluten free diet is shown to reduce symptoms of CD in a matter of weeks. The more patients adhere to the diet, the more the risk of nutrient deficiencies and anaemia reduces.
Abstract
Celiac disease (CD) is a multisystemic disorder with different clinical expressions, from malabsorption with diarrhea, anemia, and nutritional compromise to extraintestinal manifestations. Anemia might be the only clinical expression of the disease, and iron deficiency anemia is considered one of the most frequent extraintestinal clinical manifestations of CD. Therefore, CD should be suspected in the presence of anemia without a known etiology. Assessment of tissue anti-transglutaminase and anti-endomysial antibodies are indicated in these cases and, if positive, digestive endoscopy and intestinal biopsy should be performed. Anemia in CD has a multifactorial pathogenesis and, although it is frequently a consequence of iron deficiency, it can be caused by deficiencies of folate or vitamin B12, or by blood loss or by its association with inflammatory bowel disease (IBD) or other associated diseases. The association between CD and IBD should be considered during anemia treatment in patients with IBD, because the similarity of symptoms could delay the diagnosis. Vitamin B12 deficiency is common in CD and may be responsible for anemia and peripheral myeloneuropathy. Folate deficiency is a well-known cause of anemia in adults, but there is little information in children with CD; it is still unknown if anemia is a symptom of the most typical CD in adult patients either by predisposition due to the fact of age or because biochemical and clinical manifestations take longer to appear.
-
3.
Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review.
Mearns, ES, Taylor, A, Thomas Craig, KJ, Puglielli, S, Leffler, DA, Sanders, DS, Lebwohl, B, Hadjivassiliou, M
Nutrients. 2019;11(2)
-
-
-
Free full text
Plain language summary
Coeliac disease (CD) is a chronic, immune-mediated enteropathy in which dietary gluten triggers an inflammatory reaction of the small intestine in genetically predisposed individuals. The clinical presentation of the disease varies broadly and may include both intestinal symptoms and extra-intestinal manifestations, including iron-deficiency anaemia, osteoporosis, dermatitis herpetiformis, and neurological disorders, such as peripheral neuropathies and ataxia (a condition that affects co-ordination, balance and speech). Many patients who present with neurological manifestations of CD have no gastrointestinal symptoms, commonly leading to a delay in diagnosis. The aim of this systematic review was to assess the prevalence of peripheral neuropathies and gluten ataxia. Nine studies on gluten ataxia and 13 on gluten neuropathy were included in this review. The prevalence of both, neuropathy and ataxia, in the general population is very low, but this risk is increased in patients with CD. Estimates of the prevalence of neuropathy in CD patients ranged from 0% to 39%, with an increased risk in older and female patients. Prevalence of gluten ataxia varied from 0% to 6%. Symptoms of gluten neuropathy improve when patients with CD follow a gluten free diet (GFD), whilst the benefits of a GFD for ataxia vary between studies, possibly due to differences in study design. The authors note that this review primarily concentrated on patients with CD (i.e. those with evidence of enteropathy). However, neurological manifestations may exist in the presence of anti-gliadin antibodies alone (gluten sensitivity without evidence of enteropathy), and such patients benefit equally from a GFD. The authors conclude that patients with CD have an increased risk of gluten ataxia and gluten neuropathy, and that clinicians should check for gluten sensitivity in patients with ataxia and neuropathy of unknown origin.
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly reported neurological manifestations (neuropathy and ataxia) associated with CD was performed. MEDLINE, Embase, the Cochrane Library, and conference proceedings were systematically searched from January 2007 through September 2018. Included studies evaluated patients with CD with at least one neurological manifestation of interest and reported prevalence, and/or incidence, and/or clinical outcomes. Sixteen studies were included describing the risk of gluten neuropathy and/or gluten ataxia in patients with CD. Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies. Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%. Adherence to a gluten-free diet appeared to improve symptoms of both neuropathy and ataxia. The prevalence of gluten neuropathy and gluten ataxia in patients with CD varied in reported studies, but the increased risk supports the need for physicians to consider CD in patients with ataxia and neurological manifestations of unknown etiology.
-
4.
Lack of immunogenicity of hydrolysed wheat flour in patients with coeliac disease after a short-term oral challenge.
Mandile, R, Picascia, S, Parrella, C, Camarca, A, Gobbetti, M, Greco, L, Troncone, R, Gianfrani, C, Auricchio, R
Alimentary pharmacology & therapeutics. 2017;46(4):440-446
-
-
-
Plain language summary
A gluten-free diet is currently the only reliable therapeutic approach for coeliac disease (CD), an immune-mediated condition where eating gluten causes intestinal inflammation. Hydrolysing wheat flour with a sourdough enriched with lactobacilli and fungal proteases has been shown to be effective in reducing the gluten in the bread baked with it to less that 10ppm (which should be safe for CD patients). This randomised prospective study was designed to confirm the lack of an immunological response to the hydrolysed gluten in CD patients, both in vitro and in vivo. 20 CD patients who were in clinical remission and had followed a gluten-free diet (GFD) for at least three years were enrolled into this study and randomised to receive either natural wheat (10g gluten per day) or hydrolysed wheat (10g hydrolysed gluten per day) for three days. In vitro studies using intestinal cells from three of the study participants showed that the hydrolysed gluten did not elicit an immune response, whilst the natural gluten did. In vivo, there were no statistically significant increases in immune reactivity in the hydrolysed gluten patients, and no-one in this group experienced any symptoms. In the natural wheat group significant increases in immune reactivity to gluten were seen although only one person experienced symptoms (abdominal pain). The authors conclude that wheat flour hydrolysed with an enriched sourdough may be an alternative for the CD patient’s diet.
Abstract
BACKGROUND A gluten-free diet is currently the only reliable therapeutic strategy that is approved for coeliac disease (CD). For many patients, however, compliance remains inadequate. AIM: To investigate the immunogenicity of wheat flour that was pre-treated with selected lactobacilli and fungal proteases (hydrolysed wheat gluten) in coeliac patients. METHODS The immunogenicity of hydrolysed wheat gluten was evaluated both in vitro in intestinal T cell lines (TCLs) and in vivo in treated CD patients after a short-term gluten challenge. Twenty treated CD patients were enrolled and equally randomised into two groups. The patients ate bread that was prepared with hydrolysed wheat flour or natural wheat flour (10 g of gluten/d for 3 days). The interferon (INF)-γ responses to natural gliadin and a 33-mer peptide were assessed by the enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) both before and 6 days after the start of the challenge. RESULTS Hydrolysed wheat was not able to activate the TCLs from the coeliac intestinal mucosa. Consistent with the in vitro results, no significant increase in INF-γ secretion was observed in patients who consumed hydrolysed wheat flour. Conversely, the consumption of natural wheat gluten mobilised INF-γ secreting cells in the blood (P<.05). CONCLUSIONS We confirm that fermentation of wheat flour with sourdough lactobacilli and fungal proteases is capable of abolishing the T cell immunogenicity of gluten in coeliac patients. Our data also validate the short-term oral challenge as a useful tool for testing the efficacy of novel therapeutic approaches.
-
5.
Serum cytokine pattern in young children with screening detected coeliac disease.
Björck, S, Lindehammer, SR, Fex, M, Agardh, D
Clinical and experimental immunology. 2015;179(2):230-5
-
-
-
Free full text
Plain language summary
Coeliac disease (CD) is an autoimmune disorder characterised by inflammation in the small bowel after ingesting gluten. Many patients may be asymptomatic and clinically silent, prolonging their diagnosis and treatment. This may put them at risk for long-term complications due to chronic systemic inflammation. Circulating cytokines indicate inflammatory activity in the body and have been shown to be elevated in patients with CD. The aim of this study was to measure the levels of serum cytokines in 26 3-year-old children with CD, both at the time of diagnosis and after starting a gluten-free diet. The findings of this study showed that young children with CD demonstrated elevated levels of serum cytokines at the time of diagnosis. After maintaining a gluten-free diet, many cytokine levels decreased. Based on this study, the authors’ conclude that systemic inflammation due to undiagnosed disease in young children may contribute to long-term complications associated with chronic inflammation, and should be accounted for when screening for the disease.
Abstract
Coeliac disease is an autoimmune disease characterized by inflammation localized to the small bowel, but less is known about systemic signs of inflammation. The aim was to measure cytokines of the T helper 1 (Th1) and T helper 2 (Th2) cell patterns in children with screening-detected coeliac disease before and after treatment with a gluten-free diet. Serum samples selected before and after the start of a gluten-free diet from 26 3-year-old children diagnosed with biopsy-proven coeliac disease and from 52 matched controls were assayed in an multiplex enzyme-linked immunosorbent assay (ELISA) for the 10 cytokines: interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13 and tumour necrosis factor (TNF)-α. Among Th1 cytokines, IFN-γ and IL-12p70 were elevated significantly in children with coeliac disease compared to controls (P < 0.001 and P = 0.001, respectively). Similar findings were demonstrated for the Th2 cytokines IL-5 (P < 0.001), IL-10 (P = 0.001) and IL-13 (P = 0.002). No difference in cytokine levels between the two groups was found for TNF-α, IL-1β, IL-2, IL-4 and IL-8. After gluten-free diet, levels of IL-5, IL-12 and IL-10 decreased significantly (P < 0.001, P = 0.002 and P = 0.007) and IFN-γ levels were reduced (P = 0.059). Young children with coeliac disease detected by screening demonstrate elevated levels of serum cytokines at time of diagnosis. A prolonged systemic inflammation may, in turn, contribute to long-term complications known to be associated with untreated coeliac disease.
-
6.
Reintroduction of gluten following flour transamidation in adult celiac patients: a randomized, controlled clinical study.
Mazzarella, G, Salvati, VM, Iaquinto, G, Stefanile, R, Capobianco, F, Luongo, D, Bergamo, P, Maurano, F, Giardullo, N, Malamisura, B, et al
Clinical & developmental immunology. 2012;2012:329150
-
-
-
Free full text
Plain language summary
A lifelong gluten-free diet (GFD) is mandatory for celiac disease (CD) but has poor compliance, justifying new strategies. Chemically altering the protein in wheat flour (transamidation of gliadin) reduces the reaction experienced in vitro in intestinal cells of CD patients. This randomized single blinded, controlled 90-day trial in 47 CD patients examines the safety of transamidated wheat flour compared to control. 35 patients received 50g a day of transamidated flour bread and 12 received 3.7g of non-transamidated flour bread. On day 15, 75% and 37% of patients in the control and experimental groups, respectively, showed clinical relapse whereas intestinal permeability was mainly altered in the control group. On day 90, 0 controls and 14 patients in the experimental group completed the challenge with no change to the autoantibody found in CD (Ttg) and other markers of CD. This study demonstrated that a protracted intake of gluten from chemically treated wheat flour was associated with a reduced number of relapses in challenged patients. Nevertheless, the enzyme reaction did not eradicate gluten activity in all CD patients examined. Whether an upgrade of the transamidation reaction might be instrumental in blocking other immune components involved in the mucosal lesion is under investigation.
Abstract
A lifelong gluten-free diet (GFD) is mandatory for celiac disease (CD) but has poor compliance, justifying novel strategies. We found that wheat flour transamidation inhibited IFN-γ secretion by intestinal T cells from CD patients. Herein, the primary endpoint was to evaluate the ability of transamidated gluten to maintain GFD CD patients in clinical remission. Secondary endpoints were efficacy in prevention of the inflammatory response and safety at the kidney level, where reaction products are metabolized. In a randomized single blinded, controlled 90-day trial, 47 GFD CD patients received 3.7 g/day of gluten from nontransamidated (12) or transamidated (35) flour. On day 15, 75% and 37% of patients in the control and experimental groups, respectively, showed clinical relapse (P = 0.04) whereas intestinal permeability was mainly altered in the control group (50% versus 20%, P = 0.06). On day 90, 0 controls and 14 patients in the experimental group completed the challenge with no variation of antitransglutaminase IgA (P = 0.63), Marsh-Oberhuber grading (P = 0.08), or intestinal IFN-γ mRNA (P > 0.05). Creatinine clearance did not vary after 90 days of treatment (P = 0.46). In conclusion, transamidated gluten reduced the number of clinical relapses in challenged patients with no changes of baseline values for serological/mucosal CD markers and an unaltered kidney function.
-
7.
Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet.
Hallert, C, Svensson, M, Tholstrup, J, Hultberg, B
Alimentary pharmacology & therapeutics. 2009;29(8):811-6
-
-
-
Free full text
-
Plain language summary
In many cases, adults diagnosed with coeliac disease (CD) that adhere to a long-term gluten-free diet (GFD) present with vitamin deficiency and lower levels of health-related quality of life. CD patients often do not meet the recommended daily intake levels of B vitamins as they are often consumed in fortified bread and cereals. The aim of this trial was to study the biochemical and clinical effects of 6-months of B vitamin supplementation in adults with longstanding CD. The trial included 57 participants aged 45-64 with evidence of remission from CD and on a gluten-free diet for at least 8 years. Patients were randomized to a daily dose of vitamin B complex and outcome measures were psychological wellbeing and homocysteine levels, a marker of B vitamin status. The findings of this study showed that in adult with longstanding coeliac disease, B vitamin supplementation resulted in normalized homocysteine levels and a significant improvement in general wellbeing. Based on this study, the authors’ suggest that B vitamins should be considered in people advised to follow a gluten-free diet.
Abstract
BACKGROUND Patients with coeliac disease living on a gluten-free diet show vitamin deficiency and reduced subjective health status. AIM: To study the biochemical and clinical effects of B vitamin supplementation in adults with longstanding coeliac disease. METHODS In a double blind placebo controlled multicentre trial, 65 coeliac patients (61% women) aged 45-64 years on a strict gluten-free diet for several years were randomized to a daily dose of 0.8 mg folic acid,0.5 mg cyanocobalamin and 3 mg pyridoxine or placebo for 6 months. The outcome measures were psychological general well-being (PGWB) and the plasma total homocysteine (tHcy) level, marker of B vitamin status. RESULTS Fifty-seven patients (88%) completed the trial. The tHcy level was baseline median 11.7 micromol/L (7.4-23.0), significantly higher than in matched population controls [10.2 micromol/L (6.7-22.6) (P < 0.01)]. Following vitamin supplementation, tHcy dropped a median of 34% (P < 0.001), accompanied by significant improvement in well-being (P < 0.01), notably Anxiety (P < 0.05) and Depressed Mood (P < 0.05) for patients with poor well-being. CONCLUSIONS Adults with longstanding coeliac disease taking extra B vitamins for 6 months showed normalized tHcy and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.
-
8.
Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study.
Catassi, C, Rossini, M, Rätsch, IM, Bearzi, I, Santinelli, A, Castagnani, R, Pisani, E, Coppa, GV, Giorgi, PL
Gut. 1993;34(11):1515-9
-
-
-
Free full text
Plain language summary
Coeliac disease (CD) is an intestinal reaction that is caused by the ingestion of gluten. While this is well established, the relationship between the quantity ingested and the severity of adverse effects, namely for small amounts of gluten, is still unclear. The aim of this study was to assess the effects of chronic ingestion of small amounts of gluten in children with CD. 20 children who had been on a long-term gluten-free diet were given a daily dose of either 100 mg or 500 mg of gliadin for four weeks. Effects were measured through an intestinal biopsy, antibody test and sugar intestinal permeability test. The findings of this study showed that in children with CD, chronic ingestion of gluten causes dose-dependent damage to intestinal mucosa and lymphocyte infiltration.
Abstract
This study aimed to investigate the effects of chronic ingestion of small amounts of gliadin on children with coeliac disease. A four week challenge was performed on 20 children who had been on a gluten free diet for mean (SD) 14 (3) months. They were given a daily dose of either 100 mg (group A, n = 10, mean age 4 (2) years) or 500 mg of gliadin (group B, mean age 5 (3) years). The effects of the gliadin were monitored by morphometric study of the jejunal mucosa, intestinal permeability test with cellobiose/mannitol, and serum antigliadin antibody test. After the challenge, group A patients showed a significant increase in the mean intraepithelial lymphocyte count (before challenge 11 (3), afterwards 19 (6)) and a decrease in the villous height/crypt depth ratio (beforehand 1.5 (0.1), afterwards 1.3 (0.2)), while the intestinal permeability test remained normal and the IgA-antigliadin antibody increased in four of 10 children. After the challenge group B showed more pronounced histological changes, an increase in the mean urinary cellobiose/mannitol % (beforehand 0.028 (0.020), afterwards 0.058 (0.028)), and IgA-antigliadin antibody positivity in six of eight subjects. The discriminant analysis function showed that the pretreatment group, group A after challenge, and group B after challenge were correctly classified in 90% of cases by functions based on the individual intraepithelial lymphocyte count and the villous height/crypt depth ratio. This study shows that chronic ingestion of small amounts of gluten causes dose-dependent damage to the small intestinal mucosa in children with coeliac disease. The predictive value of laboratory tests, such as the antigliadin antibody test and the intestinal permeability test seems to be lower in treated patients than in those with active coeliac disease.