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Overview of the compromised mucosal integrity in celiac disease.
Taraz, T, Mahmoudi-Ghehsareh, M, Asri, N, Nazemalhosseini-Mojarad, E, Rezaei-Tavirani, M, Jahani-Sherafat, S, Naseh, A, Rostami-Nejad, M
Journal of molecular histology. 2024;(1):15-24
Abstract
Intestinal epithelium is a dynamic cellular layer that lines the small-bowel and makes a relatively impenetrable barrier to macromolecules. Intestinal epithelial cell polarity is crucial in coordinating signalling pathways within cells and mainly regulated by three conserved polarity protein complexes, the Crumbs (Crb) complex, partitioning defective (PAR) complex, and Scribble (Scrib) complex. Polarity proteins regulate the proper establishment of the intercellular junctional complexes including tight junctions (TJs), adherence junctions (AJs), and desmosomes which hold epithelial cells together and play a major role in maintaining intestinal barrier integrity. Impaired intestinal epithelial cell polarity and barrier integrity result in irreversible immune responses, the host- microbial imbalance and intestinal inflammatory disorders. Disassembling the epithelial tight junction and augmented paracellular permeability is a conspicuous hallmark of celiac disease (CD) pathogenesis. There are several dietary components that can improve intestinal integrity and function. The aim of this review article is to summarize current information about the association of polarity proteins and AJC damages with pathogenesis of CD.
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Metabolomics and lipidomics signature in celiac disease: a narrative review.
Rostami-Nejad, M, Asri, N, Bakhtiari, S, Khalkhal, E, Maleki, S, Rezaei-Tavirani, M, Jahani-Sherafat, S, Rostami, K
Clinical and experimental medicine. 2024;(1):34
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Abstract
Celiac disease (CD) is a chronic immune-mediated inflammatory disease of the small intestine caused by aberrant immune responses to consumed gluten proteins. CD is diagnosed by a combination of the patients reported symptoms, serologic and endoscopic biopsy evaluation of the small intestine; and adherence to a strict gluten-free diet (GFD) is considered the only available therapeutic approach for this disorder. Novel approaches need to be considered for finding new biomarkers to help this disorder diagnosis and finding a new alternative therapeutic method for this group of patients. Metabolomics and lipidomics are powerful tools to provide highly accurate and sensitive biomarkers. Previous studies indicated a metabolic fingerprint for CD deriving from alterations in gut microflora or intestinal permeability, malabsorption, and energy metabolism. Moreover, since CD is characterized by increased intestinal permeability and due to the importance of membrane lipid components in controlling barrier integrity, conducting lipidomics studies in this disorder is of great importance. In the current study, we tried to provide a critical overview of metabolomic and lipidomic changes in CD.
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Impact of probiotics on gut microbiota composition and clinical symptoms of coeliac disease patients following gluten-free diet.
Soheilian Khorzoghi, M, Rostami-Nejad, M, Yadegar, A, Dabiri, H, Hadadi, A, Rodrigo, L
Contemporary clinical trials communications. 2023;:101201
Abstract
Coeliac disease (CD) is associated with alterations in gut microbiota composition. This study evaluated the effects of probiotics on gut microbiota composition and clinical symptoms of treated CD patients. In this double-blind, placebo-controlled trial study, 31 CD patients that were randomly classified as probiotics (n = 15) and placebo (n = 16) groups received 109 colony-forming units/capsule for 12 weeks. Fecal samples were collected before and after probiotics, or placebo administration and the changes in intestinal microbiota were assessed by quantitative real-time PCR. Probiotic administration improved the patients' clinical symptoms when compared to the placebo group. Fatigue score was significantly reduced by the intake of probiotic supplements (P = 0.02). Except for Staphylococcus spp., the relative abundances of Bacteroidetes, Lactobacillus spp., Bifidobacterium spp., Clostridium cluster I, Enterobacteriaceae, and Firmicutes were higher in probiotics group. Accordingly, a 12-week multi-strain probiotic treatment regimen may modify the composition of intestinal microbiota and improve GI symptoms in CD patients.
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Systematic Review and Dose-Response Meta-Analysis on the Relationship between Different Gluten Doses and Risk of Coeliac Disease Relapse.
Rostami-Nejad, M, Asri, N, Olfatifar, M, Khorsand, B, Houri, H, Rostami, K
Nutrients. 2023;(6)
Abstract
Gluten proteins are known as immunological triggers for inflammation resulting in mucosal lesions in patients with coeliac disease (CD). Adherence to a strict gluten-free diet (GFD) is currently known as the only effective treatment for CD. In this study, we performed a systematic review and dose-response meta-analysis on data from previous studies to investigate the association between different gluten doses administered and the risk of CD relapse. Electronic databases were systematically searched to retrieve studies that investigated the response of CD patients to different amounts of gluten intake and evaluated the clinical, serologic, and/or histologic evidence to recognize disease relapse. Study-specific relative risks (RRs) were combined using a random effects model. A total of 440 identified published papers were screened, of which 7 records were selected following full-text reviewing and eligibility assessment for dose-response meta-analysis. According to our analysis, the risk of CD relapse is estimated to be 0.2% (RR: 1.002; 95% CI: 1.001 to 1.004) following the consumption of 6 mg gluten/day, which was increased to 7% (RR: 1.07; 95% CI: 1.03 to 1.10), 50% (RR: 1.50; 95% CI: 1.23 to 1.82), 80% (RR: 1.80; 95% CI: 1.36 to 2.38), and 100% (RR: 2.00; 95% CI: 1.43 to 2.78) by the daily intake of 150, 881, 1276, and 1505 mg gluten, respectively. Although good adherence to a GFD can adequately control CD-related symptoms, disease relapse might happen even with a very low dose of gluten, and the duration of exposure to gluten is also an important matter. The current literature has substantial limitations, such as relying on the data from just a few countries that were different in terms of the amount of gluten administered, the duration of the challenge, etc. Therefore, more randomized clinical trials using a standardized gluten challenge protocol are needed to confirm the findings of the present study.
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Effects of a gluten challenge in patients with irritable bowel syndrome: a randomized single-blind controlled clinical trial.
Saadati, S, Sadeghi, A, Mohaghegh-Shalmani, H, Rostami-Nejad, M, Elli, L, Asadzadeh-Aghdaei, H, Rodrigo, L, Zali, MR
Scientific reports. 2022;12(1):4960
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Expert Review
Conflicts of interest:
None
Take Home Message:
- The results of this study suggest that a strict gluten-free, low FODMAP diet could be used in Individuals with IBS for anxiety reduction and improvement in quality of life.
- However, only a small number of participants were included and followed for a short duration.
- IBS is a complex disorder the cause of which is largely unknown. It requires a multidisciplinary approach in its treatment.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Irritable bowel syndrome (IBS), a functional disorder of the lower gastrointestinal tract, is characterized by various somatic and psychological manifestations. Evidence suggests IBS and non-celiac gluten sensitivity (NCGS) overlap. The development of IBS is thought to be multifactorial. Low-grade inflammation and food intolerances including to gluten and fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP), may play a role. Gluten tolerance is a major dilemma in medical practice.
The aim of this randomized controlled trial is to evaluate tolerance to gluten, anxiety and quality of life in irritable bowel syndrome (IBS). Prevalence of non-celiac gluten sensitivity (NCGS) was also reported. This trial was conducted in Tehran, Iran, in adults aged 18-80 years and with symptoms of IBS according to the ROME-IV criteria.
In informing their research question, the authors reference evidence of the efficacy of a gluten-free diet (GFD) and a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet on IBS symptoms.
One hundred and seven subjects were enrolled into phase I of the study, when a strict low-FODMAP and GFD was introduced for six weeks. Seventy subjects completed phase 1, of which twenty subjects declined to continue, leaving fifty subjects. These fifty subjects were enrolled into phase 2 and randomized into three groups (i) an unrestricted gluten diet (n=10), (ii) continuation of the low-FODMAP/GFD (n=15), and (iii) a gluten challenge group (n=25), for a further six weeks.
Reductions in bloating (3.5±2.6 to 2.5±2.1, p=0.03) and pain severity (2.9±2.8 to 2±2.2, p=0.02) were observed in the GFD, and a reduction in total VAS score (45.6±15.9 to 27.8±12.8, p=0.05) in the high-gluten group. The satiety score increased (2.3±1 to 3.8±3.1, p=0.04) in the unrestricted gluten diet group. At the end of the study, differences for pain frequency, pain severity and impact on community function were observed between the groups.
In this study, a low-FODMAP strict GFD was shown to reduce anxiety and improve the quality of life.
Clinical practice applications:
- In the gluten challenge phase of the study, between-group analysis revealed significant differences for pain and impact on community function No significant differences were found for bloating, satiety, defecation, total score, anxiety scores or quality of life between the groups. These mixed results, also found in other studies, add weight to the fact that the cause of IBS is unclear. The authors hypothesize that there may be an IBS subtype or new medical term, categorized as gluten sensitivity-IBS.
- Symptoms were evaluated but not objective outcomes, for example blood biomarkers. No aggravation of symptoms was observed in this study following the gluten challenge. Other non-gluten components of food may be responsible for IBS symptoms. Recent evidence suggests that fructans may be responsible in individuals with IBS and a low-FODMAP diet may be beneficial.
- Biopsychological factors are important to consider in the duration and severity of IBS symptoms.
- A strict GFD can come with problems, as mentioned, nutritional deficiencies, difficulty finding GF foods, high cost, altered taste, impacts on social/quality of life.
- Results were mixed, however suggest a low-FODMAP strict GFD could be a therapeutic choice for the management of IBS particularly in reducing anxiety and improving quality of life.
Considerations for future research:
- Randomized controlled trials with greater numbers of participants and longer durations assessing the impact of a low-FODMAP strict GFD in IBS, are warranted.
- Including food sensitivity/intolerance testing may be useful to distinguish which individuals might benefit from a GFD alone, a low-FODMAP diet alone or a low-FODMAP GFD.
- Small intestinal bacterial overgrowth (SIBO) testing would be of interest to understand who might benefit from a low-FODMAP diet.
- Studies assessing baseline stress levels and stress management interventions in combination with dietary interventions such as low-FODMAP GFD could be important avenues of research.
Abstract
Non-celiac gluten sensitivity (NCGS) and irritable bowel syndrome (IBS) frequently overlap. Although, gluten-free diet (GFD) and low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) improve the IBS clinical picture, many aspects remain unclear. Therefore, we designed a study to evaluate gluten tolerance, anxiety and quality of life in a specific study population. Fifty IBS patients were asked to follow a low FODMAP strict GFD for 6 weeks and were then randomly allocated to the following groups for a further 6 weeks: (A) receiving 8 g/day of gluten for 2 weeks; gluten-tolerating subjects received 16 g/day for 2 weeks and then 32 g/day for a further 2 weeks; (B) continuing to follow a low FODMAP strict GFD; and (C) receiving a gluten-containing diet. After the first 6 weeks, symptom scores significantly improved. Pain severity, bloating and total score were significantly decreased in the GFD and in the high-gluten groups, while the satiety score significantly increased in group C. Between-group analysis revealed significant differences for pain severity (p = 0.02), pain frequency (p = 0.04) and impact on community function (p = 0.02) at the end of the study. Our findings suggest that low FODMAP strict GFD could be prescribed in IBS patients and would reduce anxiety and improve the quality of life.
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Biomarkers to Monitor Adherence to Gluten-Free Diet by Celiac Disease Patients: Gluten Immunogenic Peptides and Urinary miRNAs.
Paolini, A, Sarshar, M, Felli, C, Bruno, SP, Rostami-Nejad, M, Ferretti, F, Masotti, A, Baldassarre, A
Foods (Basel, Switzerland). 2022;(10)
Abstract
Celiac disease (CD) is a multifactorial autoimmune enteropathy with a prevalence greater than 1% in the pediatric population. The only therapy for CD patients is a strict gluten-free diet (GFD). Gluten-free food contamination by other cereals during packaging and cooking or accidental ingestion of gluten may cause several intestinal and extraintestinal symptoms in CD patients. Therefore, the monitoring of gluten contamination in food and assessing the level of ingested gluten by analytical biomarkers has been of great interest in recent years. To this aim, small gluten immunogenic peptides (GIPs) obtained by the hydrolysis of gluten and present in urine and feces have been studied as biomarkers of gluten intake and to monitor adherence to GFD by CD patients. More recently, the use of circulating, fecal and urinary miRNAs has emerged as a novel diagnostic tool that can be potentially applied to assess adherence to GFD. Moreover, the presence of GIPs and miRNAs in both feces and urine suggests a similar excretion modality and the possibility of using urinary miRNAs, similarly to GIPs, as potential biomarkers of GFD in CD patients.
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Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.
Rostami, K, Ensari, A, Marsh, MN, Srivastava, A, Villanacci, V, Carroccio, A, Asadzadeh Aghdaei, H, Bai, JC, Bassotti, G, Becheanu, G, et al
Nutrients. 2022;(12)
Abstract
Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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An algorithm for differentiating food antigen-related gastrointestinal symptoms.
Rostami, K, Bold, J, Ismail Ali, J, Parr, A, Dieterich, W, Zopf, Y, Htoo, A, Rostami-Nejad, M, Danciu, M
Gastroenterology and hepatology from bed to bench. 2021;14(1):8-16
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Plain language summary
Irritable bowel syndrome (IBS) is a collection of gastrointestinal symptoms. Due to multiple etiologies, the pathogenesis of IBS is poorly understood. The aim of this audit was to assess the outcomes achieved using a lactose and gluten-free diet clinical intervention in patients traditionally diagnosed with IBS. This study was an audit of outcomes from the records of 149 patients presenting with IBS symptoms at secondary and tertiary Gastroenterology outpatients in two UK hospitals. This audit has demonstrated that more than 70% of patients presenting with IBS symptoms improved by following a diet eliminating lactose and gluten containing grains (improvement for >30% in their symptoms). The success of the elimination diet did not seem to be correlated with the body mass index (BMI). The best outcome was recorded in patients with normal BMI and also in the overweight group. Patients with higher BMI >30 or low below 18 also responded well to nutrition therapy. In conclusion, multidisciplinary team management and implementation of detailed nutrition therapy using the audit algorithm might prove to be both cost effective and efficacious a treatment option in IBS.
Abstract
AIM: The aim of this clinical audit was to assess patient-reported outcomes on the effect of dietary intervention, to enhance our understanding of possible treatment options in irritable bowel syndrome (IBS). BACKGROUND A large number of food-related gastro-intestinal disorders have been attributed to IBS for decades. METHODS Patient-reported outcomes from the records of 149 IBS patients treated at secondary and tertiary Gastroenterology outpatients in two UK hospitals between January 2014 and July 2016 were audited. Patients all presented with symptoms fulfilling Rome III-IV criteria for IBS had negative coeliac serology and did not have other gastrointestinal (GI) conditions. A modified version of a low FODMAP diet had been recommended (gluten and lactose free diet (G/LFD)) and was implemented for 6 weeks. Outcomes and dietary adherence were recorded during outpatient's consultations. RESULTS A total of 134 patients complied with the diet optimally. The majority had an improvement rate >70% and continued with the diet. Fifty-three percent became completely or almost asymptomatic, while 27.6% had a poor response to the diet (scoring < 30%) to G/LFD. The improvement was excellent in patients with normal BMI and good in overweight and obese and where BMI <18. Over 50% did not require any follow-up within 12 months. CONCLUSION Although it is unclear whether symptoms are triggered by gluten, fructans or lactose, elimination of gluten and lactose proved to be an effective treatment in patients with IBS. Multidisciplinary team management and implementation of detailed nutrition therapy using the audit algorithm might prove to be both cost effective and efficacious a treatment option in IBS.
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Prevalence of celiac disease in low and high risk population in Asia-Pacific region: a systematic review and meta-analysis.
Ashtari, S, Najafimehr, H, Pourhoseingholi, MA, Rostami, K, Asadzadeh-Aghdaei, H, Rostami-Nejad, M, Tavirani, MR, Olfatifar, M, Makharia, GK, Zali, MR
Scientific reports. 2021;(1):2383
Abstract
This systematic review and meta-analysis study was conducted to estimate the pooled prevalence of CD in low and high risk groups in this region. Following keywords were searched in the Medline, PubMed, Scopus, Web of Science and Cochrane database according to the MeSH terms; celiac disease, prevalence, high risk population and Asian-Pacific region. Prevalence studies published from January 1991 to March 2018 were selected. Prevalence of CD with 95% confidence interval (CI) was calculated using STATA software, version 14. The pooled sero-prevalence of CD among low risk group in Asia-Pacific region was 1.2% (95% CI 0.8-1.7%) in 96,099 individuals based on positive anti-tissue transglutaminase (anti-t-TG Ab) and/or anti-endomysial antibodies (EMA). The pooled prevalence of biopsy proven CD in Asia-Pacific among high and low risk groups was 4.3% (95% CI 3.3-5.5%) and 0.61% (95% CI 0.4-0.8%) in 10,719 and 70,344 subjects, respectively. In addition, the pooled sero-prevalence and prevalence of CD in general population was significantly higher in children compared with adults and it was significantly greater in female vs. male (P < 0.05). Our results suggest high risk individuals of CD are key group that should be specifically targeted for prevention and control measures, and screening may prove to have an optimal cost-benefit ratio.
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The Gluten Gene: Unlocking the Understanding of Gluten Sensitivity and Intolerance.
Asri, N, Rostami-Nejad, M, Anderson, RP, Rostami, K
The application of clinical genetics. 2021;:37-50
Abstract
Wheat flour is one of the most important food ingredients containing several essential nutrients including proteins. Gluten is one of the major protein components of wheat consisted of glutenin (encoded on chromosome 1) and gliadin (encoded on chromosome 1 and 6) and there are around hundred genes encoding it in wheat. Gluten proteins have the ability of eliciting the pathogenic immune responses and hypersensitivity reactions in susceptible individuals called "gluten-related disorders (GRDs)", which include celiac disease (CD), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS). Currently removing gluten from the diet is the only effective treatment for mentioned GRDs and studies for the appropriate and alternative therapeutic approaches are ongoing. Accordingly, several genetic studies have focused on breeding wheat with low immunological properties through gene editing methods. The present review considers genetic characteristics of gluten protein components, focusing on their role in the incidence of gluten-related diseases, and genetic modifications conducted to produce wheat with less immunological properties.