Pathogenesis Of Celiac Disease Research Articles

Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52). ObjectiveTo assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes. MethodsWe employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody). ResultsIn HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens. ConclusionDONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

Helicobacter pylori infection in pediatric patients with celiac disease: A single-center experience

Aim: There are numerous studies investigating the relationship between celiac disease (CD) and Helicobacter pylori (H. pylori). In this study, we aimed to compare the prevalence of coexisting H. pylori infection and CD in pediatric patients diagnosed with celiac disease at our clinic versus an age-matched control group. Materials and Methods: A total of 198 patients with celiac disease and 131 sex and age -matched controls undergoing upper gastrointestinal endoscopy due to dyspeptic complaints were included in this study. The prevalence of H. pylori was compared between the groups. Results: Of the 198 patients with CD included in the study, 66 (33.3%) were male and 132 (66.7%) were female, while in the control group, 36 (27.5%) were male, and 95 (72.5%) were female. 89 (44%) of the patients with CD and 70 (53.4%) of the controls were H. pylori-positive. There was no statistically significant difference in the distribution of Marsh scores between the H. pylori-negative and -positive groups. Conclusion: The association between celiac disease and H. pylori remains controversial. Thus, multicenter studies are warranted to evaluate the role of H. pylori in the pathogenesis of celiac disease.

How Future Pharmacologic Therapies for Celiac Disease Will Complement the Gluten-Free Diet

The only proven treatment for celiac disease is adherence to a strict, lifelong, gluten free diet. However, complete dietary gluten avoidance is challenging and a substantial number of patients do not respond fully, clinically or histologically, despite their best efforts. As celiac disease is common and its central pathophysiology is well elucidated, it has become attractive for drug development to address the limitations of dietary treatment. Most efforts address non-responsive celiac disease, defined as continued symptoms and/or signs of disease activity despite a gluten free diet, including the more severe forms of refractory celiac disease type 1 and 2. An increasing spectrum of therapeutic approaches target defined mechanisms in celiac disease pathogenesis, and some currently advance to phase 2-3 clinical studies. We discuss these approaches in terms of potential efficiency, practicability, safety and need as defined by patients, regulatory authorities, health care providers and payors.

Relationship between vitamin D levels and pediatric celiac disease: a systematic review and meta-analysis

BackgroundThe relationship between Vitamin D levels and pediatric celiac disease (CD) remains controversial. In this study, we conducted a systematic review and meta-analysis to examine the relationship between Vitamin D and pediatric CD. Methods: We screened relevant studies from PubMed, EMBASE, and Web of Science published in English from January 1, 2000, to August 1, 2023. The included studies were assessed according to the STROBE checklist. Heterogeneity was quantified by Cochran’s Q test and the I2 statistic. Publication bias was estimated by Begg’s test and Egger’s test. Meta‐regression was used to detect potential sources of heterogeneity. Results: A total of 26 studies were included in the meta-analysis. Nineteen articles compared 25(OH)D3 levels between CD patients and control groups, average 25-hydroxyvitamin D3 [25(OH)D3 or calcidiol], and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] levels, as the main forms of Vitamin D, there was a significant difference in CD patients and healthy controls (weighted mean difference (WMD) = − 5.77, 95% confidence interval (CI) = [− 10.86, − 0.69] nmol/L). Meanwhile, eleven articles reported the numbers of patients and controls with Vitamin D deficiency, there was a significant difference in the incidence of 25(OH)D3 deficiency between CD patients and healthy controls (odds ratio 2.20, 95% CI= [1.19, 4.08]). Nine articles reported changes in 25(OH)D3 levels before and after administering a GFD in patients with CD, the result of this study revealed the increase of 25(OH)D3 levels in CD patients after a gluten-free diet (GFD) (WMD = − 6.74, 95% CI = [− 9.78, − 3.70] nmol/L). Conclusions: Vitamin D levels in pediatric CD patients were lower than in healthy controls, and 25(OH)D3 deficiency was more prevalent in CD patients. We found that 25(OH)D3 levels were elevated in CD patients after GFD, which is consistent with previous research. Further well-designed, longitudinal, prospective cohort studies focusing on the role of Vitamin D in the pathogenesis of CD are therefore needed.

Intestinal mRNA expression analysis of polarity-related genes identified the discriminatory ability of CRB3 as a diagnostic marker for celiac disease.

Celiac disease (CD) is a chronic autoimmune disorder characterized by an abnormal immune response to gluten, a protein found in wheat, barley, and rye. It is well established that the integrity of epithelial tight junctions (TJs) and adherens junctions (AJs) plays a crucial role in the pathogenesis of CD. These junctional complexes contribute to the apical-basal polarity of the intestinal epithelial cells, which is crucial for their proper functioning. Sixty CD subjects, and 50 controls were enrolled in the current study. Mucosal samples were obtained from the distal duodenum, total RNA was extracted and complementary DNA was synthesized. The relative expression levels of the desired genes were evaluated by quantitative real-time polymerase chain reaction based on ΔΔCt method. The gene-gene interaction network was also constructed using GeneMANIA. CRB3 (p = .0005), LKB1 (p < .0001), and SCRIB (p = .0005) had lower expression in CD patients compared to controls, while PRKCZ expression did not differ between groups (p > .05). CRB3 represented a significant diagnostic value for differentiating CD patients from the control group (p = .02). The aim of the current study was to evaluate the changes in the mRNA expression levels of SCRIB, PRKCZ, LKB1, and CRB3 genes in the small intestinal biopsy samples of CD patients in comparison to the healthy control subjects. Our data uncover the importance of polarity-related genes (especially CRB3) in CD pahtomechanism, that may facilitate the planning of the future studies looking for finding innovative diagnostic and therapeutic strategies for CD.

Evaluating CD4 and Foxp3 mRNA Expression in Tissue Specimens of Celiac Disease and Colorectal Cancer Patients.

Celiac disease (CD) and colorectal cancer (CRC) are distinct gastrointestinal conditions with a debated association. This study aimed to evaluate the mRNA expression of CD4 and Foxp3 in tissue specimens of CD and CRC patients. The findings can provide valuable insights into the complex connection between these different gastrointestinal conditions. Tissue samples from 100 CRC patients, 50 CD patients, and 50 healthy controls (HCs) were collected. RNA extraction, cDNA synthesis, and quantitative real-time PCR were performed. Statistical analysis was conducted using ANOVA and Pearson's correlation test. CD4 mRNA expression was significantly higher in CRC patients compared to CD patients and HCs (P<0.0001 for both). Foxp3 mRNA expression was significantly higher in CD patients compared to CRC patients and HCs (P<0.0001 for both). Clinicopathological characteristics did not correlate significantly with gene expression levels. This study reveals differential expression patterns of CD4 and Foxp3 mRNA in CRC and CD patients. Upregulated CD4 mRNA suggests its potential role in promoting tumor growth, while increased Foxp3 mRNA expression may reflect an immunosuppressive mechanism in CD pathogenesis. These findings provide insights into the molecular and immunological aspects of CRC and CD, warranting further studies for potential therapeutic strategies.

Serum zonulin level as a novel approach in diagnosis and follow-up of patients with celiac disease. A systematic review and meta-analysis

BackgroundIt has been proposed that zonulin, a tight junction protein regulator, is involved in the pathogenesis of celiac disease (CD). In this regard, various studies compared the mean serum zonulin in patients with CD and healthy controls. However, this remains a subject of controversy due to contradictory results. Therefore, the goal of the present study was to summarize the findings of studies comparing CD patients’ serum zonulin levels to healthy controls. MethodsWe searched PubMed, Scopus, and ISI Web of Science databases up to May 2022. All observational studies measured serum zonulin in adult patients with CD and healthy controls were included without language or date restrictions. The standardized mean differences (SMDs) and standard deviations were pooled using a random-effects model. ResultsOf 708 studies, six studies with 184 CD and 206 control participants were included in the systematic review and meta-analysis. According to a pooled analysis, CD patients had significantly higher zonulin levels than healthy controls (SMD=1.08ng/mL; 95% CI=0.64, 1.52; P<0.001). Subgroup analyses were performed according to adherence to a gluten-free diet (GFD), zonulin assessment method, and CD diagnosis. The significant effect was maintained in all subgroups. ConclusionCD is significantly correlated with a higher level of serum zonulin. Thus, zonulin could be a potential biomarker for the diagnosis of CD, which deserves further investigation.

Overview of the compromised mucosal integrity in celiac disease.

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.

Gut microbiota in celiac disease.

Celiac disease (CD) is an autoimmune gastrointestinal disease triggered by dietary gluten, occurring in genetically predisposed individuals. Currently, a gluten-free diet is the only current evidenced-based treatment for CD. With the growing prevalence of this condition worldwide, adjuvant therapies are needed. We understand that there are several factors that influence the pathogenesis of the condition. There is a complex interplay between genetics, environmental triggers, the immune system and gut microbiota. Recently, there has been a growing focus on the significance of gut microbiota in several autoimmune-based conditions. In particular, there has been much research involving the role of microbial flora and CD. Here, in this mini-review, we highlight the importance of gut microbiota and the symbiotic relationship with the host, introduce key factors that influence the development of the intestinal flora in early colonization, and ultimately explore its role in the pathogenesis of CD.

Non-Host Factors Influencing Onset and Severity of Celiac Disease

Celiac Disease (CeD) is a chronic autoimmune condition driven by gluten ingestion in genetically predisposed individuals, resulting in inflammatory lesions in the proximal small intestine. While the presence of specific human leukocyte antigen (HLA) linked haplotypes and gluten consumption are necessary for disease development, they alone do not account for the variable onset of CeD in susceptible individuals. This review explores the multifaceted role of non-host factors in CeD development, including dietary and microbial influences. We discuss clinical associations and observations highlighting the impact of these factors on disease onset and severity. Furthermore, we discuss studies in CeD-relevant animal models that offer mechanistic insights into how diet, the microbiome, and enteric infections modulate CeD pathogenesis. Finally, we address the clinical implications and therapeutic potential of understanding these cofactors, offering a promising avenue for preventive and therapeutic interventions in CeD management.

Emerging Pharmaceutical Therapies to Address the Inadequacy of a Gluten-Free Diet for Celiac Disease.

Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD.

The Contribution of the Intestinal Microbiota to the Celiac Disease Pathogenesis along with the Effectiveness of Probiotic Therapy.

The development of many human disorders, including celiac disease (CD), is thought to be influenced by the microbiota of the gastrointestinal tract and its metabolites, according to current research. This study's goal was to provide a concise summary of the information on the contribution of the intestinal microbiota to the CD pathogenesis, which was actively addressed while examining the reported pathogenesis of celiac disease (CD). We assumed that a change in gluten tolerance is formed under the influence of a number of different factors, including genetic predisposition and environmental factors. In related investigations, researchers have paid increasing attention to the study of disturbances in the composition of the intestinal microbiota and its functional activity in CD. A key finding of our review is that the intestinal microbiota has gluten-degrading properties, which, in turn, may have a protective effect on the development of CD. The intestinal microbiota contributes to maintaining the integrity of the intestinal barrier, preventing the formation of a "leaky" intestine. On the contrary, a change in the composition of the microbiota can act as a significant link in the pathogenesis of gluten intolerance and exacerbate the course of the disease. The possibility of modulating the composition of the microbiota by prescribing probiotic preparations is being considered. The effectiveness of the use of probiotics containing Lactobacillus and Bifidobacterium bacteria in experimental and clinical studies as a preventive and therapeutic agent has been documented.

Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark

ObjectivesOur aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth...

The association of interleukin-10 single nucleotide polymorphisms (rs1800871) and serum levels in Iraqi patients with celiac disease: A case-control study

BackgroundCeliac disease is one of the autoimmune diseases resulting from ingesting gluten, in addition to the diverse microbiota in the gut, micronutrient deficiencies, and genetic predisposition. Several immunological factors impact celiac disease pathogenesis; interleukin-10 is one of these immunological factors that have a role in disease development. MethodsThe present study was designed to examine the genotypes and alleles frequency of IL10 rs1800871in celiac disease patients compared to the healthy control volunteers using allele-specific primers-polymerase chain reaction technique. Fifty celiac disease patients volunteered to participate in the current study (age mean ± SD was 23.5 ± 11.88 years) who enrolled during the period from November 2021–February 2022, compared with 50 healthy volunteers (age mean ± SD was 23.5 ± 11.88 years). ResultsThe genetic variations of IL-10 SNPs rs1800871 results showed that the TT genotype and T allele were more frequent than the other genotypes and allele C in the patients' group (58.0% and 73.0% vs 30.0%, 12.0% and 27.0%, respectively). Also, the TT genotype and T allele have higher OR values than the CC, CT genotypes and C allele in the patients' group (15.88 and 7.70 vs 0.11, 0.76 and 0.13, respectively). These findings might be due to the risk of TT and T in the disease development than CC, CT/C genotypes/allele. ConclusionFrom the obtained results, the present study concluded that the TT/T genotype/allele might be associated with autoimmune disease development, such as celiac disease, more than the other genotypes.

A review of the long-term use of proton pump inhibitors and risk of celiac disease in the context of HLA-DQ2 and HLA-DQ8 genetic predisposition.

Proton pump inhibitors (PPIs) are among the most prescribed and widely used medications; however, the long-term effects of these medications are only beginning to be investigated. Since the introduction of omeprazole in 1989, PPIs have become the first-choice treatment for esophagitis, peptic ulcer disease, Zoster-Ellison syndrome, dyspepsia, and the prevention of ulcers with non-steroidal anti-inflammatory drugs. Recent studies have specifically examined the rise in celiac disease (CD) in this context. This review explores how PPIs may impact the development of CD and highlights the need for additional research into the environmental and genetic factors that influence the development and progression of the disease. A literature search was performed using the keywords celiac disease, proton pump inhibitors, human leukocyte antigen (HLA)-DQ2, HLA-DQ8. The pathogenesis of CD is multifactorial, and human leukocyte antigens are one factor that may contribute to its development. Additionally, pharmaceuticals, such as PPIs, that cause gut dysbiosis have been linked to the inflammatory response present in CD. Recent studies have suggested that the rise in CD could be attributed to changes in the gut microbiome, highlighting the significant role that gut microbiota is proposed to play in CD pathogenesis. Although PPI therapy is helpful in reducing acid production in gastroesophageal disorders, additional information is needed to determine whether PPIs are still an appropriate treatment option with the possibility of developing CD in the future, particularly in the context of HLA-DQ2 and HLA-DQ8 predispositions. This review emphasizes the importance of personalized medicine for individuals with gastroesophageal disorders that require long-term use of PPIs.

Transcriptome profile and immune infiltrated landscape revealed a novel role of γδT cells in mediating pyroptosis in celiac disease.

Celiac disease (CeD) is a primary malabsorption syndrome with no specific therapy, which greatly affects the quality of life. Since the pathogenesis of CeD remains riddled, based on multiple transcriptome profiles, this study aimed to establish an immune interaction network and elucidated new mechanisms involved in the pathogenesis of CeD, providing potentially new evidence for the diagnosis and treatment of CeD. Three microarray and three RNA sequencing datasets of human duodenal tissue with or without CeD were included in Gene Expression Omnibus and respectively merged into derivation and validation cohorts. Differential expression gene and functional enrichment analysis were developed, then pyroptosis enrichment score (PES) model was established to quantify pyroptosis levels. Immune infiltration and co-expression network were constructed based on Xcell database. Protein-protein interaction and weighted gene co-expression network analysis were determined to identify pyroptosis relative hub genes, whose predictive efficiency were tested using a least absolute shrinkage and selection operator (LASSO) regression model. CeD animal and in vitro cell line models were established to verify the occurrence of pyroptosis and molecules expression employing immunofluorescence, western blotting, cell counting kit-8 assay and enzyme-linked immunosorbent assay. Analysis of single-cell RNAseq (scRNAseq) was performed using "Seurat" R package. Differentially expressed genes (DEGs) (137) were identified in derivation cohort whose function was mainly enriched in interferon response and suppression of metabolism. Since an enrichment of pyroptosis pathway in CeD was unexpectedly discovered, a PES model with high efficiency was constructed and verified with two external databases, which confirmed that pyroptosis was significantly upregulated in CeD epithelia. γδT cells exhibited high expression of IFN-γ were the most relevant cells associated with pyroptosis and occupied a greater weight in the LASSO predictive model of CeD. An accumulation of GSDMD expressed in epithelia was identified using scRNAseq, while animal model and in vitro experiments confirmed that epithelium cells were induced to become "pre-pyroptotic" status via IFN-γ/IRF1/GSDMD axis. Furthermore, gluten intake triggered pyroptosis via caspase-1/GSDMD/IL-1β pathway. Our study demonstrated that pyroptosis was involved in the pathogenesis of CeD, and elucidated the novel role of γδT cells in mediating epithelial cell pyroptosis.

The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment.

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

Advances in Understanding the Human Gut Microbiota and Its Implication in Pediatric Celiac Disease-A Narrative Review.

Celiac disease (CD) is a multifactorial disorder, defined by a complex interplay of genetic and environmental factors. Both genetic predisposition and dietary exposure to gluten are essential factors in triggering CD. However, there is proof that their presence is necessary, but not sufficient, for disease development. Through gut microbiota modulation, several additional environmental factors have shown their potential role as co-factors in CD pathogenesis. The aim of this review is to illustrate the possible mechanisms that stand behind the gut microbiota's involvement in CD pathogenesis. Furthermore, we discuss microbiota manipulation's potential role as both a preventative and therapeutic option. The available literature provides evidence that even before CD onset, factors including cesarean birth and formula feeding, as well as intestinal infection exposure, amplify the risk of CD in genetically predisposed individuals, due to their influence on the intestinal microbiome composition. Active CD was associated with elevated levels of several Gram-negative bacterial genera, including Bacteroides, Escherichia, and Prevotella, while beneficial bacteria such as lactobacilli and bifidobacteria were less abundant. Viral and fungal dysbiosis has also been described in CD, evidencing specific taxa alteration. A gluten-free diet (GFD) may improve the clinical symptoms and duodenal histopathology, but the persistence of intestinal dysbiosis in CD children under a GFD urges the need for additional therapy. Probiotics, prebiotics, and fecal microbial transplant have demonstrated their efficacy in restoring gut microbiota eubiosis in adult CD patients; however, their efficacy and safety as adjunctive therapies to a GFD in pediatric patients needs further investigation.

Assessment of causal associations among gut microbiota, metabolites, and celiac disease: a bidirectional Mendelian randomization study.

A growing number of studies have implicated that gut microbial abundance and metabolite concentration alterations are associated with celiac disease (CD). However, the causal relationship underlying these associations is unclear. Here, we used Mendelian randomization (MR) to reveal the causal effect of gut microbiota and metabolites on CD. Genome-wide association study (GWAS) summary-level data for gut microbiota, metabolites, and CD were extracted from published GWASs. Causal bacterial taxa and metabolites for CD were determined by two-sample MR analyses. The robustness of the results was assessed with sensitivity analyses. Finally, reverse causality was investigated with a reverse MR analysis. Genetically, increased genus Bifidobacterium was potentially associated with higher CD risk (odds ratio [OR] = 1.447, 95% confidence interval [CI]: 1.054-1.988, p = 0.022) while phylum Lentisphaerae (OR = 0.798, 95% CI: 0.648-0.983, p = 0.034) and genus Coprobacter (OR = 0.683, 95% CI: 0.531-0.880, p = 0.003) were related to lower CD risk. Moreover, there were suggestive associations between CD and the following seven metabolites: 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 1,6-anhydroglucose, phenylacetylglutamine, tryptophan betaine, 10-undecenoate, and tyrosine. Sensitivity analyses deemed the results reliable without pleiotropy. We investigated the causal relationships between gut microbiota, metabolites, and CD with two-sample MR. Our findings suggest several novel potential therapeutic targets for CD treatment. Further understanding of the underlying mechanism may provide insights into CD pathogenesis.