Advances in understanding and managing celiac disease: Pathophysiology and treatment strategies.

In this editorial, we comment on an article published in the recent issue of the World Journal of Gastroenterology. Celiac disease (CeD) is a disease occurring in genetically susceptible individuals, which is mainly characterized by gluten intolerance in the small intestine and clinical symptoms such as abdominal pain, diarrhea, and malnutrition. Therefore, patients often need a lifelong gluten-free diet, which greatly affects the quality of life and expenses of patients. The gold standard for diagnosis is intestinal mucosal biopsy, combined with serological and genetic tests. At present, the lack of safe, effective, and satisfactory drugs for CeD is mainly due to the complexity of its pathogenesis, and it is difficult to find a perfect target to solve the multi-level needs of patients. In this editorial, we mainly review the pathological mechanism of CeD and describe the current experimental and improved drugs for various pathological aspects.

Celiac Disease Masking Duodenal Adenocarcinoma: A Case Report and Literature Review.

Small bowel adenocarcinoma (SBA) is an uncommon gastrointestinal malignancy, with the duodenum being the most commonly affected site. This report describes a 33-year-old woman who initially presented with abdominal pain and vomiting. Initial imaging revealed abnormalities of the proximal jejunum. Endoscopic evaluation initially revealed celiac disease (CD); however, with disease progression, the patient developed bowel obstruction that led to surgical intervention with an open duodenal biopsy. The open duodenal biopsy confirmed the presence of duodenal adenocarcinoma (DA). This case demonstrates the diagnostic complexity of DA in the presence of concurrent CD due to overlapping presentations. Physicians must maintain a high suspicion of DA in the setting of progressive and difficult-to-treat CD, as early diagnosis and management of DA can significantly improve patient outcomes.

Dietary patterns drive loss of fiber-foraging species in the celiac disease patients gut microbiota compared to first-degree relatives.

BACKGROUND: Celiac disease is an autoimmune disorder triggered by dietary gluten in genetically predisposed individuals that primarily affects the small intestine. Studies have reported differentially abundant bacterial taxa in the gut microbiota of celiac patients compared with non-celiac controls. However, findings across studies have inconsistencies and no microbial signature of celiac disease has been defined so far. RESULTS: Here, we showed, by comparing celiac patients with their non-celiac 1st-degree relatives, that bacterial communities of related individuals have similar species occurrence and abundance compared with non-relatives, regardless the disease status. We also found in celiac patients a loss of bacterial species associated with fiber degradation, and host metabolic and immune modulation, as ruminiclostridia, ruminococci, Prevotella, and Akkermansia muciniphila species. We demonstrated that the differential abundance of bacterial species correlates to different dietary patterns observed between the two groups. For instance, Ruminiclostridium siraeum, Ruminococcus bicirculans, and Bacteroides plebeious, recognized as fiber-degraders, appear more abundant in non-celiac 1st-degree relatives, which have a vegetable consumption pattern higher than celiac patients. Pattern of servings per day also suggests a possible link between these species' abundance and daily calorie intake. CONCLUSIONS: Overall, we evidenced that a kinship approach could be valuable in unveiling potential celiac disease microbial traits, as well as the significance of dietary factors in shaping microbial profiles and their influence on disease development and progression. Our results pave the way for designing and adopting novel dietary strategies based on gluten-free fiber-enriched ingredients to improve disease management and patients' quality of life.

Development of the celiac disease symptom diary version 2.1© (CDSD 2.1©) patient-reported outcome measure.

PURPOSE: For patients with celiac disease (CeD), the only current management option is adherence to a strict gluten-free diet (GFD); however, many patients on a GFD continue to experience symptoms with a significant impact on quality of life. Potential new treatments for CeD are under development and a validated patient-reported outcome measure is required to evaluate their utility in clinical trials. The purpose of this article is to provide a history of the development of the Celiac Disease Symptom Diary (CDSD) 2.1© for use in clinical trials. METHODS: Qualitative and quantitative studies were conducted from 2010 to 2021, including concept elicitation and cognitive debriefing interviews with adult and adolescent participants with CeD (N = 93) diagnosed via biopsy and/or serology and input from eight interviews with CeD clinical experts. During these studies, different iterations of the CDSD were presented to the US Food and Drug Administration and the European Medicines Agency, and modifications were made in line with their feedback. RESULTS: These studies ultimately led to the development of CDSD 2.1©, a daily diary which focuses on key symptoms of CeD (abdominal pain, bloating, diarrhea, nausea and tiredness). This patient-reported outcome measure was readily understood by adult and adolescent participants with CeD and content validity was demonstrated in both populations. CONCLUSION: CDSD 2.1© is a content-valid patient-reported outcome measure developed in accordance with best practices and regulatory guidance. A thorough exploration of the psychometric properties of CDSD 2.1© for both adult and adolescent participants with CeD is ongoing to support utilization in clinical trials.

Role of interleukin-18 in mediating the impacts of celiac disease on osteoporosis: a Mendelian randomization study.

Background: Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns. Methods: We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using two-step mediation analyses. Results: The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, p=0.001), total body bone mineral density (ß: -0.025, p=0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, p=0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, p=0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, p=0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis. Conclusion: The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18.

The Versatile Role of Peroxisome Proliferator-Activated Receptors in Immune-Mediated Intestinal Diseases.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that sense lipophilic molecules and act as transcription factors to regulate target genes. PPARs have been implicated in the regulation of innate immunity, glucose and lipid metabolism, cell proliferation, wound healing, and fibrotic processes. Some synthetic PPAR ligands are promising molecules for the treatment of inflammatory and fibrotic processes in immune-mediated intestinal diseases. Some of these are currently undergoing or have previously undergone clinical trials. Dietary PPAR ligands and changes in microbiota composition could modulate PPARs' activation to reduce inflammatory responses in these immune-mediated diseases, based on animal models and clinical trials. This narrative review aims to summarize the role of PPARs in immune-mediated bowel diseases and their potential therapeutic use.

Food insecurity and other barriers to adherence to a gluten-free diet in individuals with coeliac disease and non-coeliac gluten sensitivity in the Netherlands: a mixed-methods study.

OBJECTIVES: To determine the prevalence of food insecurity among individuals with coeliac disease (CeD) and non-coeliac gluten sensitivity (NCGS) in the Netherlands and explore its association with diet quality and other barriers to adherence to a gluten-free diet. DESIGN: Mixed-method design comprising a survey and semistructured interviews. SETTING: An online survey was distributed through social media accounts and the newsletter of the Dutch Association for Celiac Disease. Community-dwelling patients were surveyed and interviewed between June and November 2023. PARTICIPANTS AND OUTCOME MEASURES: In total 548 adults with CeD and NCGS in the Netherlands who adhered to a gluten-free diet completed the survey including questions related to demographics, household food insecurity, financial stress and diet quality. Regression analyses were conducted to assess associations between food insecurity and diet quality, and between food insecurity and perceived difficulty of gluten-free eating and cooking. Additionally, semistructured interviews with eight food insecure adults with CeD were conducted. RESULTS: The prevalence of food insecurity was 23.2%, with 10.4% reporting very low food security. Very low food insecurity was associated with poorer diet quality (ß=-5.5; 95% CI=-9.2 to -1.9; p=0.003). Food insecurity was associated with heightened perceived barriers across multiple themes. In age, income and education adjusted models, compared with food secure participants, low food secure participants were more likely to experience difficulty regarding skills (OR=2.5; 95% CI=1.5 to 4.3; p≤0.001), social circumstances (OR=2.6; 95% CI=1.1 to 6.4; p=0.038), resources (OR=2.5; 95% CI=1.5 to 4.4; p=0.001) and naturally gluten-free products (OR=1.8; 95% CI=1.0 to 3.1; p=0.045) in gluten-free eating and cooking. Participants with very low food security were more likely to experience difficulty regarding skills (OR=4.4; 95% CI=2.4 to 8.1; p≤0.001) and resources (OR=4.2; 95% CI=2.3 to 7.8; p<0.001) in gluten-free eating and cooking. The qualitative analysis provided a deeper understanding of these challenges, including employed strategies to manage costs and insights into the mental burden associated with adhering to a gluten-free diet. CONCLUSION: These findings indicate that food insecurity is prevalent among Dutch people with CeD and NCGS, with potential impact on diet quality and adherence to a gluten-free diet. It further provided insight into perceived barriers to adhering to a gluten-free diet among this target population. These challenges should be taken into account by clinicians and policy makers.

ViCE: An automated and quantitative program to assess intestinal tissue morphology.

Background and objective: The tissue morphology of the intestinal surface is architecturally complex with finger-like projections called villi, and glandular structures called crypts. The ratio of villus height-to-crypt depth ratio (Vh:Cd) is used to quantitatively assess disease severity and response to therapy for intestinal enteropathies, such as celiac disease and is currently quantified manually. Given the time required, manual Vh:Cd measurements have largely been limited to clinical trials and are not used widely in clinical practice. We developed ViCE (Villus Crypt Evaluator), a user-friendly software that automatically quantifies histological parameters in standard hematoxylin and eosin-stained intestinal biopsies. Methods: ViCE is based on mathematical morphology operations and is scale and staining agnostic. It evaluates tissue orientation, identifies geometrical structure, and outputs key tissue measurements. Results: The output measurements of Vh:Cd are concordant with manual quantifications across multiple datasets. Conclusions: The underlying mathematical morphological approach for ViCE is robust, and reproducible and easily adaptable for measurement of morphological features in other tissues.

Mediterranean Diet Adherence and Eating Disorders Screening in Adults with Celiac Disease in Morocco.

Background: Celiac disease is a chronic autoimmune disease of the small intestine, related to gluten intolerance occurring in genetically predisposed patients. This study aimed to evaluate Mediterranean diet adherence, screen eating disorders and establish the relationship between Mediterranean diet and eating disorders. Methods: This study included 81 adults with celiac disease, and 85 without celiac disease from Rabat-Sale-Kenitra hospitals between May 2022 and Nov 2022. The Mediterranean Diet Serving Score (MDSS) questionnaire was used to determine adherence to the Mediterranean diet and SCOFF questionnaire was used to screen eating disorders. Results: The results showed a significant difference between the two groups in age (P=0.000), weight (P=0.041), height (P=0.000) and non-adherence to Mediterranean diet (P=0.032). Participants without celiac disease reported a significantly (P=0.032) lower adherence score to the Mediterranean diet (62.35%) than participants with celiac disease (29.62%). Additionally, the results of the Khi2 test which revealed a significant association between MDSS and SCOFF (P=0.024). In addition, based on logistic regression the Mediterranean diet Serving Score was significantly associated with eating disorders (P=0.025) in adults with celiac disease, on the other hand, weight, height, BMI and MDSS were significantly associated with eating disorders in adults without celiac disease. Conclusion: Our study showed good adherence to the Mediterranean diet by celiac adults so it can be assumed that the Mediterranean diet could have a protective effect against eating disorders in celiac patients.

Celiac disease gut microbiome studies in the third millennium: reviewing the findings and gaps of available literature.

Celiac disease is an autoimmune enteropathy caused by the ingestion of minute amounts of gluten in a subset of genetically predisposed individuals. Its onset occurs at different ages and with variable symptoms. The gut microbiome may contribute to this variability. This review aims to provide an overview of the available research on celiac disease gut microbiome and identify the knowledge gap that could guide future studies. Following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews (PRISMA-ScR), four electronic databases were searched for literature from January 2000 to July 2023 addressing celiac disease gut microbiome characterization using next-generation sequencing (NGS) approaches. From the 489 publications retrieved, 48 publications were selected and analyzed, focusing on sample characterization (patients, controls, and tissues) and methodologies used for NGS microbiome analysis and characterization. The majority of the selected publications regarded children and adults, and four were randomized clinical trials. The number of participants per study greatly varied and was typically low. Feces were the most frequently tested sample matrix, and duodenal samples were analyzed in one-third of the studies. Incomplete and diverse information on the methodological approaches and gut microbiome results was broadly observed. While similar trends regarding the relative abundance of some phyla, such as Pseudomonadota (former Proteobacteria), were detected in some studies, others contradicted those results. The observed high variability of technical approaches and possibly low power and sample sizes may prevent reaching a consensus on celiac disease gut microbiome composition. Standardization of research protocols to allow reproducibility and comparability is required, as interdisciplinary collaborations to further data analysis, interpretation, and, more importantly, health outcome prediction or improvement.

Computer aided villi morphometric quantification in video-capsule enteroscopy: A newly developed software to quantify small bowel atrophy.

BACKGROUND AND AIMS: Small bowel capsule endoscopy (SBCE) has an established role in patients with non-responsive celiac disease (CeD). A non-invasive method to quantify small bowel atrophy is still lacking. METHODS: We analysed SBCE frames from CeD patients from 2018 to 2020. Histology was the reference standard, with atrophy defined as Marsh-Oberhuber score ≥ 3a. Three regions of interest (ROI) were blindly selected from each frame by an expert gastroenterologist and analysed using a National Institute of Health J image-processing software into a numerical scale. A 3D surface plot macro identified intestinal villi density through isolines plots. RESULTS: We acquired 306 ROIs from 57 frames with macroscopic atrophy and 45 with normal mucosa. Frames were classified as atrophic (n = 63) or non-atrophic (n = 39) per Marsh-Oberhuber classification. Median density score significantly differed between atrophic and non-atrophic frames (p < 0.001). The morphometric analysis showed a sensitivity of 77 % and a specificity of 79 % in discriminating between atrophic or non-atrophic mucosa with a 14.10 cut-off (Youden Index) and an overall AUC of 0.805 (CI 95 % 0.712-0.897). CONCLUSIONS: Our newly developed SBCE software can effectively quantify villous atrophy. Further studies are needed to validate its applicability in an external cohort.

Coexistence of Celiac Disease and Allergic Wheat Sensitivity: An Observational Study of Daily Clinical Practice.

INTRODUCTION: Although separate immunogenic mechanisms are involved, IgE-type sensitization to wheat and celiac disease (CD) may coexist. We observationally assessed the importance of this relationship in daily practice using CD and wheat sensitization screenings. METHODS: Celiac antibody (CA) screening and food prick tests (FPTs) were requested simultaneously from patients who presented to the Allergy Clinic between January 2022 and December 2023 and had any complaint accompanied by CD symptoms/findings (non-celiac group). Patients with positive CA (CA+) underwent endoscopy. As another group, FPT results were recorded for patients previously diagnosed with CD following a gluten-free diet (celiac group). RESULTS: In total, 169 patients (124 non-celiac and 45 celiac) were included in the study. Wheat prick positivity (WP+) was observed in 1 patient with CD. Among 65 WP+ patients without a CD diagnosis, 14 (20.3%) tested positive for CA+, and histopathology detected CD in 4 of these cases. Among the 59 WP- patients, 4 (8.8%) had CA+. The CA+ status of those with WP+ was significantly higher than those with WP- (p = 0.023). CONCLUSION: The 4 patients unaware of their CD exhibited WP+, with a higher rate of CA+ observed in the WP+ group. The association between WP+ and CA+ suggests that an impaired intestinal barrier may lead to simultaneous T helper 1 and 2 type inflammatory responses. Although different types of sensitization to the same food would not typically be expected, growing evidence indicates that this phenomenon does occur. Further studies are necessary to confirm these findings and to explore the underlying causes.

Knowledge and Attitude of Celiac Disease Among the Population of Riyadh, Saudi Arabia.

Background and aims Celiac disease (CD) is a chronic autoimmune disease that is characterized by inflammation of the intestinal mucosa, primarily triggered by gluten. So far, the effective management of CD only includes a gluten-free diet. For early diagnosis and management, adequate knowledge and a positive attitude towards CD are crucial. This study aims to investigate the CD-related knowledge and attitudes of the public in Riyadh, Saudi Arabia. Methods A cross-sectional online survey was conducted among individuals aged 16 and older. The data regarding demographic factors, knowledge, and attitudes about CD was collected via an online questionnaire. Statistical analysis was conducted using version 26 of SPSS (IBM Corp., Armonk, NY). Results In the current study, 669 individuals responded to the online survey. The majority of participants (82.1%) were familiar with CD. A total of 59.9% of respondents had adequate knowledge, 32.3% had outstanding knowledge, and 7.8% reported no knowledge of CD. The majority (69.5%) of respondents held negative attitudes concerning CD. The correlation between age and CD knowledge (P<0.05) and attitude (P<0.05) was statistically significant. Similarly, the correlation between occupation and CD knowledge (P<0.05) and attitude (P<0.05) was statistically significant. However, no significant association between gender and CD knowledge (p=0.720) or attitude (p=0.244) was found in males and females. Conclusion This study revealed that the majority of the residents of Riyadh, Saudi Arabia, had an adequate or excellent understanding of CD. However, the majority of respondents had a negative attitude towards CD management.

Noonan Syndrome and Celiac Disease in an Adolescent With Short Stature and Delayed Puberty.

Background/Objective: We present an adolescent male with Noonan syndrome (NS) and celiac disease (CD) who attained normal adult height with growth hormone (GH) treatment and gluten-free diet (GFD). Case Report: A 15 ½ year old healthy male presented with short stature and delayed puberty. His mother and maternal grandmother were short with heights 142.2 cm and 147.3 cm, respectively. Examination showed bilateral epicanthal folds and down slanting eyes like his mother, fifth finger clinodactyly, height 147.5 cm (<1%; standard deviation score, -2.96), growth velocity 2.5 cm/y, weight 48.2 kg (11%; standard deviation score, -1.24), Tanner 2 pubic hair and Tanner 1 genitalia. Midparental target height was 169.1 cm. He had normal screening studies for GH deficiency and thyroid disorders, prepubertal gonadotropins and testosterone levels, and normal total immunoglobulin A, and elevated antitissue transglutaminase immunoglobulin A 134.7units/mL (0-20). Bone age was 13 years. Genetic evaluation revealed heterozygous missense variant of BRAF gene in him and his mother confirming a diagnosis of NS. He was diagnosed with CD by intestinal biopsy. Patient was started on GH therapy and a GFD with subsequent improvement in growth velocit (6.8-12.3 cm/y) and advancement of puberty. The patient stopped GH therapy at 17 ½ years with a height 165.9 cm. Discussion: Coexistence of NS caused by BRAF missense variant and CD has not been previously reported. Our patient attained normal adult height with GH therapy and GFD. Conclusion: NS and CD can co-occur and addressing both these disorders can help patients attain normal height potential.

The prevalence of obesity and underweight in celiac patients at the time of diagnosis: a systematic review and meta-analysis.

BACKGROUND: This study aimed to estimate the prevalence of obesity, overweight, and underweight in celiac disease (CD) at diagnosis before starting the Gluten-free diet (GFD). METHODS: A comprehensive search was conducted in PubMed, Embase, Scopus, and Web of Science until July 2024 to find the cross-sectional and longitudinal studies that measured the body mass index (BMI) in CD patients at diagnosis. The risk of bias assessment was conducted using the Newcastle-Ottawa Quality Assessment scale. Meta-regression analyses were applied to understand whether weight status is associated with CD. RESULTS: A total of 23 studies involving 15,299 CD patients and 815,167 healthy individuals were included in this study. In newly diagnosed CD patients, pooled estimates of the prevalence of obesity, overweight, and underweight before GFD were 11.78%, 18.42%, and 11.04%, respectively. The prevalence of overweight and obesity in newly diagnosed CD patients increased from 22.15% in 2003-2009 to 32.51% in 2016-2021. Meta-regression analyses indicated that the CD patients with higher BMI had a higher mean age (p = 0.001), and female gender had a marginally significant (p = 0.055) association with higher BMI. Only a few CD patients were underweight at the time of diagnosis, and more patients were overweight/obese. CONCLUSIONS: our meta-analysis demonstrated that only a few CD patients were underweight at the time of diagnosis, and almost 37% were overweight or obese. Meta-regression showed a significant association between higher BMI and higher mean age and female gender. A delay or failure for diagnosis of CD is more common in overweight/obese patients, resulting in more progression of the disease and counteracting any advantages of diagnosis.

Enteropathy-Associated T-Cell Lymphoma Treated With Autologous Hematopoietic Stem-Cell Transplant: A Glimmer of Hope?

We report a case of primary enteropathy-associated T-cell lymphoma in a 50-year-old man presenting with abdominal pain, chronic diarrhea, and significant weight loss over 6 months. Diagnosis was confirmed through endoscopy, biopsy, and positron emission tomography-computed tomography, staging the disease as stage 1E. The patient underwent initial treatment with the cyclophosphamide, doxorubicin (also known as hydroxydaunorubicin), vincristine (also known as oncovin), etoposide, and prednisolone chemotherapy regimen, followed by high-dose hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy and autologous stem cell transplantation. Despite developing febrile neutropenia and septic shock during treatment, the patient achieved disease remission and symptom resolution. This case underscores the potential of autologous stem-cell transplantation as a curative approach for primary enteropathy-associated T-cell lymphoma and highlights the need for further research on its effectiveness.

Circulating MicroRNAs and Cytokines Associated with Celiac Disease.

Background: The current research examines the molecular terrain of celiac disease (CD) through microRNA (miRNA) and cytokines as potential new diagnostic and therapeutic markers. Gluten-appropriate immune response is a key feature of an autoimmune clinical entity known as CD that leads to inflammation and degeneration of small intestine mucosa. However, the mechanisms responsible for this remain unclear. Methods: Quantitative reverse transcription polymerase chain reaction (RT-qPCR ) was carried out on serum samples obtained from patients with CD and control groups to unravel their pathogenesis. Assessing miR-155, miR-15b, interleukin (IL)-2, IL-7, IL-35and IL-37 levels in expression might be useful in diagnosing or treating the disorder. Results: A significant dysregulation of these molecular players in patients with CD compared with healthy controls has been evidenced by results from this study. For instance, miR-155 was up-regulated, whereas miR-15b was significantly down-regulated in CD, illustrating their roles in immune responses and inflammation-mediated processes. Besides, there was an over-expression of IL-2 and an under-expression of IL-37 in patients with CD, indicating these biomolecules' role in immuno-dysregulation and inflammatory process underlying CD. In addition, a positive correlation between IL-2 and miRNA 155 expression levels was observed in patients with CD, suggesting that they could be involved together with other cytokines, showing the interplay between immune response pathways and inflammatory cascades during CD pathogenesis. Conclusion: These molecular signature discoveries might result in new and revolutionary diagnostic modalities and molecular-targeted therapies for CD pathogenesis. When used with the scientific understanding of miRNAs and cytokines associated with CD pathophysiology, it creates a basis for personalized medicine based on the individualized molecular profile of all patients. This will undoubtedly increase the efficacy of CD treatment strategies. In brief, more research on molecular pathways' workings should be done to harness their potential in CD diagnosis and treatment.

Characteristics of Hospitalized Patients With and Without Celiac Disease on a Gluten-Free Diet.

BACKGROUND: Most people maintaining a gluten-free diet (GFD) do not have celiac disease (CD). Comorbidities and associated conditions in this population are largely unknown. AIMS: This study identified demographics, dietary patterns, and diagnoses for patients prescribed a GFD during hospitalization and compared patients with CD to those without CD. METHODS: We performed a retrospective cross-sectional study for hospital admissions with a GFD between Jan 1, 2010 and June 30, 2022, while excluding patients missing demographic data (n = 113). We compared patients with and without a CD diagnosis, including multivariable logistic regression to identify characteristics independently associated with a CD diagnosis. RESULTS: We analyzed 1527 hospitalized patients of all ages. A minority (n = 467, 30.6%) carried a CD diagnosis. Age, sex, body mass index, and Medicare/Medicaid enrollment and additional diagnoses associated with a GFD (e.g., IBS) were not significantly different. The CD cohort was more predominantly white (66.6% vs 58.4%, p = 0.007) and non-Hispanic (62.5% vs. 52.7%, p = 0.001). While hospitalized, patients with CD had fewer additional dietary restrictions (mean 0.33 vs 0.56, p < 0.001) and more frequent micronutrient supplementation (26.6% vs 21.4%, p = 0.03). CD was independently associated with malnutrition (OR 1.86, 95% CI 1.31-2.65) and inversely associated with a vegetarian diet (OR 0.35, 95% CI 0.15-0.81), reduced lactose diet (OR 0.25, 95% CI 0.13-0.50), and Hispanic ethnicity (OR 0.56, 95% CI 0.35-0.90) while controlling for other covariates. DISCUSSION: Two-thirds of hospitalized patients receiving a GFD do not have a diagnosis of CD. Among GFD inpatients, CD is associated with fewer dietary restrictions and independently associated with malnutrition.

Strain-specific differences in reovirus infection of murine macrophages segregate with polymorphisms in viral outer-capsid protein σ3.

Mammalian orthoreovirus (reovirus) strains type 1 Lang (T1L) and type 3 Dearing-RV (T3D-RV) infect the intestine in mice but differ in the induction of inflammatory responses. T1L infection is associated with the blockade of oral immunological tolerance to newly introduced dietary antigens, whereas T3D-RV is not. T1L infection leads to an increase in infiltrating phagocytes, including macrophages, in gut-associated lymphoid tissues that are not observed in T3D-RV infection. However, the function of macrophages in reovirus intestinal infection is unknown. Using cells sorted from infected intestinal tissue and primary cultures of bone-marrow-derived macrophages (BMDMs), we discovered that T1L infects macrophages more efficiently than T3D-RV. Analysis of T1L × T3D-RV reassortant viruses revealed that the viral S4 gene segment, which encodes outer-capsid protein σ3, is responsible for strain-specific differences in infection of BMDMs. Differences in the binding of T1L and T3D-RV to BMDMs also segregated with the σ3-encoding S4 gene. Paired immunoglobulin-like receptor B (PirB), which serves as a receptor for reovirus, is expressed on macrophages and engages σ3. We found that PirB-specific antibody blocks T1L binding to BMDMs and that T1L binding to PirB-/- BMDMs is significantly diminished. Collectively, our data suggest that reovirus T1L infection of macrophages is dependent on engagement of PirB by viral outer-capsid protein σ3. These findings raise the possibility that macrophages function in the innate immune response to reovirus infection that blocks immunological tolerance to new food antigens.IMPORTANCEMammalian orthoreovirus (reovirus) infects humans throughout their lifespan and has been linked to celiac disease (CeD). CeD is caused by a loss of oral immunological tolerance (LOT) to dietary gluten and leads to intestinal inflammation following gluten ingestion, which worsens with prolonged exposure and can cause malnutrition. There are limited treatment options for CeD. While there are genetic risk factors associated with the illness, triggers for disease onset are not completely understood. Enteric viruses, including reovirus, have been linked to CeD induction. We found that a reovirus strain associated with oral immunological tolerance blockade infects macrophages by virtue of its capacity to bind macrophage receptor PirB. These data contribute to an understanding of the innate immune response elicited by reovirus, which may shed light on how viruses trigger LOT and inform the development of CeD vaccines and therapeutic agents.