Citations

ABSTRACT Coeliac disease (CeD) and immunoglobulin A deficiency (IgAD) frequently co‐occur and share a genetic background within the HLA‐DQ2 region. Although this has been known for decades, the underlying mechanisms linking the two conditions remain unclear. We conducted a scoping review to evaluate the prevalence, clinical characteristics, diagnostic challenges and histopathological features of IgAD in patients with CeD. Thirty‐one studies published between 1985 and 2024 were included. IgAD was more prevalent among individuals with CeD, 1.4%–4.8% than in the general population, and CeD occurred in 5.9%–14.1% of patients with IgAD. Most patients presented with gastrointestinal symptoms, although selection bias was common. IgG‐based serology remains essential for diagnosis and monitoring, but its reliability during follow‐up is limited by the slow decline of antibodies. Histological findings indicate compensatory IgM and IgG responses and persistent mucosal immune activation. Improved strategies for diagnosis and long‐term monitoring of patients with both conditions are warranted.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) enhance anti‐tumour immunity by modulating immune pathways but can also trigger immune‐related adverse events. We aimed to evaluate the risk of developing coeliac disease (CeD) among patients with malignancy treated with ICIs. Methods Using the TriNetX US Collaborative Network, we identified adults (≥ 18 years) diagnosed with malignancies for which ICIs are routinely used between January 2010 and December 2024 and stratified them by exposure to immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, or avelumab). Patients with pre‐existing celiac disease (CeD) were excluded. Cohorts were propensity score matched for demographics and autoimmune comorbidities. The primary outcome was incident CeD occurring ≥ 90 days after the index event. Adjusted hazard ratios (aHRs) were calculated, with subgroup analyses by age and sex. Statistical significance was defined as p < 0.05. Results After propensity score matching, 158,208 patients were included in each cohort. CeD was diagnosed more frequently among patients exposed to ICIs than among matched controls (0.152% vs. 0.071%; aHR 3.95, 95% CI 3.11–5.03; p < 0.001), corresponding to a number needed to harm (NNH) of 1235. The increased risk persisted across sex and age subgroups, including females (aHR 3.43, 95% CI 2.55–4.62), males (aHR 5.36, 95% CI 3.53–8.12), with the risk being highest among patients older than 60 years (0.14% vs. 0.06%; aHR 4.24, 95% CI 3.17–5.67; p < 0.001). Conclusion In this large real‐world cohort, ICI exposure was associated with nearly a fourfold increase in the risk of being diagnosed with CeD compared with matched controls.

ABSTRACT Background Coeliac disease is due to an acquired, lifelong gluten‐specific immune response resulting in a gluten‐dependent chronic immune‐mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten‐free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies. Aims To summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi‐stakeholder meeting focused on accelerating clinical trials. Methods A pre‐competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions. Results Participants described high symptom burden and psychosocial impact despite gluten‐free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co‐primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit‐for‐purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre‐specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double‐blind period, including a shorter 24‐week double‐blind study with an open‐label extension versus a 52‐week double‐blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer‐term safety and durability data, with flexibility to tailor the approach to context. Conclusions Progress in coeliac disease drug development will require patient‐centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi‐stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which environmental factors play an important role in shaping disease risk, activity, and progression. Over the past decade, human and experimental studies have consistently shown alterations in the gut microbiome across the phenotypic spectrum of MS and have linked these changes to immune dysregulation, barrier dysfunction, neuroinflammation, and demyelination. Additionally, emerging evidence indicates that microbial function, particularly metabolite production plays a more direct role in shaping immune responses and associated neuropathology. Evidence from both human studies and experimental autoimmune encephalomyelitis models supports a functional role for microbial metabolites in shaping neuroimmune responses. Bacterially derived metabolites such as short-chain fatty acids, bile acids, polyamines, phytoestrogen metabolites, and tryptophan-derived compounds can influence T-cell differentiation, glial activation, epithelial integrity, and neuroimmune communication. Recent longitudinal studies also show associations between metabolite profiles and disability worsening. Because disease-modifying therapies, diet, and microbiome-directed interventions can reshape microbial metabolism, microbial metabolites may represent promising therapeutic targets in the gut-immune-brain axis. In this Review , we integrate current evidence to propose a mechanistic framework in which microbial metabolites act as central regulators of mucosal and systemic immunity that influence different aspects of MS biology. We discuss how this perspective shifts gut microbiome research from descriptive associations to biological mechanisms that more directly link the gut to immune responses and downstream neuropathology. We then evaluate therapeutic strategies that target microbial metabolism and outline key priorities for longitudinal, multi-omics, and interventional studies that are needed to enable microbiome-informed precision therapies in MS.

Abstract Genome-resolved virome analysis remains inaccessible for many samples, including those with clinical relevance, because viral nucleic acid recovered after enrichment is often too scarce to support de novo genome assembly. As a result, many analyses are limited to sparse read-level detection, which cannot recover divergent viruses, resolve strains, or interpret gene-level variation. Here, we developed Low Biomass Viral Sequencing (LBV-Seq), a workflow that couples low-input viral sample handling with modified primary template-directed amplification and short- or long-read sequencing to enable de novo reconstruction of DNA and RNA viral genomes from sub-femtogram to nanogram inputs. LBV-Seq reproducibly captures the same relative community composition, amplifies diverse viruses, and achieved broad genome coverage across nearly all targets regardless of viral genome structure, Baltimore class, abundance, or input mass. Short-read assemblies recovered near-complete genomes from femtogram-scale inputs. Long-read sequencing provided orthogonal support for genome structure, with PacBio HiFi reads spanning large portions of viral genomes and, in some cases, complete small viral genomes. Applied to virus-enriched human duodenal biopsy eluates, LBV-Seq provided proof-of-feasibility for recovering both bacteriophage and eukaryotic viral genomes from low-input biopsy-derived material. In the eluates tested, LBV-Seq recovered co-occurring Alphatorquevirus and Betatorquevirus genomes estimated to be present at roughly 10 copies/µL and at viral masses below 0.1 fg/µL. LBV-Seq enables genome-resolved virome analysis in samples previously limited to detection-based viromics, supporting viral discovery and strain-resolved analyses in settings where viral mass is low, including viruses enriched from human tissue biopsies.

Background: Mastocytic enterocolitis has been proposed as a cause of chronic diarrhea and abdominal pain, characterized by increased mast cells in gastrointestinal mucosal biopsies. However, its clinical significance remains uncertain. Methods: We present a case report of a patient identified to have high levels of mast cells on gastrointestinal biopsies. We then reviewed cases at Mayo Clinic where patients had >20 mast cells per high-power field (HPF) on gastrointestinal biopsies. Patients with alternative explanations for mast cell elevation, including systemic mastocytosis were excluded. We analyzed demographics, clinical presentations, pathology reports, serum and urine mast cell mediators, inflammatory markers, bone marrow biopsies, motility testing, and treatment responses. Results: We identified 42 patients (30 female and 12 male) with elevated mast cells on biopsy (mean age: 41 y, range: 17 to 81). Mast cells were quantified using KIT (CD117) staining, with no abnormal clumping or morphology, and CD25 immunostaining was negative in all cases. Eosinophilic infiltration was absent in all but one case. Small intestinal bacterial overgrowth (SIBO) was found in 78% of patients tested. Treatments varied widely, with antihistamines and cromolyn being the most common. Among 21 patients with sufficient follow-up, only 5 (24%) reported partial or complete symptom improvement, while 76% experienced persistent symptoms. Conclusion: Routine assessment of mast cells on gastrointestinal biopsies is not supported by our findings. Elevated mucosal mast cells, in the absence of systemic mast cell disorders, may not indicate a distinct disease entity. Evaluation should focus on ruling out other inflammatory, allergic, infectious, and motility disorders, as well as SIBO. Further research is needed to determine the clinical significance of increased mucosal mast cells and their role in gastrointestinal symptomatology.

Abstract Background and Aims Celiac disease (CeD) is a chronic digestive autoimmune disorder affecting approximately 1% of the worldwide population. It is driven by T cells activated by specific HLA-DQ2 or HLA-DQ8 molecules leading to the destruction of intestinal villi. We aimed to characterize shared CeD-specific T cells in patients on and off a gluten-free diet (GFD) from a large cohort of cases and controls. Methods We performed bulk TCRβ immune sequencing of the peripheral blood of 1,604 biopsy-confirmed CeD patients (1,339 on GFD, 265 on normal diet) and 1,100 controls. We identified over 300 TCRβs enriched in CeD cases versus controls in an HLA-aware manner, controlling for CeD risk alleles. Results CeD-associated TCRβs were found to be more predictive of disease than previously characterized gliadin and glutenin-binding TCRs in a validation cohort. Furthermore, the clonal breadth of these TCRβs was associated with increased intestinal damage. Immune sequencing of the peripheral blood also uncovered repertoire-level differences between CeD patients and controls. CeD patients displayed significantly higher productive clonality compared to age-matched controls as well as expansion of TCRβs specific to cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). Conclusions These findings underscore the value of unbiased immune repertoire sequencing to identify novel biomarkers for autoimmune disease and to discover new disease mechanisms which can improve both diagnosis and treatment of disease.

Coeliac disease is characterised by immune-mediated damage to the small intestine in response to dietary gluten in genetically predisposed individuals. Increased intestinal permeability is a central component to its pathophysiology. This review explores the evidence for increased permeability in coeliac disease and the underlying mechanisms, including the roles of zonulin, inflammatory cytokines, microbial alterations and immune responses to gliadin peptides. We also review comprehensively the therapies targeting barrier integrity and normalising intestinal permeability, including particular diets and supplements, and experimental and improved medications including larazotide acetate and IMU-856. Finally, we highlight the need for reliable biomarkers for evaluating increased permeability in coeliac disease and advocate for further research on therapies which normalise barrier function, particularly as a strategy to maintain remission.

Abstract Celiac disease (CeD) is an immune-mediated condition driven by dietary gluten resulting in small intestinal mucosal inflammation and injury, along with myriads of symptoms. The only treatment is a lifelong gluten-free diet (GFD) and although most patients improve, the restriction can lead to nutrient deficiencies including fiber. While duodenal microbiota is altered in CeD, its fiber metabolic capacity is unknown. Here we show that both active and GFD-treated CeD patients had impaired microbial fiber metabolism in the small intestine which associates with depletion of the carbolytic taxa Prevotella spp. Colonization of germ-free mice with Prevotella spp increased small intestinal short chain fatty acids (SCFA). In gluten-sensitized mice expressing the celiac risk gene, HLA-DQ8, an inulin-supplemented diet facilitated microbial carbolytic function, SCFAs production and accelerated mucosal healing in the small intestine during GFD. The results support clinical investigations of dietary fiber supplementation and microbial carbolytic function to enhance responses to GFD in CeD.