Paul Moayyedi

Background: Non‐ Helicobacter pylori ( H. pylori ), non‐nonsteroidal anti‐inflammatory drug (NSAID) peptic ulcer disease (PUD) is increasingly recognized as a distinct subgroup, but its proportion across clinical presentations remains unclear. Aim: We aimed to estimate this proportion. Methods: We searched MEDLINE, Embase and CENTRAL from their inception to March 2026 for observational studies. The primary outcome was the proportion of non‐ H. pylori , non‐NSAID PUD among adults with overall, bleeding and perforated PUD. Random‐effects meta‐analysis of logit‐transformed proportions was performed using restricted maximum likelihood. Meta‐regression assessed associations with study year, country‐level H. pylori prevalence and region. Protocol registered in PROSPERO (CRD420251174202). Results: Overall, 92 studies (60,816 patients) from 32 countries were included. The pooled proportions of non‐ H. pylori , non‐NSAID PUD cases were 13.0% (95% confidence interval [CI], 10.4–16.2) in overall PUD, 11.3% (95% CI, 8.8–14.4) in bleeding PUD, and 22.0% (95% CI, 13.1%–34.7%) in perforated PUD. In univariable meta‐regression, a more recent study year was associated with a higher proportion of bleeding PUD ( β = 0.076; 95% CI, 0.031–0.120). This association remained statistically significant after adjustment for country‐level H. pylori prevalence ( β = 0.070; 95% CI, 0.026–0.113). Lower H. pylori prevalence was also associated with a higher proportion after further adjustment for region ( β = −0.025; 95% CI, −0.046 to −0.005). Conclusion: Non‐ H. pylori , non‐NSAID PUD represents a non‐negligible but heterogeneous component of PUD. In bleeding PUD, exploratory ecological analyses suggest a temporal increase, potentially reflecting evolving etiologic patterns beyond H. pylori infection and NSAID exposure.

Adherent-invasive Escherichia coli (AIEC) exhibits proinflammatory properties and has been implicated in the pathogenesis of Crohn’s disease (CD), a form of inflammatory bowel disease (IBD). Antibiotic use in CD lacks specificity and may worsen microbiome disruption, prompting interest in bacteriophages (phages) for targeted microbiome editing. Here, we identified HER259, a phage active against clinical AIEC isolates. HER259 ameliorated colitis in gnotobiotic models and attenuated the virulence of AIEC strain NRG857c, including suppression of the FimH adhesin through inversion of the fimS promoter to its “off” orientation. The effects were confirmed in CD-microbiota colitis models. Withdrawal of HER259 treatment led to reversion of the fimS promoter and reactivated colitis. The HER259 phage also enhanced the therapeutic effect of subtherapeutic budesonide independent of microbial drug metabolism. These findings support targeted phage therapy as an adjunct treatment approach in IBD, demonstrating modulation of bacterial virulence and improved response to conventional treatments that may reduce drug-related side effects.

Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation ^1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Lay Summary: In our pilot study, combining weekly fecal transplantation with vedolizumab for induction of remission in ulcerative colitis patients who had previously failed other advanced therapy did not result in any adverse events; however, recruitment was limited, likely due to changes in prescribing patterns in this patient population.

Supplementary Figure from eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma