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Background: To decipher the mechanisms underlying the protective role of the Mediterranean diet (MED) in Crohn's disease (CD), we explored the implications of adherence to MED on CD course, inflammatory markers, microbial and metabolite composition., Methods: Patients with newly diagnosed CD were recruited and followed prospectively. MED adherence was assessed by repeated food frequency questionnaires (FFQ), using a predefined IBDMED score, alongside validated MED adherence screeners. Crohn's disease activity index (CDAI), C-reactive protein (CRP), fecal calprotectin and microbial composition (16S-rRNA-sequencing) were assessed each visit. Baseline serum and fecal samples were analyzed for targeted quantitative metabolomics., Results: Consecutive patients: 271 (52% males, average age- 31±12 years, B1 phenotype- 75%). FFQ collected: 636 (range 1-5 FFQ per patient). Adherence to MED was associated with a non-complicated CD course, and inversely correlated with CDAI, fecal calprotectin, CRP and microbial dysbiosis index (all P < .05). Increasing adherence to MED over time correlated with reduced CDAI and inflammatory markers (P < .05). Adherence to MED correlated with a microbial cluster of commensals and short-chain fatty acid producers including Faecalibacterium, and with plant metabolites, vitamin derivatives and amino acids. Conversely, adherence to MED inversely correlated with a cluster of oral genera, Escherichia coli and Ruminococcus gnavus, known CD-associated species, and with tryptophan metabolites, ceramides and primary bile acids (FDR < .2)., Conclusion: Adherence to MED is associated with beneficial clinical outcomes and decreased inflammatory markers. These may be driven by lower levels of primary bile-acids and microbial dysbiosis and a beneficial microbial and metabolite composition. Randomized controlled trials are needed to evaluate the role of MED in CD management., (Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Janus kinase [JAK] inhibitors are used for treating inflammatory bowel diseases [IBD]. We aimed to identify the molecular effects of JAK inhibition in human intestinal mucosa, considering IBD location and phenotype., Methods: Colonic and ileal explants from patients with ulcerative colitis [UC], Crohn's disease [CD], and non-IBD controls [NC] were assessed for levels of phosphorylated signal transducers and activators of transcription [p-STAT] and expression of inflammatory genes in response to an ex vivo JAK inhibitor [tofacitinib]. Cytokine production by lamina propria lymphocytes in response to tofacitinib was assessed. Human intestinal organoids were used to investigate the effects of JAK inhibitors on inducible nitric oxide synthase [iNOS] expression., Results: Explants were collected from 68 patients [UC = 20, CD = 20, NC = 28]. p-STAT1/3/5 inhibition rates varied, being higher in colonic compared to ileal explants. p-STAT1/3 inhibition rates negatively correlated with levels of C-reactive protein [CRP]. While significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in five genes, including NOS2. JAK inhibition significantly decreased Th1/Th2/Th17-related cytokine production from lamina propria lymphocytes. Various JAK inhibitors reduced the interferon-γ-induced increase in iNOS expression in organoids., Conclusions: A site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noted, whereby the colon was more robustly affected than the ileum. The ex vivo response to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression. Ex vivo mucosal platforms may be a valuable resource for studying personalized drug effects in patients with IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)