Unveiling the Porphyromonadaceae-TFF1 Interaction and ITGAM as Critical Factors in Post-operative Recurrence of Crohn's Disease

BackgroundCrohns disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by high post-operative recurrence (POR) rates, reaching up to 90% within one year. Current clinical and endoscopic predictors show limited accuracy. ObjectiveThis study aimed to identify molecular mechanisms associated with POR at the time of surgery through integrated transcriptomic and bacteriomic analyses of ileal tissue. DesignIleal samples were obtained during surgery from 20 patients with CD and 10 inflammatory bowel disease-free controls, with an independent validation cohort of 49 patients with CD. POR was evaluated every six months using ileocolonoscopy and defined by Rutgeerts score. Host gene expression and tissue-associated microbiome profiles were integrated using correlation and pathway enrichment analyses to uncover host-microbe interactions linked to POR. ResultsIn the inflamed mucosa of patients who developed endoscopic POR, we identified a novel immune interaction involving the Porphyromonadaceae family, mainly Parabacteroides gordonii, which was slightly depleted. This depletion was associated with downregulation of epithelial barrier and tissue repair genes, including TFF1 and LSR, findings confirmed in the validation cohort. Porphyromonadaceae abundance positively correlated with short-chain fatty acid levels, particularly propionate. Additionally, omics integration revealed an association between Xanthomonadaceae and increased expression of ITGAM, a gene involved in neutrophil activation. ConclusionThese results highlight microbial-host gene interactions associated with POR. The pathogenic ITGAM-driven immune signature and the protective Porphyromonadaceae-TFF1-propionate axis supporting epithelial integrity may enable microbiome-informed prognostic tools and therapeutic strategies for CD POR. O_LIWhat is already known on this topic: Post-operative recurrence in Crohns disease is linked to microbial dysbiosis, particularly reduced diversity and expansion of Enterobacteriaceae. However, how microbial changes translate into host molecular mechanisms driving POR remains unclear. C_LIO_LIWhat this study adds: This prospective multi-omic study identifies a disrupted Porphyromonadaceae-SCFA-epithelial barrier axis and the participation of neutrophil responses in patients who develop POR at surgery time. C_LIO_LIHow this study might affect research, practice or policy: The findings provide mechanistic targets for microbiome-informed risk stratification and prevention of POR. They support development of microbial or metabolite-based interventions aimed at restoring epithelial barrier function after surgery. C_LI