P0209 Unraveling the microbial dynamics in Crohn’s Disease-associated Fibrosis: insights from RNA-seq and Spatial Transcriptomics

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Abstract Background In Crohn’s disease (CD), over 50% of cases develop fibrosis, often resulting in strictures. Despite advances in anti-inflammatory therapies, these complications persist due to chronic inflammation, which causes tissue injury and disrupts mucosal functions. Recent studies highlight microbiota dysbiosis as a potential inflammation-independent driver of fibrosis in CD 1,2, but specific microbial signatures across fibrosis stages remain underexplored. Methods We performed a meta-analysis of RNA-seq data from fibrotic CD-associated and healthy tissues. Cells, including immune, fibroblast, endothelial, and epithelial populations, were isolated via flow cytometry (FACS) and analyzed at the transcriptomic level. Co-culture experiments were conducted to explore cellular-bacterial interactions in fibrosis progression, and fibrosis markers (alpha-SMA, vimentin, and FAP) in fibroblasts were evaluated through immunofluorescence (IF). Results Gene ontology analysis revealed activation of antimicrobial immune processes, indicating a targeted response to microbiota during fibrosis progression. Microbiota analysis showed an increased abundance of Roseomonas mucosa in CD patients compared to controls across multiple cell types (endothelial, epithelial, fibroblast, and immune cells). Moreover, fibroblast co-cultures with Roseomonas mucosa (50 MOI/cell) displayed elevated fibrosis markers in IF compared to unstimulated controls. Conclusion Our findings suggest that Roseomonas mucosa, or its products, may modulate the transcriptional state of mucosal cells, including fibroblasts, contributing to intestinal fibrosis. To further elucidate the role of bacterial proteins in the progression from healthy to fibrotic tissue, we are performing spatial transcriptomics analysis on ileo-cecal resection tissues, followed by RNA-scope with bacteria-specific probes. This integrative approach aims to map the temporal progression of fibrosis in relation to microbiota, offering deeper insights into its development. References 1.Massimino, L. et al. The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework. Nat. Comput. Sci. 1, 511–515 (2021). 2.Watanabe, D. & Kamada, N. Contribution of the gut microbiota to intestinal fibrosis in crohn’s disease. Front Med (Lausanne) 9, 826240 (2022).

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