DOP144 Escherichia coli shapes intestinal B-cell responses and influences susceptibility to Inflammatory Bowel Disease

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Abstract Background Escherichia coli (Ec) is among the earliest commensals to colonize the neonatal gut and becomes enriched during IBD1,2, likely reflecting metabolic advantages during colitis. While these ecological shifts are well documented, how dysregulated mucosal immune responses to Ec influence inflammatory outcomes remains poorly understood. We recently showed that neonatal Ec colonization drives B-cell accumulation in Peyer’s patches via curli, an amyloid fiber essential for biofilm formation and epithelial adhesion, acting through TLR2. Curli-deficient Ec strains failed to induce this response, revealing a novel role for microbial amyloids in shaping early life mucosal immunity3. Here, we investigate how Ec-mediated early-life immune imprinting affects susceptibility to experimental IBD. In a complementary translational approach, we isolated Ec strains from healthy newborn infants to assess curli expression and functional properties of naturally acquired isolates. Methods Specific-pathogen-free wild-type, Il-10-/-, and B-cell-deficient μMT mice were colonized at birth via maternal transfer with curli-proficient or -deficient commensal and probiotic Ec strains or kept Ec-free. At 4 weeks, mice received streptomycin to eliminate Ec and isolate immune imprinting effects from colitis-driven Ec blooms. After a microbiome recovery period, wild-type and μMT mice were challenged with DSS, while Il-10-/- mice were monitored for spontaneous colitis. Disease severity was assessed by clinical and histological parameters, and flow cytometry-based immune profiling. Neonatal Ec isolates were screened for the curli gene csgA, and phenotypic curli expression was assessed using Congo red assays. Results Wild-type mice primed with curli-expressing Ec were protected from DSS-induced colitis, whereas Ec-naïve mice or mice primed with curli-deficient Ec showed increased susceptibility. Curli-expressing Ec induced regulatory B cells, whereas curli-deficient Ec elicited proinflammatory immune signatures. In contrast, Ec-primed μMT and Il-10-/- mice developed severe colitis, regardless of curli status, compared to Ec-naïve μMT and Il-10-/- controls. Among neonatal isolates, 70 out of 86 strains carried the curli operon; however, phenotypic curli expression varied widely among curli-encoding strains. Conclusion Early-life colonization with curli-expressing Ec establishes a lasting, B-cell- and IL-10-dependent imprint that enhances resilience to intestinal inflammation, indicating that curli-mediated signalling promotes mucosal tolerance. Future studies using neonatal isolates with defined curli status will determine whether the specific Ec strain colonizing infants influences their susceptibility to divergent inflammatory outcomes later in life. References: 1. Bäckhed F, Roswall J, Peng Y, et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host Microbe. 2015;17(5):690-703. doi:10.1016/j.chom.2015.04.0042. 2. Gevers D, Kugathasan S, Denson LA, et al. The treatment-naïve microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15(3):382-392. doi:10.1016/j.chom.2014.02.0053. 3. Gerner RR, Walker GT, Klaus SM, et al. Commensal Escherichia coli colonization triggers Peyer’s patch development. Microbiology. Preprint posted online October 7, 2025. doi:10.1101/2025.10.06.680803 Conflict of interest: Adlkirchner, Sophia: No conflict of interest Becker, Valeria: No conflict of interest Betz, Valentin: No conflict of interest Mühlschlegel, Konstantin: No conflict of interest Hubersberger, Manuela: No conflict of interest Stecher, Bärbel: No conflict of interest Gerner, Romana: No conflicts

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