Peyer's patches are a niche for antibiotic-driven expansion of Crohn's disease-associated adherent-invasive Escherichia coli

Antibiotic exposure is a significant risk factor for Crohns disease, yet the tissue-specific consequences of antibiotic-driven dysbiosis remain poorly defined. Adherent-invasive Escherichia coli (AIEC), a pathobiont enriched in Crohns disease, expands following antibiotic treatment, but whether discrete mucosal niches support this expansion is unknown. Peyers patches are specialized lymphoid structures that coordinate mucosal immunity and are frequently associated with early disease lesions, suggesting they may represent a vulnerable site for pathobiont colonization. Here, we show that vancomycin disrupts the Peyers patch-associated microbiome, creating a permissive niche that is selectively exploited by AIEC and associated with focal inflammation. Antibiotic treatment markedly increased AIEC burden within Peyers patches. AIEC localized within the lymphoid follicle was accompanied by focal tissue pathology and a distinct cytokine signature. In contrast, expansion of resident E. coli in the absence of AIEC did not elicit comparable inflammation, indicating that the pathogenic traits of AIEC are required to trigger disease-relevant responses in this niche. Supporting this, genetic disruption of flagellin, long polar fimbriae, or antimicrobial peptide resistance in AIEC attenuated Peyers patch colonization or inflammation, revealing separable mechanisms governing niche access and immunopathology. Together, these findings identify Peyers patches as a previously unrecognized reservoir for antibiotic-driven AIEC expansion and define a localized host-microbe interaction that links dysbiosis to focal intestinal inflammation. These results provide a mechanistic framework for understanding how antibiotic exposure may precipitate site-specific pathology in Crohns disease. Further, these findings highlight that mucosal lymphoid tissues should be considered when evaluating microbiome-targeted therapeutic interventions in Crohns disease.