Narrative review discusses M cell manipulation limitations in inflammatory bowel disease models

Dysbiosis of the gut microbiota is a key driver in the onset and persistence of inflammatory bowel disease (IBD). However, the mechanisms by which microbes influence mucosal immunity via specific epithelial routes remain incompletely elucidated. Microfold (M) cells within follicle-associated epithelium serve as a critical “gateway” for luminal antigens and microbes to access the mucosal immune system. While essential for surveillance of commensal microbes, M cells could also be exploited by adherent-invasive strains and adverse environmental factors to amplify inflammation. Recent studies suggest that both in Crohn’s disease and ulcerative colitis, M cell abundance and function are aberrantly regulated, linking microbial imbalance with heterogeneous mucosal inflammatory phenotypes. Traditional animal models and two-dimensional culture systems retain limited capacity to selectively manipulate M cells without perturbing systemic immunity, thereby constraining systematic studies of microbiota–M cell co-cultures. Advances in intestinal organoid technology now enable controlled induction of functionally mature M cells within three-dimensional epithelial structures, and have started to shed light on the roles of RANKL signaling, negative regulators, and microbe-associated factors in M cell differentiation and homeostasis. In this review, we focused on key evidence supporting microbiota–M cell interactions in IBD, discussed how M cell-enriched intestinal organoid models could be leveraged to dissect the impact of pathogenic microbes, candidate probiotics, dietary components, and existing therapies on these interactions as well as to evaluate the related potential and limitations for microbiome interventions and drug screening. Integrating gut microbial plasticity with M cell epithelial entry and organoid platforms promises to provide new experimental foundations and theoretical support for individualized microbiome-based therapies and targeted mucosal treatments in IBD.