IDDF2024-ABS-0296 Maximizing the therapeutic potential of trained immunity in DSS-induced colitis management

<h3>Background</h3> Inflammatory bowel disease (IBD), encompassing conditions such as ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenging group of chronic gastrointestinal inflammatory disorders. The gut microbiota and innate immunity play crucial roles in the development of inflammatory bowel disease (IBD). This study aims to explore the immunoregulatory effects of trained immunity and its potential in the prevention of IBD. <h3>Methods</h3> The impact of β-glucan-induced trained immunity was evaluated using dextran sodium sulfate (DSS) and <i>Salmonella typhimurium</i> infection in mice. Multi-color flow cytometry, various transgenic mouse models, single-cell RNA sequencing and 16S sequencing were employed to identify the major cell types involved. <h3>Results</h3> Mice pretreated with the prototypic trained immunity inducer, β-glucan, showed significant improvement in DSS-induced colitis. This improvement was attributed to β-glucan’s ability to activate central immunity within the hematopoietic compartment, consequently triggering a ‘trained’ monocyte response in the periphery. Both bone marrow transplantation from trained donors to naïve recipients and adoptive transfer of trained peripheral monocytes provided protection against DSS colitis. Notably, trained mice displayed enhanced bactericidal activity against intestinal bacterial infections. Furthermore, single-cell RNA sequencing revealed that β-glucan-induced trained immunity resulted in an expansion of reparative Cx3cr1 intestinal macrophages originating from Ly6Chi monocytes, facilitating faster recovery of the colon epithelium. Additionally, 16S sequencing demonstrated that β-glucan-induced trained immunity helped maintain gut microbiota homeostasis. <h3>Conclusions</h3> β-glucan induced functional change of bone marrow-derived monocytes, which migrate to the intestine and differentiate into macrophages upon inflammatory chemotaxis. This enhances the antimicrobial functions of monocytes/macrophages in the tissue, and promotes intestinal microbial homeostasis, thereby achieving long-term alleviation of colitis.