Klebsiella ARO112 promotes microbiota recovery, pathobiont clearance and prevents inflammation in IBD mice.

Abstract

Precise microbiota modulation towards improving immune function and metabolic homeostasis is a major goal in clinical research. It is also critical for reducing pathogen invasion or pathobiont expansion, contributors to epidemic Inflammatory Bowel Diseases (IBD), where recurrent antibiotic treatments often exacerbate microbiota imbalances. Within the thousands of strains of a natural gut microbiota, we previously identified a specific Klebsiella strain, ARO112, capable of promoting resistance to, and clearance of, pathogenic Enterobacteriaceae. Here, we assess its therapeutic potential using a comprehensive genomic and phenotypic analysis and experiments in mouse models of IBD. We demonstrate that ARO112 not only exhibits a safety profile comparable to the widely used probiotic Escherichia coli Nissle 1917, but also has a reduced capacity to acquire antibiotic resistance, via horizontal gene transfer, and to capture iron, thereby bypassing major concerns associated with pathogenic Enterobacteriaceae strains. In antibiotic-treated, genetically predisposed IBD mice, ARO112 accelerates pathobiont clearance, promotes the recovery of microbiota diversity, elevates intestinal butyrate concentration, and prevents mild inflammation. Moreover, even in the absence of pathogen infection, ARO112 prevents severe inflammation-driven pathology in a chemically-induced colitis model. Our findings highlight ARO112 as a potential biotherapeutic agent that disrupts inflammation-treatment-infection cycles characteristic of chronic gut inflammatory diseases.