The gut microbiota – from interindividual differences to novel therapeutics

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Abstract:
Healthcare-associated infections, particularly those caused by Gram-negative multidrug-resistant organisms (GN-MDR), are a pressing global issue, significantly impacting morbidity and mortality rates. Gut colonization with these GN-MDRs often precedes systemic infections in patients. Decolonization strategies based on antibiotic treatments have a long-lasting and broad impact on the gut microbiota and put further selective pressure on developing multi- and pan-resistant nosocomial pathogens. Therefore, the need for alternative methods to eliminate selectively MDR pathogens is not just urgent but crucial.
We aim to develop “live biotherapeutic drugs” (LBP) as novel therapeutics against GN-MDR, selectively targeting the pathogen while leaving the surrounding microbiota intact. Our approach is based on ecological principles: nutrient competition between related bacteria. Utilizing ex vivo assays and large strain collections of commensal bacteria, we identified in the past years that Klebsiella oxytoca promotes colonization resistance against various GN-MDR and enteropathogens in the gut. In two instances, we have linked the phenotype to competition for different nutrients in vivo. Moreover, the microbial context of the competition, i.e., the presence of additional commensal bacteria, plays an important role in decolonization that is in line with the current understanding of gut microbiota ecology.