FACTORS AFFECTING MICROBIOME RECOVERY AND COLONIZATION RESISTANCE AFTER DRUG-INDUCED DYSBIOSIS

Abstract

The gut microbiota is inextricably linked to human health and disease. It can confer colonization resistance against invading pathogens either through niche occupation and nutrient competition or via its secreted metabolites. A stable microbiome maintains homeostasis and colonization resistance against enteric pathogens or pathobionts like hypervirulent Klebsiella pneumoniae (hvKP) which reside asymptomatically in the gut but can cause invasive community acquired infections in the healthy. Antibiotic usage is a major cause of dysbiosis by decreasing microbial abundance and diversity, thereby increasing host susceptibility to these infections. The gut microbiota is instrumental in breaking down dietary fibre into short-chain fatty acids (SCFA). I demonstrate a general inhibition of different bacterial taxa via inhibition of bacterial membrane potential by these SCFAs at physiological cecum and ascending colonic pH. Bacterial inhibition increases with alkyl-chain length. I also developed simplified consortium models using stools cultured anaerobically via in-vitro static culture and mini bioreactor array (MBRA) continuous flow. I demonstrate that stools grown under different carbohydrate richness result in different community composition, alpha diversity and SCFA production, but exert equally strong resistance against hvKP invasion. These findings shed light on formulating defined therapeutic strategies for hvKP decolonization.