Klebsiella pneumoniae L-Fucose metabolism promotes gastrointestinal colonization and modulates its virulence determinants

Abstract

Colonization of the gastrointestinal (GI) tract by Klebsiella pneumoniae (K. pneumoniae) is generally considered asymptomatic. However, gut colonization allows K. pneumoniae to either translocate to sterile site within the same host or transmit through the fecal-oral route to another host. K. pneumoniae gut colonization is poorly understood, but knowledge of this first step toward infection and spread is critical for combatting its disease manifestations. K. pneumoniae must overcome colonization resistance (CR) provided by the host microbiota to establish itself within the gut. One such mechanism of CR is through nutrient competition. Pathogens that metabolizes a broad range of substrates have the ability to bypass nutrient competition and overcome CR. Herein, we demonstrate that in response to mucin derived fucose, the conserved fucose metabolism operon (fuc) of K. pneumoniae is upregulated in the murine gut and subsequently show that fucose metabolism promotes robust gut colonization. Growth studies using cecal filtrate as a proxy for the gut lumen illustrates the growth advantage that the fuc operon provides K. pneumoniae. We further show that fucose metabolism allows K. pneumoniae to be competitive with a commensal E. coli isolate (Nissle). However, Nissle is eventually able to out-compete K. pneumoniae, suggesting that it can be utilized to enhance CR. Lastly, we observed that fucose metabolism positively modulates hypermucoviscosity, auto-aggregation, and biofilm formation, but not capsule biogenesis. Together, these insights enhance our understanding of the role of alternative carbon sources on K. pneumoniae gut colonization and the complex relationship between metabolism and virulence in this species. ImportanceKlebsiella pneumoniae (K. pneumoniae) is a leading cause of hospital-acquired infection. Treatment of infection by K. pneumoniae isolates is becoming difficult as this pathogen becomes increasingly antibiotic resistant. While there has been extensive investigation into the disease states associated with K. pneumoniae, its colonization of the gastro-intestinal (GI) tract is poorly understood. Epidemiological data suggest that in many cases the strain that colonizes the GI tract causes disease manifestations in the same host. Herein, we used our newly developed murine model of K. pneumoniae gut colonization, where colonization is achieved without disrupting the resident gut microbiota. We demonstrate that K. pneumoniae uses fucose as an alternative carbon source present in the gut lumen to overcome the intense nutritional competition. We further illustrate that K. pneumoniae, through fucose metabolism, is initially competitive with the probiotic E coli isolate Nissle 1917 (EcN). Lastly, we show that fucose metabolism modulates several virulence determinants of K. pneumoniae. Thus, our results provide new insight into the role fucose metabolism plays in gut colonization and virulence of K. pneumoniae, and furthermore identify EcN as having the ability to out-compete K. pneumoniae and be used as a probiotic.