Host-derived arginine promotes Klebsiella pneumoniae colonization and dissemination through ArtP–ArgR–capsule signaling

Intestinal colonization is a critical precursor to invasive Klebsiella pneumoniae infection, yet the host-derived metabolic cues that license this transition remain unclear. Here, we identify arginine as a consistently enriched amino acid across inflammation-, diet-, and antibiotic-induced gut perturbations. Arginine markedly enhances capsular polysaccharide production and virulence in both hypervirulent ST23-KL1 and carbapenem-resistant ST11-KL64 lineages under conditions reflective of the gut microenvironment. Mechanistically, arginine must be transported by the ArtP ATP-binding transporter to activate the regulator ArgR, which directly binds capsular polysaccharide operon promoters and indirectly upregulates rmpA , forming a conserved ArtP–ArgR–capsule signaling axis. In mouse models, elevated intestinal arginine increases gut colonization, accelerates mucosal invasion, and promotes systemic dissemination, whereas arginase-mediated arginine depletion or loss of ArtP/ArgR abrogates these effects. Together, our findings reveal intestinal arginine as a key host-derived signal that drives K. pneumoniae pathogenic progression and identify arginine metabolism as a tractable therapeutic target.