Lactate dynamics at the Pseudomonas aeruginosa-host interface: bacterial metabolism, host defense, and emerging links to histone lactylation

At the Pseudomonas aeruginosa-host interface, lactate is both a host immunometabolic product and a preferred bacterial carbon source. Its local concentration reflects host production, bacterial utilization, transport, and clearance rather than inflammation alone. P. aeruginosa uses D- and L-lactate through stereospecific, conditionally regulated systems. It preferentially consumes lactate in human burn-wound exudate, and this capacity contributes to early intracellular survival in macrophages. Lactate-associated acidity also increases bacterial vesicle release and quinolone signaling, weakening antimicrobial-peptide activity independently of chromatin modification. On the host side, bacterial L-lactate utilization and virulence-factor-associated suppression of epithelial glycolysis lower epithelial lactate and histone H3 lysine 18 lactylation (H3K18la). These changes are linked to disrupted RNA regulation and impaired ciliary clearance. In macrophages, the quorum-sensing signal 2-aminoacetophenone (2-AA) reprograms bioenergetics, autophagy, and lipid metabolism, promoting tolerance and intracellular persistence. A separate hypothesis connecting 2-AA to increased macrophage lactate and H3K18la is supported only by a supplement abstract and requires full-length validation. Histone lactylation is therefore an emerging extension of this biology. This narrative review follows two linked strands: bacterial lactate utilization and lactate-associated changes in host defense. It distinguishes established metabolic effects from proposed lactylation-dependent mechanisms and considers potential therapeutic directions and their trade-offs. These include targeting bacterial lactate utilization, airway acidity, host transport or modification enzymes, and 2-AA-associated tolerance. Any benefit must be assessed against the possibility of supplying bacterial nutrients or worsening host injury.