Gut metabolite L-lactate supports population expansion during acute infection.

How the microaerobic pathogen establishes its niche and expands in the gut lumen during infection is poorly understood. Using 6-wk-old ferrets as a natural disease model, we examined this aspect of pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with , ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after infection in ferrets reflects closely how human infection proceeds. Rapid growth of and associated intestinal inflammation was observed within 2 to 3 d of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A mutant lacking , which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter () led to identification of a putative thiol-based redox switch regulator (LctR) that may repress transcription under anaerobic conditions. Our work provides better insights into the pathogenicity of .