Gut metabolite L-lactate supports <i>Campylobacter jejuni</i> population expansion during acute infection.

Abstract

How the microaerobic pathogen <i>Campylobacter jejuni</i> 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 <i>C. jejuni</i> pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with <i>C. jejuni</i>, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after <i>C. jejuni</i> infection in ferrets reflects closely how human <i>C. jejuni</i> infection proceeds. Rapid growth of <i>C. jejuni</i> 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 <i>C. jejuni</i> mutant lacking <i>lctP</i>, which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion by <i>C. jejuni</i> to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (<i>lctP</i>) led to identification of a putative thiol-based redox switch regulator (LctR) that may repress <i>lctP</i> transcription under anaerobic conditions. Our work provides better insights into the pathogenicity of <i>C. jejuni</i>.