Role of the gut metabolite lactate on Campylobacter jejuni pathogenicity

"This study investigates how the microaerobic pathogen Campylobacter jejuni establishes and expands its niche in the gastrointestinal tract during acute infection, focusing on the role of the gut metabolite L-lactate. Using six-week-old ferrets as a natural and clinically relevant disease model that does not require manipulation of the host microbiome or immune system, the study documents rapid C. jejuni growth and pronounced intestinal inflammation within two to three days after orogastric inoculation. Ferrets replicate key features of human C. jejuni infection—rapid bacterial expansion, severe inflammatory responses, and pathophysiological alterations of the gut—making this an advantageous model compared with conventional mouse systems that need antibiotic treatment or immune alteration to permit colonization.

Through histological and molecular analyses, the work reports cryptic hyperplasia, induction of tissue repair programs, accumulation of undifferentiated amplifying cells on the colonic surface, and instability of HIF-1α in colonocytes, collectively indicating increased epithelial oxygenation during infection. Metabolomic profiling of colon contents from infected animals revealed elevated lactate levels, prompting functional studies of bacterial lactate utilization. A Campylobacter mutant lacking lctP, the gene encoding an L-lactate transporter, showed significantly diminished colonization capacity during infection, directly implicating lactate import as important for population expansion in the inflamed gut. Complementary in vitro assays demonstrated that lactate influences adhesion to and invasion of a human colon carcinoma cell line (HCT116), suggesting lactate availability may modulate key pathogenic interactions with the epithelium.

The oxygenation-dependent expression of lctP led to the identification of a putative thiol-based redox regulator, LctR, which binds the lctP promoter and may repress lctP transcription under anaerobic conditions. This putative regulator provides a mechanistic link between local oxygen levels, transcriptional control of lactate uptake, and C. jejuni’s ability to exploit host-derived metabolites during inflammation. By identifying L-lactate as a growth substrate and demonstrating the necessity of the lctP lactate transporter for in vivo expansion, the study addresses central questions about how C. jejuni competes with the gut microbiota, selects carbon sources, and responds to microenvironmental cues in the inflamed gut.

Given the rising burden of Campylobacter infections and increasing antibiotic resistance, understanding metabolic strategies that support pathogen expansion in the host lumen has translational importance. The findings offer insight into environmental conditions that enable C. jejuni colonization and suggest that targeting lactate uptake or its regulation might represent a potential avenue to limit pathogen growth during acute infection. Overall, DiRita and coauthors provide a detailed picture of host-pathogen metabolic interplay, establishing L-lactate and its transporter as central contributors to C. jejuni pathogenicity during the early, inflammatory stages of infection in a physiologically relevant animal model.