Journal article
Gut metabolite L- lactate supports Campylobacterjejuni population expansion during acute infection
Proceedings of the National Academy of Sciences - PNAS, Vol.121(2), 2316540120
01/09/2024
DOI: 10.1073/pnas.2316540120
PMCID: PMC10786315
PMID: 38170751
Abstract
How the microaerobic pathogen Campylobacter jejuni 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 C. jejuni pathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized with C. jejuni, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease after C. jejuni infection in ferrets reflects closely how human C. jejuni infection proceeds. Rapid growth of C. jejuni 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-1 alpha in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. A C. jejuni mutant lacking lctP, which encodes an L- lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhe-sion and invasion by C. jejuni to a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (lctP) led to identification of a putative thiol-based redox switch regulator (LctR) that may repress lctPtranscription under anaer-obic conditions. Our work provides better insights into the pathogenicity of C. jejuni. Significance There is a gap in knowledge about the mechanisms by which Campylobacter jejuni populations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut after C. jejuni infection. Our study identified the gut metabolite L- lactate as playing an important role as a growth substrate for C. jejuni during acute infection. We identified a DNA binding protein, LctR, that binds to the lctP promoter and may repress lctP expression, resulting in decreased lactate transport under low oxygen levels. This work provides greater insights into C. jejuni pathogenicity.
Details
- Title: Subtitle
- Gut metabolite L- lactate supports Campylobacterjejuni population expansion during acute infection
- Creators
- Ritam Sinha - Michigan State UniversityRhiannon M. LeVeque - Michigan State UniversitySean M. Callahan - University of Tennessee at KnoxvilleShramana Chatterjee - Michigan State UniversityNejc Stopnisek - Michigan State UniversityMatti Kuipel - Michigan State UniversityJeremiah G. Johnson - University of Tennessee at KnoxvilleVictor J. DiRita - Michigan State University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.121(2), 2316540120
- Publisher
- Natl Acad Sciences
- DOI
- 10.1073/pnas.2316540120
- PMID
- 38170751
- PMCID
- PMC10786315
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Number of pages
- 12
- Grant note
- AI166535 / Michigan State Rudolph Hugh Endowment GM128959; CHE2203472 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Michigan State University Plant Resilience Institute SEC Emerging Scholars Program
- Language
- English
- Date published
- 01/09/2024
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984696717502771
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