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

• 成果类型: Article
• 署名作者: Sinha, Ritam; LeVeque, Rhiannon M.; Callahan, Sean M.; Chatterjee, Shramana; Stopnisek, Nejc; Kuipel, Matti; Johnson, Jeremiah G.; DiRita, Victor J.
• 署名单位: Michigan State University; University of Tennessee System; University of Tennessee Knoxville; Michigan State University; University of Pennsylvania; Royal Netherlands Academy of Arts & Sciences; Netherlands Institute of Ecology (NIOO-KNAW)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12856
• DOI: 10.1073/pnas.2316540120
• 发表日期: 2024-01-09
• 关键词: virulence factors; jejuni infection; microbiota; oxygen; colonization; dysbiosis; promotes; diseases; hypoxia; culture

摘要

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.