Microbiota-derived indole limits Campylobacter jejuni colonization by inhibiting respiration and metabolism

Campylobacter jejuni is a major enteric pathogen whose ability to grow in the inflamed gut remains poorly understood, limiting the development of effective therapeutic strategies. Our prior study in ferrets suggested that intestinal inflammation promotes C. jejuni expansion during infection. However, conventional mice are naturally resistant to C. jejuni colonization unless the microbiota or host inflammatory pathways are altered. To directly investigate the role of inflammation in C. jejuni infection, transient colitis was induced in conventional mice using short-term dextran sodium sulfate (DSS) treatment. DSS-mediated inflammation disrupted colonization resistance and enabled rapid C. jejuni growth in the colon within three days of infection, accompanied by aggravated intestinal inflammation. Microbiota analysis revealed enrichment of mucin-degrading bacteria and depletion of taxa associated with short-chain fatty acid and indole production. Metabolomic profiling further demonstrated significantly reduced colonic indole levels in DSS-treated and infected mice. In vitro studies showed that physiological concentrations of indole inhibited C. jejuni growth and downregulated genes involved in major energy-generating pathways, including nitrate respiration ( napA ), aerobic respiration ( ccoN ), lactate utilization ( lctP ), and the acetate switch ( ackA/ptaA ). Consistent with these findings, mutations in these pathways reduced bacterial fitness in DSS-treated mice, highlighting their importance for colonization in the inflamed intestine. Furthermore, administration of indole or the indole-producing probiotic Escherichia coli Nissle 1917 significantly decreased C. jejuni colonization in vivo. Collectively, these findings demonstrate that intestinal inflammation facilitates C. jejuni colonization while microbiota-derived metabolites, particularly indole, play a critical role in suppressing pathogen growth and pathogenicity.