bioRxiv2026
How the microaerophilic Campylobacter jejuni grows in the inflamed gut is poorly understood, hampering our ability to identify novel targets for controlling infections by this pathogen. Our prior ferret study indicated that C. jejuni growth during infection is driven by intestinal inflammation. Without manipulating microbiota or introducing pro-inflammatory genetic lesions (or both), conventional mice are naturally resistant to C. jejuni colonization and infection. To test the impact of inflammation per se on C. jejuni infection, we induced transient intestinal inflammation in mice using short-term dextran sodium sulfate (DSS) treatment. The resulting colitis disrupted colonization resistance, enabling rapid C. jejuni growth in the murine colon within three days of infection, accompanied by exacerbated intestinal inflammation. DSS-induced colitis led to enrichment of mucin-degrading bacteria and depletion of taxa producing short-chain fatty acids and indole; metabolomic profiling confirmed a marked reduction in colonic indole levels in both DSS-treated and infected mice. At physiological concentrations, indole inhibited C. jejuni growth in vitro and resulted in reduced transcript levels from key energy-generating pathways, including nitrate respiration (napA), aerobic respiration (ccoN), lactate utilization (lctP), and the acetate switch (ackA/ptaA); consistent with this, mutations in these pathways led to fitness defects in DSS-treated mice, highlighting their importance for C. jejuni colonization in the inflamed gut. Moreover, treatment with indole or the indole-producing probiotic Escherichia coli Nissle 1917 significantly reduced C. jejuni colonization in vivo. Our findings show how C. jejuni establishes and grows in the inflamed gut and demonstrate that microbiota-derived metabolites play a key role in regulating C. jejuni pathogenicity. SignificanceThe mechanisms by which the microaerophilic pathogen C. jejuni proliferates in the inflamed intestine remain poorly understood. Using a DSS-induced colitis mouse model, we identify host physiological changes, microbiota alterations, and metabolic factors that promote C. jejuni colonization during intestinal inflammation. These findings provide mechanistic insight into why Campylobacter species are frequently detected in patients with Inflammatory Bowel Disease (IBD) and how infection can exacerbate intestinal inflammation and worsen disease symptoms. We further identify the microbiota-derived metabolite indole as a potent inhibitor of C. jejuni colonization, highlighting a potential metabolite-based therapeutic strategy to combat emerging multidrug-resistant C. jejuni infections.