Abstract Background Pathobiont–immune interactions are increasingly recognized as central drivers of chronic intestinal inflammation. Fusobacterium nucleatum is enriched in IBD, yet how it perturbs host metabolic and immune networks remains unclear. Methods We combined DSS and Fn–exacerbated colitis models with bulk RNA-seq, CIBERSORT immune deconvolution, multiorgan flow cytometry, and in vitro dendritic cell assays. Untargeted metabolomics of bacterial supernatants and clinical samples was performed to identify microbe-associated metabolic disruptions. A HutH-deficient Fn strain was generated to establish genetic causality. Structure-based virtual screening of 70,000 compounds, followed by biochemical assays and in vivo testing, was used to identify and evaluate selective HutH inhibitors. Results Fn markedly exacerbated intestinal inflammation by orchestrating a dendritic cell (DC)–centered immunologic cascade. Transcriptomic deconvolution and flow cytometry demonstrated that Fn shifted colonic DCs toward an immunogenic CD80+CD86+ phenotype, amplifying IL-6, IL-1β, and IL-23 production and driving a pronounced Th17/Treg imbalance. To determine what initiated this inflammatory reprogramming, untargeted metabolomics revealed striking depletion of luminal and systemic histidine in both Fn supernatants and samples from Crohn’s disease patients. Restoring histidine levels through dietary supplementation curtailed MAPK activation in DCs, normalized Th17/Treg dynamics, and significantly ameliorated both DSS- and Fn–aggravated colitis, implicating histidine scarcity as the metabolic trigger for immune activation. This model was genetically validated using a HutH-deficient Fn strain, which displayed a markedly reduced capacity to degrade histidine and consequently failed to intensify colitis, establishing HutH as the metabolic driver of the bacterium’s pathogenicity. Guided by this mechanism, virtual screening identified a selective HutH inhibitor, F3385-1872, which blocked bacterial histidine degradation without altering microbial growth. Consistent with the genetic findings, F3385-1872 selectively attenuated Fn–exacerbated colitis, reduced DC immunogenicity, restored Th17/Treg balance, and suppressed MAPK activation, all while preserving gut microbiota composition and systemic safety. Conclusion This work reveals a previously unrecognized microbiota–immune metabolic axis in which Fusobacterium nucleatum hijacks luminal histidine via the HutH enzyme to activate MAPK-driven DC immunogenicity and fuel Th17/Treg dysregulation. Genetic and pharmacologic disruption of HutH dismantles this inflammatory program, highlighting microbial histidine catabolism as a druggable vulnerability with therapeutic potential for IBD. Conflict of interest: Wang, Mingyuan: No conflict of interest Li, Jiajia: No conflict of interest Zhang, Hongjie: No conflict of interest
Wang et al. (Thu,) studied this question.