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Fusobacterium nucleatum-derived succinic acid aggravates colitis by triggering macrophage pro-inflammatory phenotypic transformation via SUCNR1/NF-κB axis
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DOI：10.1080/19490976.2026.2702183.png)
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Abstract
En 中文
Fusobacterium nucleatum (F. nucleatum) has been increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD), yet the mechanisms underlying its effects remain incompletely defined. In this study, we integrated human fecal and mucosal samples, comparative metabolomics, multiple experimental colitis models, bacterial genetic manipulation, macrophage functional assays, and host signaling analyses to identify a macrophage-centered mechanism through which F. nucleatum exacerbates colitis. We show that F. nucleatum colonization increases intestinal and systemic levels of its metabolite succinic acid, upregulates the expression of its cognate receptor SUCNR1 on intestinal macrophages, activates NF-κB signaling, and promotes pro-inflammatory macrophage activation. This macrophage inflammatory response is associated with epithelial barrier disruption, increased epithelial apoptosis, and aggravated mucosal and systemic inflammation. A fumarate reductase-deficient (frdA-KO) F. nucleatum strain with impaired succinic acid production showed a markedly reduced capacity to activate macrophage NF-κB signaling, induce macrophage inflammatory activation, and aggravate colitis, whereas exogenous succinic acid restored these effects in the frdA-KO setting. Moreover, siSUCNR1 and pharmacological NF-κB inhibition substantially attenuated succinic acid-induced macrophage inflammatory activation, supporting the involvement of a SUCNR1–NF-κB signaling cascade. Collectively, these findings demonstrate that F. nucleatum exacerbates colitis by producing succinic acid and engaging SUCNR1–NF-κB–dependent inflammatory activation of macrophages, highlighting the F. nucleatum–succinic acid–SUCNR1–NF-κB axis as a potential therapeutic target in IBD.
Keywords:
Inflammatory bowel disease
Fusobacterium nucleatum
succinic acid
SUCNR1
macrophage
NF-κB
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