The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD⁺ Salvage Pathway in Ulcerative Colitis

Approximately 50% of the patients with ulcerative colitis (UC) are primarily nonresponsive to anti-tumor necrosis factor (TNF) therapy or lose their responsiveness over time. The gut microbiota plays an important role in the resistance of UC to anti-TNF therapy; however, the underlying mechanism remains unknown. Here, it is found that the transplantation of gut fecal microbiota from patients with UC alters the diversity of the gut microbiota in dextran sulfate sodium-induced colitis mice and may affect the therapeutic responsiveness of mice to infliximab. Furthermore, the abundances of Romboutsia and Fusobacterium increase in the tissues of patients with UC who do not respond to anti-TNF therapy. Differentially abundant metabolites are mainly enriched in nicotinate and nicotinamide metabolism in NCM460 cells after Fusobacterium nucleatum infection. Mechanistically, F. nucleatum promotes the nicotinamide adenine dinucleotide (NAD⁺) salvage pathway by upregulating NAMPT expression, which subsequently leads to the activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway and promotes the secretion of inflammatory factors, ultimately inhibiting the therapeutic response to anti-TNF drugs. These findings demonstrate that the gut microbiota can influence the response to anti-TNF therapy in patients with UC and highlight the therapeutic potential of targeting F. nucleatum and its associated pathways for preventing and treating drug resistance in UC.