The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis
Abstract 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 mech...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413128 |
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| author | Jing Lei Lin Lv Li Zhong Feng Xu Wenhao Su Yan Chen Zhixuan Wu Song He Yongyu Chen |
| author_facet | Jing Lei Lin Lv Li Zhong Feng Xu Wenhao Su Yan Chen Zhixuan Wu Song He Yongyu Chen |
| author_sort | Jing Lei |
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| description | Abstract 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. |
| format | Article |
| id | doaj-art-b2c2014aca184901ae9bdeea364a7652 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-b2c2014aca184901ae9bdeea364a76522025-08-20T02:30:35ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202413128The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative ColitisJing Lei0Lin Lv1Li Zhong2Feng Xu3Wenhao Su4Yan Chen5Zhixuan Wu6Song He7Yongyu Chen8Department of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology Renmin Hospital of Wuhan University Hubei 430060 ChinaDepartment of Dermatovenereology Chengdu Second People's Hospital Sichuan 610011 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Gastroenterology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaAbstract 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.https://doi.org/10.1002/advs.202413128anti‐tumor necrosis factor therapyfusobacterium nucleatummicrobiotaNAD+ salvage pathwayulcerative colitis |
| spellingShingle | Jing Lei Lin Lv Li Zhong Feng Xu Wenhao Su Yan Chen Zhixuan Wu Song He Yongyu Chen The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis Advanced Science anti‐tumor necrosis factor therapy fusobacterium nucleatum microbiota NAD+ salvage pathway ulcerative colitis |
| title | The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis |
| title_full | The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis |
| title_fullStr | The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis |
| title_full_unstemmed | The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis |
| title_short | The Gut Microbiota Affects Anti‐TNF Responsiveness by Activating the NAD+ Salvage Pathway in Ulcerative Colitis |
| title_sort | gut microbiota affects anti tnf responsiveness by activating the nad salvage pathway in ulcerative colitis |
| topic | anti‐tumor necrosis factor therapy fusobacterium nucleatum microbiota NAD+ salvage pathway ulcerative colitis |
| url | https://doi.org/10.1002/advs.202413128 |
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