Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer
Abstract Background Fusobacterium nucleatum (F. nucleatum) is prevalent in colorectal cancer (CRC), and it can promote proliferation and induce chemoresistance via multiple pathways. The development of treatment strategies for F. nucleatum-infected CRC is of great importance. Methods Shotgun metagen...
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BMC
2025-08-01
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| Series: | Microbiome |
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| Online Access: | https://doi.org/10.1186/s40168-025-02133-7 |
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| author | Zhongkun Zhou Yuqing Niu Yunhao Ma Dekui Zhang Yiqing Wang Rui Ji Jianfang Zhao Chi Ma Hongmei Zhu Yingqian Liu Lixue Tu Juan Lu Baizhuo Zhang Hua Zhang Xin Ma Peng Chen |
| author_facet | Zhongkun Zhou Yuqing Niu Yunhao Ma Dekui Zhang Yiqing Wang Rui Ji Jianfang Zhao Chi Ma Hongmei Zhu Yingqian Liu Lixue Tu Juan Lu Baizhuo Zhang Hua Zhang Xin Ma Peng Chen |
| author_sort | Zhongkun Zhou |
| collection | DOAJ |
| description | Abstract Background Fusobacterium nucleatum (F. nucleatum) is prevalent in colorectal cancer (CRC), and it can promote proliferation and induce chemoresistance via multiple pathways. The development of treatment strategies for F. nucleatum-infected CRC is of great importance. Methods Shotgun metagenomic and metabolomic analyses of human feces, as well as metabolomic analysis of human blood, were performed to reveal the dysbiosis and metabolic dysregulation in CRC. Furthermore, the effects of Bifidobacterium animalis (B. animalis) on F. nucleatum and CRC were assessed in vitro and in vivo. Using a mouse CRC model, the function of bile salt hydrolase (BSH) in B. animalis was verified through heterologous expression in Escherichia coli (E. coli). Bile acids and drug library screening experiments were performed to inhibit F. nucleatum and tumor proliferation. Results We identified an increase in F. nucleatum, enrichment of lipid metabolites, and depletion of Bifidobacterium in CRC patients. Furthermore, B. animalis inhibited F. nucleatum and CRC cells growth in an acid-dependent manner and reduced F. nucleatum-induced tumor increasement in mice. Mechanistically, F. nucleatum caused lipid accumulation, exacerbated inflammation, and intestinal barrier disruption, whereas B. animalis alleviated these changes, increased the Simpson diversity index, reduced lipid metabolites, and altered secondary bile acid composition in mice. Moreover, E. coli-BSH and ursodeoxycholic acid (UDCA) inhibited F. nucleatum-induced lipid accumulation and FASN/CPT1/NF-κB upregulation. Additionally, they alleviated F. nucleatum-related intestinal tumorigenesis in vivo. Targeting F. nucleatum-infected CRC cells and subcutaneous tumors in mice, penfluridol or the combination of orlistat and 5-FU exhibited superior inhibitory effects compared to 5-FU alone. Conclusions F. nucleatum and lipid metabolites are enriched in CRC patients. Furthermore, BSH-expressing E. coli, UDCA, and penfluridol can alleviate F. nucleatum-induced lipid accumulation and tumor growth in mice. Video Abstract Graphical Abstract |
| format | Article |
| id | doaj-art-9fdab5a8f88c42bebfee7c864fb715ad |
| institution | Kabale University |
| issn | 2049-2618 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj-art-9fdab5a8f88c42bebfee7c864fb715ad2025-08-20T03:43:14ZengBMCMicrobiome2049-26182025-08-0113112110.1186/s40168-025-02133-7Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancerZhongkun Zhou0Yuqing Niu1Yunhao Ma2Dekui Zhang3Yiqing Wang4Rui Ji5Jianfang Zhao6Chi Ma7Hongmei Zhu8Yingqian Liu9Lixue Tu10Juan Lu11Baizhuo Zhang12Hua Zhang13Xin Ma14Peng Chen15School of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversityThe Second Hospital of Lanzhou UniversityThe First Hospital of Lanzhou UniversityThe First Hospital of Lanzhou UniversityThe Third People‘s Hospital of Gansu ProvinceThe Second Hospital of Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversityAbstract Background Fusobacterium nucleatum (F. nucleatum) is prevalent in colorectal cancer (CRC), and it can promote proliferation and induce chemoresistance via multiple pathways. The development of treatment strategies for F. nucleatum-infected CRC is of great importance. Methods Shotgun metagenomic and metabolomic analyses of human feces, as well as metabolomic analysis of human blood, were performed to reveal the dysbiosis and metabolic dysregulation in CRC. Furthermore, the effects of Bifidobacterium animalis (B. animalis) on F. nucleatum and CRC were assessed in vitro and in vivo. Using a mouse CRC model, the function of bile salt hydrolase (BSH) in B. animalis was verified through heterologous expression in Escherichia coli (E. coli). Bile acids and drug library screening experiments were performed to inhibit F. nucleatum and tumor proliferation. Results We identified an increase in F. nucleatum, enrichment of lipid metabolites, and depletion of Bifidobacterium in CRC patients. Furthermore, B. animalis inhibited F. nucleatum and CRC cells growth in an acid-dependent manner and reduced F. nucleatum-induced tumor increasement in mice. Mechanistically, F. nucleatum caused lipid accumulation, exacerbated inflammation, and intestinal barrier disruption, whereas B. animalis alleviated these changes, increased the Simpson diversity index, reduced lipid metabolites, and altered secondary bile acid composition in mice. Moreover, E. coli-BSH and ursodeoxycholic acid (UDCA) inhibited F. nucleatum-induced lipid accumulation and FASN/CPT1/NF-κB upregulation. Additionally, they alleviated F. nucleatum-related intestinal tumorigenesis in vivo. Targeting F. nucleatum-infected CRC cells and subcutaneous tumors in mice, penfluridol or the combination of orlistat and 5-FU exhibited superior inhibitory effects compared to 5-FU alone. Conclusions F. nucleatum and lipid metabolites are enriched in CRC patients. Furthermore, BSH-expressing E. coli, UDCA, and penfluridol can alleviate F. nucleatum-induced lipid accumulation and tumor growth in mice. Video Abstract Graphical Abstracthttps://doi.org/10.1186/s40168-025-02133-7Colorectal cancerMultiomicsF. nucleatumLipid accumulationBile acidDrug rediscovery |
| spellingShingle | Zhongkun Zhou Yuqing Niu Yunhao Ma Dekui Zhang Yiqing Wang Rui Ji Jianfang Zhao Chi Ma Hongmei Zhu Yingqian Liu Lixue Tu Juan Lu Baizhuo Zhang Hua Zhang Xin Ma Peng Chen Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer Microbiome Colorectal cancer Multiomics F. nucleatum Lipid accumulation Bile acid Drug rediscovery |
| title | Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer |
| title_full | Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer |
| title_fullStr | Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer |
| title_full_unstemmed | Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer |
| title_short | Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer |
| title_sort | lipid accumulation inhibition strategies alleviate fusobacterium nucleatum infected colorectal cancer |
| topic | Colorectal cancer Multiomics F. nucleatum Lipid accumulation Bile acid Drug rediscovery |
| url | https://doi.org/10.1186/s40168-025-02133-7 |
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