{"title":"脂质积累抑制策略可减轻核梭杆菌感染的结直肠癌。","authors":"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","doi":"10.1186/s40168-025-02133-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18447,"journal":{"name":"Microbiome","volume":"13 1","pages":"181"},"PeriodicalIF":12.7000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326762/pdf/","citationCount":"0","resultStr":"{\"title\":\"Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer.\",\"authors\":\"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\",\"doi\":\"10.1186/s40168-025-02133-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":18447,\"journal\":{\"name\":\"Microbiome\",\"volume\":\"13 1\",\"pages\":\"181\"},\"PeriodicalIF\":12.7000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326762/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Microbiome\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s40168-025-02133-7\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microbiome","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s40168-025-02133-7","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：核梭杆菌（Fusobacterium nucleatum， F. nucleatum）在结直肠癌（colorectal cancer， CRC）中普遍存在，它可以通过多种途径促进增殖并诱导化疗耐药。研究核梭菌感染结直肠癌的治疗策略具有重要意义。方法：对人粪便进行鸟枪宏基因组和代谢组学分析，对人血液进行代谢组学分析，揭示结直肠癌患者的生态失调和代谢失调。此外，在体外和体内研究了动物双歧杆菌（B. animalis）对具核双歧杆菌和结直肠癌的作用。采用小鼠结直肠癌模型，通过大肠杆菌（E. coli）的异源表达，验证了BSH在动物双歧杆菌（B. animalis）中的功能。通过胆汁酸和药物文库筛选实验对具核梭菌的抑制作用和肿瘤的增殖进行了研究。结果：我们在结直肠癌患者中发现了核梭菌的增加、脂质代谢物的富集和双歧杆菌的减少。此外，动物双歧杆菌以酸依赖的方式抑制核梭菌和结直肠癌细胞的生长，并减少核梭菌诱导的小鼠肿瘤增加。在机制上，核仁梭菌引起脂质积累，加剧炎症和肠屏障破坏，而动物梭菌减轻了这些变化，增加了辛普森多样性指数，减少了脂质代谢物，改变了小鼠的次级胆汁酸组成。此外，大肠杆菌bsh和熊去氧胆酸（UDCA）抑制F. nucleatum诱导的脂质积累和FASN/CPT1/NF-κB上调。此外，它们还能在体内减轻与核梭菌相关的肠道肿瘤发生。针对核胞梭菌感染的结直肠癌细胞和小鼠皮下肿瘤，喷氟利多或奥利司他与5-FU联合使用比单独使用5-FU具有更好的抑制效果。结论：结直肠癌患者中核仁梭菌和脂质代谢物富集。此外，表达bsh的大肠杆菌、UDCA和戊氟利多可以减轻核梭菌诱导的小鼠脂质积累和肿瘤生长。视频摘要。
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.
期刊介绍：
Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.
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