美国弗雷德哈钦森癌症中心Christopher D. Johnston和Susan Bullman共同合作，近期取得重要工作进展。他们研究提出，一个独特的核杆菌分枝在结直肠癌生态位中占主导地位，相关研究成果2024年3月20日在线发表于《自然》杂志上。

据介绍，核杆菌（Fn）是一种存在于人类口腔中的细菌，很少在健康人的下消化道中发现，在人类结直肠癌（CRC）肿瘤中富集。肿瘤内高Fn负荷与复发、转移和较差的患者预后相关。

研究人员描述促进肿瘤定植的Fn遗传因子，生成了135个Fn菌株的封闭基因组；来自无癌症个体的80种口服菌株和来自51名CRC患者的肿瘤培养的55种独特的癌症菌株。全基因组分析鉴定了483个富含CRC的遗传因子。肿瘤分离株主要属于Fn亚种动物（Fna）。

然而，基因组分析显示，被认为是单一亚种的Fna实际上是由两个不同的分支(Fna C1和Fna C2)组成的。其中，只有Fna C2在CRC肿瘤生态位中占主导地位。Inter-Fna分析确定了195个与Fna c2相关的遗传因素，这些遗传因素与胃肠道代谢潜力和定植的增加一致。Fna C2治疗的小鼠的肠腺瘤数量增加，代谢产物发生改变也证明了这一点。116名CRC患者肿瘤组织的微生物组分析显示Fna C2富集。对62个配对标本的比较显示，与正常邻近组织相比，只有Fna C2是肿瘤富集的。627名CRC患者和619名健康人的粪便样本的宏基因组分析进一步支持了这一点。

总之，这一研究结果确定了Fna分支的分支，表明Fna C2特异性地驱动了报道的Fn在人类CRC中的富集，并揭示了Fna C2对CRC生态位的病理适应的遗传基础。

附： 英文原文

Title: A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche

Author: Zepeda-Rivera, Martha, Minot, Samuel S., Bouzek, Heather, Wu, Hanrui, Blanco-Mguez, Aitor, Manghi, Paolo, Jones, Dakota S., LaCourse, Kaitlyn D., Wu, Ying, McMahon, Elsa F., Park, Soon-Nang, Lim, Yun K., Kempchinsky, Andrew G., Willis, Amy D., Cotton, Sean L., Yost, Susan C., Sicinska, Ewa, Kook, Joong-Ki, Dewhirst, Floyd E., Segata, Nicola, Bullman, Susan, Johnston, Christopher D.

Issue&Volume: 2024-03-20

Abstract: Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals1, is enriched in human colorectal cancer (CRC) tumours2,3,4,5. High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis5,6,7,8. Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche.

DOI: 10.1038/s41586-024-07182-w

Source: https://www.nature.com/articles/s41586-024-07182-w