BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism

IF 20.6 1区 医学 Q1 MICROBIOLOGY Cell host & microbe Pub Date : 2024-08-05 DOI:10.1016/j.chom.2024.07.012
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Abstract

Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.

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产生 BCAA 的共生梭菌通过调节宿主胆固醇代谢促进结直肠肿瘤发生
识别结直肠肿瘤发生过程中的潜在细菌一直是研究的重点。在本文中,我们发现共生梭菌(C. symbiosum)选择性地富集于结直肠癌(CRC)患者的肿瘤组织中,并与内镜息肉切除术后结直肠腺瘤复发率较高有关。在多种小鼠模型中都观察到了共生菌的致瘤效应。单细胞转录组分析和功能测试表明,共生草能促进结肠干细胞增殖并增强癌症干性。从机理上讲,共生草通过产生支链氨基酸(BCAAs)来加强细胞胆固醇合成,进而激活音速刺猬信号。低BCAA膳食摄入量或他汀类药物阻断胆固醇合成可部分缓解共生菌诱导的体内和体外细胞增殖。总之,我们揭示了共生菌是结直肠肿瘤发生的细菌驱动因素,从而确定了预测、预防和治疗结直肠肿瘤的潜在靶点。
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来源期刊
Cell host & microbe
Cell host & microbe 生物-微生物学
CiteScore
45.10
自引率
1.70%
发文量
201
审稿时长
4-8 weeks
期刊介绍: Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.
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