Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer.
Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer.
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DOI：
10.1038/s41467-023-36089-9
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发表时间：
2023-02-10
影响因子：
16.6
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Sun, Lulu;Zhang, Yi;Cai, Jie;Rimal, Bipin;Rocha, Edson R.;Coleman, James P.;Zhang, Chenran;Nichols, Robert G.;Luo, Yuhong;Kim, Bora;Chen, Yaozong;Krausz, Kristopher W.;Harris, Curtis C.;Patterson, Andrew D.;Zhang, Zhipeng;Takahashi, Shogo;Gonzalez, Frank J.
类杆菌中的胆盐水解酶（BSH）被认为是治疗肥胖相关代谢性疾病的潜在药物靶点，但其与结肠肿瘤发生的关系尚未得到研究。在超重的结直肠癌（CRC）患者的粪便和高脂饮食（HFD）诱导的CRC小鼠模型的粪便中发现了高丰度的表达FSH的拟杆菌。B的定殖。fragilis 638 R是一株BSH活性低的菌株，它能高效表达来自B的重组bsh基因。fragilis NCTC 9343菌株，导致结肠中未结合的胆汁酸增加，并加速HFD治疗下CRC的进展。在存在高BSH活性的情况下，未结合的脱氧胆酸和石胆酸的升高激活G蛋白偶联的胆汁酸受体，导致结肠肿瘤中β-连环蛋白调节的趋化因子（C-C基序）配体28（CCL 28）表达增加。β-连环蛋白/CCL 28轴的活化导致肿瘤内免疫抑制性CD 25 + FOXP 3 + Treg细胞升高。β-连环蛋白/CCL 28轴的阻断释放免疫抑制以增强肿瘤内抗肿瘤应答，这在HFD治疗下降低CRC进展。BSH的药理学抑制减少了HFD加速的CRC进展，与β-连环蛋白/CCL 28途径的抑制一致。这些研究结果为类杆菌在肥胖相关的CRC进展中的促癌作用提供了见解，并将BSH描述为CRC预防和治疗的潜在靶点。非肠促炎性脆弱拟杆菌（NTBF）在结直肠癌（CRC）患者和高脂饮食（HFD）诱导的CRC模型中大量存在。在此，作者表明表达胆盐水解酶的NTBF在超重的CRC患者中富集，并在HFD诱导的CRC小鼠模型中促进肿瘤生长。
Bile salt hydrolase (BSH) in Bacteroides is considered a potential drug target for obesity-related metabolic diseases, but its involvement in colon tumorigenesis has not been explored. BSH-expressing Bacteroides is found at high abundance in the stools of colorectal cancer (CRC) patients with overweight and in the feces of a high-fat diet (HFD)-induced CRC mouse model. Colonization of B. fragilis 638R, a strain with low BSH activity, overexpressing a recombinant bsh gene from B. fragilis NCTC9343 strain, results in increased unconjugated bile acids in the colon and accelerated progression of CRC under HFD treatment. In the presence of high BSH activity, the resultant elevation of unconjugated deoxycholic acid and lithocholic acid activates the G-protein-coupled bile acid receptor, resulting in increased β-catenin-regulated chemokine (C-C motif) ligand 28 (CCL28) expression in colon tumors. Activation of the β-catenin/CCL28 axis leads to elevated intra-tumoral immunosuppressive CD25+FOXP3+ Treg cells. Blockade of the β-catenin/CCL28 axis releases the immunosuppression to enhance the intra-tumoral anti-tumor response, which decreases CRC progression under HFD treatment. Pharmacological inhibition of BSH reduces HFD-accelerated CRC progression, coincident with suppression of the β-catenin/CCL28 pathway. These findings provide insights into the pro-carcinogenetic role of Bacteroides in obesity-related CRC progression and characterize BSH as a potential target for CRC prevention and treatment. Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.
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影响因子：
7.7
作者：
Beghini F;McIver LJ;Blanco-Míguez A;Dubois L;Asnicar F;Maharjan S;Mailyan A;Manghi P;Scholz M;Thomas AM;Valles-Colomer M;Weingart G;Zhang Y;Zolfo M;Huttenhower C;Franzosa EA;Segata N
通讯作者：
Segata N
影响因子：
24.5
作者：
Betts G;Jones E;Junaid S;El-Shanawany T;Scurr M;Mizen P;Kumar M;Jones S;Rees B;Williams G;Gallimore A;Godkin A
通讯作者：
Godkin A
影响因子：
29.4
作者：
Cao, Yingying;Wang, Zhenhua;Hong, Jie
通讯作者：
Hong, Jie
影响因子：
64.8
作者：
Clemente-Casares, Xavier;Blanco, Jesus;Santamaria, Pere
通讯作者：
Santamaria, Pere
影响因子：
15.5
作者：
Dai Z;Coker OO;Nakatsu G;Wu WKK;Zhao L;Chen Z;Chan FKL;Kristiansen K;Sung JJY;Wong SH;Yu J
通讯作者：
Yu J