Shi Zhuangzhuang, Li Min, Zhang Chen, Li Hongwen, Zhang Yue, Zhang Lei, Li Xin, Li Ling, Wang Xinhua, Fu Xiaorui, Sun Zhenchang, Zhang Xudong, Tian Li, Zhang Mingzhi, Chen Wei-Hua, Li Zhaoming
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Bioinformatics and Systems Biology, Huazhong University of Science and Technology, Wuhan, China.
Gut. 2025 Mar 6;74(4):557-570. doi: 10.1136/gutjnl-2024-333530.
Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.
To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL.
This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms.
We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of in NKTCL mouse models. Furthermore, culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1.
These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of to ameliorate this malignancy.
自然杀伤/T细胞淋巴瘤（NKTCL）是一种侵袭性很强的恶性肿瘤，预后很差，在影响疾病预后的决定因素方面仍存在认知空白。
描述肠道微生物群特征，并确定可改善NKTCL发展的潜在益生菌。
这项横断面研究采用鸟枪法宏基因组测序对两个中国NKTCL队列中的肠道微生物群进行分析，并在一个独立的韩国队列中进行验证。应用单变量和多变量Cox比例风险分析来评估已鉴定的标记物种与患者预后之间的关联。使用全面的体内和体外模型研究肿瘤抑制作用。此外，还采用代谢组学、RNA测序、染色质免疫沉淀测序、蛋白质免疫印迹分析、免疫组织化学和慢病毒介导的基因敲低系统来阐明潜在机制。
我们首次揭示了NKTCL患者存在明显的肠道微生物群失调，其显著特征是[具体物种]明显减少，这与患者较短的生存期密切相关。随后，我们在NKTCL小鼠模型中证实了[具体物种]的抗肿瘤特性。此外，[具体物种]培养上清液在抑制NKTCL细胞生长方面显示出显著效果。代谢组学分析表明丁酸盐是这些肿瘤抑制作用的关键代谢物，在三种人类NKTCL细胞系和多个荷瘤小鼠模型中得到验证。机制上，丁酸盐通过增强组蛋白乙酰化抑制Janus激酶-信号转导子和转录激活子途径的激活，促进细胞因子信号抑制因子1的表达。
这些发现揭示了NKTCL独特的肠道微生物群特征，并为利用[具体物种]的治疗潜力改善这种恶性肿瘤提供了新的视角。
