Dysbiotic oral microbiota-derived kynurenine, induced by chronic restraint stress, promotes head and neck squamous cell carcinoma by enhancing CD8+ T cell exhaustion.

IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Pub Date : 2025-02-04 DOI:10.1136/gutjnl-2024-333479
Fangzhi Lou, Li Yan, Shihong Luo, Yunmei Dong, Jingyi Xu, Ning Kang, Haiyang Wang, Yiyun Liu, Juncai Pu, Bing Yang, Richard D Cannon, Peng Xie, Ping Ji, Xin Jin
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Abstract

Background: Chronic restraint stress (CRS) is a tumour-promoting factor. However, the underlying mechanism is unknown.

Objective: We aimed to investigate whether CRS promotes head and neck squamous cell carcinoma (HNSCC) by altering the oral microbiota and related metabolites and whether kynurenine (Kyn) promotes HNSCC by modulating CD8+ T cells.

Design: 4-nitroquinoline-1-oxide (4NQO)-treated mice were exposed to CRS. Germ-free mice treated with 4NQO received oral microbiota transplants from either CRS or control mouse donors. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were performed on mouse saliva, faecal and plasma samples to investigate alterations in their microbiota and metabolites. The effects of Kyn on HNSCC were studied using the 4NQO-induced HNSCC mouse model.

Results: Mice subjected to CRS demonstrated a higher incidence of HNSCC and oral microbial dysbiosis than CRS-free control mice. Pseudomonas and Veillonella species were enriched while certain oral bacteria, including Corynebacterium and Staphylococcus species, were depleted with CRS exposure. Furthermore, CRS-altered oral microbiota promoted HNSCC formation, caused oral and gut barrier dysfunction, and induced a host metabolome shift with increased plasma Kyn in germ-free mice exposed to 4NQO treatment. Under stress conditions, we also found that Kyn activated aryl hydrocarbon receptor (AhR) nuclear translocation and deubiquitination in tumour-reactive CD8+ T cells, thereby promoting HNSCC tumourigenesis.

Conclusion: CRS-induced oral microbiota dysbiosis plays a protumourigenic role in HNSCC and can influence host metabolism. Mechanistically, under stress conditions, Kyn promotes CD8+ T cell exhaustion and HNSCC tumourigenesis through stabilising AhR by its deubiquitination.

慢性约束应激诱导的口腔微生物源性犬尿氨酸通过增强CD8+ T细胞耗竭促进头颈部鳞状细胞癌。
背景:慢性抑制应激(CRS)是一种促肿瘤因子。然而,其潜在机制尚不清楚。目的:探讨CRS是否通过改变口腔微生物群及相关代谢物促进头颈部鳞状细胞癌(HNSCC)的发生,以及犬尿氨酸(Kyn)是否通过调节CD8+ T细胞促进HNSCC的发生。设计:4-硝基喹啉-1-氧化物(4NQO)处理小鼠暴露于CRS。用4NQO处理的无菌小鼠接受来自CRS或对照小鼠供体的口腔微生物群移植。对小鼠唾液、粪便和血浆样品进行16S rRNA基因测序和液相色谱-质谱分析,研究其微生物群和代谢物的变化。采用4nqo诱导的HNSCC小鼠模型,研究Kyn对HNSCC的影响。结果:与无CRS对照小鼠相比,CRS小鼠HNSCC和口腔微生物失调的发生率更高。假单胞菌和细孔菌种类丰富,而某些口腔细菌,包括棒状杆菌和葡萄球菌种类,在CRS暴露下减少。此外,在4NQO处理的无菌小鼠中,crs改变的口腔微生物群促进了HNSCC的形成,引起口腔和肠道屏障功能障碍,并诱导宿主代谢组变化,增加血浆Kyn。在应激条件下,我们还发现Kyn在肿瘤反应性CD8+ T细胞中激活芳烃受体(AhR)核易位和去泛素化,从而促进HNSCC的肿瘤发生。结论:crs诱导的口腔微生物群失调在HNSCC中具有产蛋白作用,并可影响宿主代谢。在机制上,在应激条件下,Kyn通过其去泛素化稳定AhR,促进CD8+ T细胞衰竭和HNSCC肿瘤发生。
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来源期刊
Gut
Gut 医学-胃肠肝病学
CiteScore
45.70
自引率
2.40%
发文量
284
审稿时长
1.5 months
期刊介绍: Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
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