PO.PR02.03 · 预防研究
高红肉饮食通过肠道菌群介导的Th17/Treg失衡促进结直肠肿瘤发生
High red meat diet promotes colorectal tumorigenesis via gut microbiota mediated Th17/Treg imbalance
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：过量摄入红肉和加工肉类是结直肠癌（CRC）的已知危险因素，但其潜在机制仍不明确。鉴于膳食成分会重塑肠道微生物生态和黏膜免疫，我们假设高红肉摄入通过破坏维持肠道稳态的菌群-免疫交互作用来促进CRC。
方法：给C57BL/6小鼠喂食等热量饮食，其中红肉来源蛋白质比例逐渐升高（20%、50%、100%），并与20%酪蛋白对照饮食比较。在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的小鼠模型和Apc Min/+小鼠模型中评估肿瘤发生，并辅以原位植入MC38-Luc的小鼠模型，以及AOM/DSS诱导的Lgr5 GFP-Slp-mCherry转基因小鼠——该小鼠经改造可示踪肠道干细胞（GFP+ mCherry-）和肿瘤微环境细胞（GFP- mCherry+）。对结肠肿瘤进行单细胞RNA测序以刻画免疫图谱的变化，同时对粪便样本进行宏基因组学和代谢组学分析，以描绘菌群及微生物代谢物特征。
结果：膳食红肉比例越高，结肠肿瘤负荷呈剂量依赖性显著增加。scRNA-seq显示T细胞环境逐渐向促炎方向转变，Th17/Treg比值不断升高：0.26（对照饮食）、0.44（20%红肉饮食）、0.61（50%红肉饮食）和0.71（100%红肉饮食）。在红肉喂养小鼠的肿瘤中，包括IL17A和RORγt在内的Th17转录特征以及IL-6/STAT3信号通路增强，与Th17应答的放大一致。宏基因组分析发现一个共生菌群“PFIO”的耗竭，该菌群由Parasutterella excrementihominis、Faecalibaculum rodentium、Ileibacterium valens和Oscillospiraceae物种组成，与短链脂肪酸合成和胆汁酸稳态相关。代谢组学数据证实短链脂肪酸（SCFA）和次级胆汁酸水平降低，与有利于Th17极化的炎性肠道环境一致。
结论：这些发现确立了一条菌群-Th17/Treg轴，从机制上将红肉摄入与结直肠肿瘤发生联系起来。产SCFA共生菌的耗竭放大了Th17优势，驱动促肿瘤炎症。通过治疗性恢复菌群组成或Th17/Treg平衡，可能为红肉饮食相关CRC提供预防策略。
查看英文原文 English abstract
Background: Excess red and processed meat consumption is a known risk factor for colorectal cancer (CRC), but the underlying mechanisms remain unclear. Given that dietary components reshape gut microbial ecology and mucosal immunity, we hypothesized that high red meat consumption promotes CRC by disrupting microbiota-immune crosstalk that maintains intestinal homeostasis.
Methods: The C57BL/6 mice were fed isocaloric diets with increasing proportions of red meat-derived protein (20%, 50%, 100%) compared with a 20% casein control. Tumorigenesis was assessed in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse and Apc Min/+ mouse models, complemented by orthotopic MC38-Luc-implantated mouse models as well as AOM/DSS-induced Lgr5 GFP-Slp-mCherry transgenic mouse engineered to trace intestinal stem cells (GFP + mCherry - ) and tumor microenvironmental cells (GFP - mCherry + ). Colonic tumors were subjected to single-cell RNA sequencing to delineate immune landscape shifts, while fecal samples were analyzed by metagenomics and metabolomics to profile microbiota and microbial metabolites.
Results: Higher dietary red meat led to significantly increased colonic tumor burden in a dose-dependent manner. scRNA-seq revealed a progressive shift toward a pro-inflammatory T cell milieu with escalating Th17/Treg ratios: 0.26 (control diet), 0.44 (20% red meat diet), 0.61 (50% red meat diet) and 0.71 (100% red meat diet) . Th17 transcriptional signature including IL17A and RORgammat as well as IL-6/STAT3 signaling was enhanced in tumors from red meat-fed mouse, consistent with amplified Th17 responses. Metagenomic profiling identified the depletion of a commensal consortium “PFIO” comprising Parasutterella excrementihominis , Faecalibaculum rodentium , Ileibacterium valens and Oscillospiraceae species linked to short-chain fatty acid synthesis and bile acid homeostasis. Metabolomic data confirmed reduced SCFA and secondary bile acids levels, consistent with an inflammatory gut environment conducive to Th17 polarization.
Conclusions: These findings define a microbiota-Th17/Treg axis that mechanistically links red meat consumption to colorectal tumorigenesis. Disruption of SCFA-producing commensals amplifies Th17 dominance, driving tumor-promoting inflammation. Therapeutically restoring microbiota composition or Th17/Treg balance may offer preventive strategies for red meat diet associated CRC.
利益披露 Disclosure
Y. Hu, None..
Y. Wei, None..
R. Song, None..
Y. Tang, None..
D. Pei, None..
Z. Dong, None.