Department of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Medicine and Therapeutics, Faculty of Medicine, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
EBioMedicine. 2023 Jul;93:104670. doi: 10.1016/j.ebiom.2023.104670. Epub 2023 Jun 19.
Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown.
Azoxymethane (AOM)-treated, Apc and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated.
Conventional AOM-treated and Apc mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth.
Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC.
This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).
肥胖是结直肠癌（CRC）的一个风险因素。肠道微生物群在介导肥胖促进癌症的作用方面的作用尚不清楚。
用偶氮甲烷（AOM）处理、Apc 和无菌小鼠分别用肥胖个体和对照个体的粪便灌胃。在两种致癌模型的终点记录结肠肿瘤负荷和数量。通过宏基因组测序和 RNA 测序分别评估肠道微生物群组成和结肠转录组。验证了从肥胖个体粪便中耗尽的细菌的抗癌作用。
接受肥胖个体粪便的常规 AOM 处理和 Apc 小鼠与接受对照个体粪便的小鼠相比，结肠肿瘤形成明显增加。接受肥胖个体粪便的 AOM 处理小鼠表现出肠道屏障功能受损和促炎细胞因子的显著上调以及致癌 Wnt 信号通路的激活。同样，将肥胖个体的粪便转移到无菌小鼠中会导致结肠细胞增殖增加、肠道屏障功能受损以及致癌和促炎基因表达的诱导。此外，与接受来自正常体重指数（BMI）人类供体的粪便的无菌小鼠相比，接受来自肥胖人类供体粪便的无菌小鼠的潜在条件致病菌 Alistipes finegoldii 的丰度增加，而共生菌 Bacteroides vulgatus 和 Akkermansia muciniphila 的丰度降低。验证实验表明，Bacteroides vulgatus 和 Akkermansia muciniphila 在 CRC 中表现出抗增殖作用，而 Alistipes finegoldii 则促进 CRC 肿瘤生长。
我们的结果支持肥胖相关微生物群在结直肠致癌中的作用，并确定了可能介导其机制的潜在细菌候选物。肥胖个体的微生物群调节可能为预防或治疗包括 CRC 在内的肥胖相关癌症提供新的方法。
这项工作得到了中国国家重点研发计划（2020YFA0509200/2020YFA0509203）、国家自然科学基金（81922082）、香港研究资助局主题研究计划（T21-705/20-N）、香港研究资助局研究影响基金（R4632-21F）、香港研究资助局合作研究基金（C4039-19GF 和 C7065-18GF）、香港研究资助局研究生奖学金（14110819、14111621）和 NTU 启动资金（021337-00001）的支持。
