Chao Xu, Lei Zhang, Hongqin Liu, Ziwei Wang, Dechuan Li, Weidong Du, Lu Xu, Haitao Chen, Bo Zhang, Haixing Ju, Qinghua Yao
Department of Integrated Chinese and Western Medicine, Cancer Hospital of the University of Chinese Academy of Sciences (CHUCAS, Zhejiang Cancer Hospital), Hangzhou, 310022, China.
Department of Thoracic Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (CHUCAS, Zhejiang Cancer Hospital), Hangzhou, 310022, China.
Clin Nutr. 2022 Mar;41(3):632-644. doi: 10.1016/j.clnu.2022.01.001. Epub 2022 Jan 10.
Malnutrition has been confirmed to play an important role in colorectal cancer (CRC) progression via the gut microenvironment. However, the characteristics of the gut microbiota or its potential biological mechanism in CRC remain inconclusive.
In this work, Patient-Generated Subjective Global Assessment (PG-SGA) tool and 16sRNA sequencing were prepared to detect the variation in gut microbiota and the association between nutrition status and gut microbiota. RDA/CCA analysis was used to evaluate the relationship between faecal microbiota from malnourished CRC and clinical nutrition indicators. To investigate the mechanism of the gut microbiota in CRC, faecal samples from malnourished CRC patients were transplanted into C57BL/6J and DSS/AOM mouse models. Moreover, FACS and IHC were prepared to detect the infiltration of B cells and macrophages. qPCR and Elisa assays were performed to explore the expression of cytokines.
We found dramatic variation in the faecal microbiota among patients with different nutritional statuses, discovering that specific microbiota species, namely, Atopobium vaginae, Selenomonas sputigena and Faecalibacterium prausnitzii, may be considered diagnostic biomarkers in malnutrition and indicate poor prognosis. High expression level of A. vaginae in CRC tissues revealed the poorer overall survival compared with low expression level (Mean survival: 23.0 months vs 29.0 months). Faecal from malnourished colorectal cancer were found to be protumorigenic. More importantly, our evidence suggests that after faecal microbiota transplantation, B cells and macrophages are recruited to activate specific tumour immunity in CRC. Depletion of B cells significantly suppressed faecal microbiota-induced M2b polarization as well as the protumorigenic activity of tumour-associated macrophages in vivo.
Faecal microbiota in CRC under malnutrition conditions exhibits specific characteristics that accelerate CRC progression and regulate B cells and macrophages. The use of specific faecal microbial species could be a feasible approach for identifying the malnutrition status of patients and demonstrating the poor prognosis of CRC.
营养不良已被证实在通过肠道微环境促进结直肠癌（CRC）进展中发挥重要作用。然而，CRC中肠道微生物群的特征或其潜在生物学机制仍无定论。
在本研究中，采用患者主观整体评定法（PG-SGA）工具和16sRNA测序来检测肠道微生物群的变化以及营养状况与肠道微生物群之间的关联。利用冗余分析/典范对应分析（RDA/CCA）评估营养不良CRC患者粪便微生物群与临床营养指标之间的关系。为了探究肠道微生物群在CRC中的作用机制，将营养不良CRC患者的粪便样本移植到C57BL/6J和葡聚糖硫酸钠/氧化偶氮甲烷（DSS/AOM）小鼠模型中。此外，采用荧光激活细胞分选术（FACS）和免疫组化（IHC）检测B细胞和巨噬细胞的浸润情况。通过实时定量聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）检测细胞因子的表达。
我们发现不同营养状况患者的粪便微生物群存在显著差异，发现特定的微生物种类，即阴道阿托波菌、生痰月形单胞菌和普拉梭菌，可能被视为营养不良的诊断生物标志物，并预示预后不良。CRC组织中阴道阿托波菌的高表达水平显示与低表达水平相比总体生存率更低（平均生存期：23.0个月对29.0个月）。发现营养不良结直肠癌患者的粪便具有促肿瘤作用。更重要的是，我们的证据表明，粪便微生物群移植后，B细胞和巨噬细胞被募集以激活CRC中的特异性肿瘤免疫。B细胞的耗竭显著抑制了粪便微生物群诱导的M2b极化以及体内肿瘤相关巨噬细胞的促肿瘤活性。
营养不良条件下CRC中的粪便微生物群表现出加速CRC进展并调节B细胞和巨噬细胞的特定特征。使用特定的粪便微生物种类可能是识别患者营养不良状态并证明CRC预后不良的一种可行方法。
