美国大样本长期随访发现：肠道菌群、饮食模式与结直肠癌风险相关

JAMA Oncology

　　2017年1月26日，《美国医学会杂志肿瘤学分册》在线发表哈佛医学院、麻省总医院、布莱根女子医院、哈佛大学与麻省理工学院联合研究所、哈佛陈曾熙公共卫生学院、达纳法伯癌症研究所、西蒙斯学院的大样本长期随访报告，发现人体肠道菌群可能对饮食模式与特定类型结直肠癌风险的相关性起到关键桥梁作用。

　　该前瞻队列研究对两项大样本人群调查的173229位成人随访长达26～32年，并检测了其中结直肠癌患者的肿瘤标本具核梭杆菌。具核梭杆菌是寄居于人类肠道的常见细菌，同时也被认为在结直肠癌发生过程中发挥关键作用。

　　上述两项大样本人群调查均以白人为主，分别为：

• 护士健康研究（NHS）：1980年6月1日～2012年6月1日，随访32年，121700位30～55岁女性护士

• 医生随访研究（HPFS）：1986年6月1日～2012年6月1日，随访26年，51529位40～75岁男性医生

　　26～32年随访期间共发生1019例结直肠癌并获得具核梭杆菌数据。

　　2015年3月15日～2016年8月10日，研究者对其中符合要求的137217位成人（男性47449位，占34.6%，入组时平均年龄54.0±9.8岁；其余为女性，46.3±7.2岁）进行饮食分析。

　　结果发现，谨慎饮食者（全谷物、膳食纤维为主）与西方饮食者（红色和加工肉类、精制谷物、甜点为主）的结直肠癌风险，与具核梭杆菌水平有显著相关性（异质性分析P值：0.01）。

• 根据谨慎饮食评分，最高与最低四分位数相比，具核梭杆菌阳性的结直肠癌风险显著减少57%，阴性仅减少5%（趋势分析P值分别为：0.003、0.47，多变量风险比：0.43、0.95，95%置信区间：0.25～0.72、0.77～1.17）。

• 根据西方饮食评分，各个亚组之间，结直肠癌风险无显著差异。

　　因此，谨慎饮食能够减少具核梭杆菌阳性的结直肠癌风险。虽然该研究仅针对一种细菌，但是却指向更为广泛的现象，即肠道细菌能够与饮食模式相互作用，减少或增加某些结直肠癌的风险。

　　该研究数据首次在人类体内研究获得，阐明了长期饮食模式与肿瘤组织细菌水平之间的关系，同时也验证了早期研究的发现。既往研究发现，动物体内肠道细菌能够直接诱发癌症。动物实验研究结果表明，具核梭杆菌可能通过干扰机体免疫系统、激活结肠细胞生长通路，促进结直肠癌发生；当饮食模式从高纤维的谨慎饮食转变到低纤维的西方饮食后，粪便具核梭杆菌水平显著增加，就理论而言，谨慎饮食与结直肠癌风险减少之间的相关性，在具核梭杆菌阳性肿瘤中更为显著。

　　该研究结果表明，谨慎饮食者的具核梭杆菌阳性结直肠癌风险较低，但是具核梭杆菌阴性结直肠癌风险区别不大。该研究提出明显证据表明饮食能够通过影响肠道菌群水平，间接影响特殊类型结直肠癌的风险。

　　该研究对于开发治疗癌症的新型疗法提供了新的研究思路和线索，有必要开展进一步研究阐明饮食模式、肠道菌群、癌症风险三者之间的复杂相关性，

JAMA Oncol. 2017 Jan 26. [Epub ahead of print]

Association of Dietary Patterns With Risk of Colorectal Cancer Subtypes Classified by Fusobacterium Nucleatum in Tumor Tissue.

Mehta RS, Nishihara R, Cao Y, Song M, Mima K, Qian ZR, Nowak JA, Kosumi K, Hamada T, Masugi Y, Bullman S, Drew DA, Kostic AD, Fung TT, Garrett WS, Huttenhower C, Wu K, Meyerhardt JA, Zhang X, Willett WC, Giovannucci EL, Fuchs CS, Chan AT, Ogino S.

Massachusetts General Hospital and Harvard Medical School, Boston; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge; Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Simmons College, Boston, Massachusetts.

KEY POINTS

QUESTION: Does the association between prudent diets (rich in whole grains and dietary fiber) and risk of colorectal cancer vary by presence of the bacterial species Fusobacterium nucleatum in tumor tissue?

FINDINGS: In this cohort study of 137,217 adults, the association of a prudent diet with colorectal cancer was more evident for a cancer subgroup enriched with tumor F nucleatum than a subgroup without detectable tumor F nucleatum.

MEANING: There may be a potential role for intestinal microbiota, such as F nucleatum, in mediating the complex association between diet and the development of colorectal cancer.

ABSTRACT

IMPORTANCE: Fusobacterium nucleatum appears to play a role in colorectal carcinogenesis through suppression of the hosts' immune response to tumor. Evidence also suggests that diet influences intestinal F nucleatum. However, the role of F nucleatum in mediating the relationship between diet and the risk of colorectal cancer is unknown.

OBJECTIVE: To test the hypothesis that the associations of prudent diets (rich in whole grains and dietary fiber) and Western diets (rich in red and processed meat, refined grains, and desserts) with colorectal cancer risk may differ according to the presence of F nucleatum in tumor tissue.

DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted using data from the Nurses' Health Study (June 1, 1980, to June 1, 2012) and the Health Professionals Follow-up Study (June 1, 1986, to June 1, 2012) on a total of 121,700 US female nurses and 51,529 US male health professionals aged 30 to 55 years and 40 to 75 years, respectively (both predominantly white individuals), at enrollment. Data analysis was performed from March 15, 2015, to August 10, 2016.

EXPOSURES: Prudent and Western diets.

MAIN OUTCOMES AND MEASURES: Incidence of colorectal carcinoma subclassified by F nucleatum status in tumor tissue, determined by quantitative polymerase chain reaction.

RESULTS: Of the 173,229 individuals considered for the study, 137,217 were included in the analysis, 47,449 were male (34.6%), and mean (SD) baseline age for men was 54.0 (9.8) years and for women, 46.3 (7.2) years. A total of 1019 incident colon and rectal cancer cases with available F nucleatum data were documented over 26 to 32 years of follow-up, encompassing 3,643,562 person-years. The association of prudent diet with colorectal cancer significantly differed by tissue F nucleatum status (P = .01 for heterogeneity); prudent diet score was associated with a lower risk of F nucleatum-positive cancers (P = .003 for trend; multivariable hazard ratio of 0.43; 95% CI, 0.25-0.72, for the highest vs the lowest prudent score quartile) but not with F nucleatum-negative cancers (P = .47 for trend, the corresponding multivariable hazard ratio of 0.95; 95% CI, 0.77-1.17). There was no significant heterogeneity between the subgroups in relation to Western dietary pattern scores.

CONCLUSIONS AND RELEVANCE: Prudent diets rich in whole grains and dietary fiber are associated with a lower risk for F nucleatum-positive colorectal cancer but not F nucleatum-negative cancer, supporting a potential role for intestinal microbiota in mediating the association between diet and colorectal neoplasms.

PMID: 28125762

DOI: 10.1001/jamaoncol.2016.6374