肠道菌群与结直肠癌

doi:10.3877/cma.j.issn.2095-3224.2021.01.005

近年来，肠道菌群在结直肠癌中的作用引起了广泛关注。越来越多的证据表明，肠道菌群与结直肠癌的发生、发展及治疗相关，潜在的致病菌和代谢标志物的发现将有助于结直肠癌的早期诊断和有效治疗。流行病学数据表明，不同地域人群结直肠癌发病率高低不一，西方化人群发病率普遍较高。西方化与非西方化人群有着不同的肠道菌群结构，因此考虑可能是饮食与环境差异等因素引起不同地域人群肠道菌群结构不同，一定程度上导致结直肠癌易感性的差异。为此，本文总结了不同地域/种族肠道菌群组成的特点以及与结直肠癌发生发展相关的肠道菌群及其代谢物，探讨肠道菌群在不同人群结直肠癌易感性中发挥的作用以及是否存在独立于地理来源的结直肠癌相关肠道菌群。

关键词: 结直肠肿瘤, 肠道菌群, 地域/种族, 饮食

In recent years, the influence of gut microbiome on colorectal cancer has been widely concerned. Growing body of evidence indicates that gut microbiome is associated with the development and treatment of colorectal cancer, and the discovery of potentially pathogenic microbiome and metabolic biomarkers will help to early diagnosis and effective treatment of colorectal cancer. According to epidemiological data, the incidence of colorectal cancer varies regionally and is generally higher in westernized populations. Meanwhile, the composition of gut microbiome also has differences between westernized and non-westernized populations. Therefore, it is considered that factors such as diet and environment may cause regional differences in the composition of gut microbiome, which ultimately leads to regional differences in colorectal cancer susceptibility in a way. To this end, in this review we summarize the composition of gut microbiome of different regional/ethnic groups, as well as gut microbiome and metabolites related to the occurrence and development of colorectal cancer, with the purpose to explore the role of gut microbiome in colorectal cancer susceptibility in different population and the existence of colorectal cancer related gut microbiome independent of geographical sources.

Key words: Colorectal neoplasms, Gut microbiome, Region/race, Diet

表1 不同地域/种族健康人群肠道菌群特征

作者，年份	地域/民族	生活方式	样本量（例）	测序方法	肠道菌群特征
Qin,et al,2010年^[13]	欧洲	工业化生活	124	16S rRNA	拟杆菌门和厚壁菌门丰度最高，核心菌群主要与复杂多糖的降解以及短链脂肪酸、必需氨基酸和维生素的合成有关
美国国立卫生研究院（NIH），2012年^[10]	美国	工业化生活	242	16S rRNA	门水平上，多以拟杆菌门为主，少数以厚壁菌门为主；属水平上，以拟杆菌属为主；普遍存在与生命基础代谢相关的“核心”通路，如核糖体转录和翻译等
De,et al,2010年^[14]	欧洲城镇儿童	工业化生活	15	16S rRNA	厚壁菌门和变形菌门丰度相对较高
De,et al,2010年^[14]	非洲农村儿童	传统农业生活	15	16S rRNA	放线菌门和拟杆菌门丰度相对较高；含碳水化合物和木聚糖降解菌如普氏菌属、Xylanibacter、丁酸弧菌属和特征性密螺旋体属；短链脂肪酸相关菌丰度较高，但双歧杆菌丰度较低
Yatsunenko,et al,2012年^[15]	美国	工业化生活	316	16S rRNA	肠道菌群多样性较低；富含单糖代谢
Yatsunenko,et al,2012年^[15]	非洲马拉维、南美洲委内瑞拉	传统农业生活	215	16S rRNA	两者间肠道菌群的差异明显小于二者与美国人群间的差异；富含淀粉酶等多糖代谢
Schnorr,et al,2014年^[16]；Rampelli,et al,2015年^[17]*	意大利	工业化生活	16；11*	16S rDNA；鸟枪法测序	物种丰富度和多样性较低；富含单糖如葡萄糖、半乳糖和蔗糖及外毒素代谢
Schnorr,et al,2014年^[16]；Rampelli,et al,2015年^[17]*	非洲坦桑尼亚哈扎族人	狩猎-采集生活	27	16S rDNA；鸟枪法测序	普氏菌属、密螺旋体和未分类的拟杆菌门细菌丰度较高，拟杆菌属丰度较低，未检测到双歧杆菌；富含短链脂肪酸代谢
Clemente, et al,2015年^[18]	亚诺马米印第安人	半游牧式的狩猎生活	34	16S rRNA	物种多样性高；普氏菌属丰度较高，拟杆菌属丰度较低
Obregon,et al, 2015年^[19]	美国	工业化生活	23	16S rRNA、鸟枪法测序	物种丰富度较低；以放线菌门为主
Obregon,et al, 2015年^[19]	秘鲁	狩猎-采集和传统农业生活	56	16S rRNA、鸟枪法测序	以变形菌门为主；可检测到不属于致病性分支的密螺旋体属
Martínez,et al, 2015年^[20]	美国	工业化生活	22	16S rRNA	与美国人群相比，新几内亚人群α多样性较高而β多样性较低
Martínez,et al, 2015年^[20]	新几内亚	传统农业生活	40	16S rRNA	与美国人群相比，新几内亚人群α多样性较高而β多样性较低
Dehingia,et al, 2015年^[21]	印度	传统农业生活	193	16S rDNA、下一代基因测序	参与碳水化合物代谢的普雷沃氏菌科、瘤胃菌科、毛螺菌科及真杆菌科丰度较高
Zhang,et al, 2015年^[22]	中国多个省份与民族	传统农业生活	314	16S rRNA	门水平上，以厚壁菌门、拟杆菌门、变形菌门和放线菌门为主；属水平上，考拉杆菌属丰度最高；9个“核心”菌属在人群中共享，均与短链脂肪酸产生相关
Gomez,et al,2016年^[23]	俾格米人	狩猎-采集生活	28	16S rRNA	普雷沃氏菌科、密螺旋体属和梭菌科丰度较高
Gomez,et al,2016年^[23]	班图人	传统农业生活	29	16S rRNA	以厚壁菌门为主；糖和外源性物质代谢富集
Deschasaux,et al,2018年^[24]	荷兰阿姆斯特丹六个最大的民族	工业化生活	2 084	16S rRNA	门水平上，厚壁菌门丰度最高，其次为拟杆菌们；属水平上，普氏菌属、粪杆菌属、拟杆菌属丰度最高，其中摩洛哥人、土耳其人、加纳人的肠道菌群以普氏菌属为主，非洲苏里南人、南亚苏里南人以拟杆菌属为主，而丹麦人则以梭菌目为主
Liao,et al,2018年^[25]	居住在同一地区的瑶族、壮族和汉族人群	传统农业生活	47名汉族、28名壮族和59名瑶族成人	16S rDNA	拟杆菌属和普氏菌属在三个人群中丰度最高，其中巨单胞菌属和琥珀酸弧菌属分别是汉族和瑶族人群的特征性菌属
He,et al,2018年^[26]	中国广东地区	传统农业生活	7 009	下一代基因测序	拟杆菌门、厚壁菌门和变形菌门丰度最高
Ayeni,et al,2018年^[27]	非洲城镇尼日利亚	工业化生活	30	16S rRNA	拟杆菌属、双歧杆菌和粪杆菌属等丰度相对较高
Ayeni,et al,2018年^[27]	非洲农村巴萨	传统农业生活	18	16S rRNA	个体间差异相对较小；以纤维消化功能为主的细菌如普氏菌属、密螺旋体菌属、琥珀酸弧菌属、杆菌属和丁酸弧菌属等丰度较高

表1 不同地域/种族健康人群肠道菌群特征

作者，年份	地域/民族	生活方式	样本量（例）	测序方法	肠道菌群特征
Qin,et al,2010年^[13]	欧洲	工业化生活	124	16S rRNA	拟杆菌门和厚壁菌门丰度最高，核心菌群主要与复杂多糖的降解以及短链脂肪酸、必需氨基酸和维生素的合成有关
美国国立卫生研究院（NIH），2012年^[10]	美国	工业化生活	242	16S rRNA	门水平上，多以拟杆菌门为主，少数以厚壁菌门为主；属水平上，以拟杆菌属为主；普遍存在与生命基础代谢相关的“核心”通路，如核糖体转录和翻译等
De,et al,2010年^[14]	欧洲城镇儿童	工业化生活	15	16S rRNA	厚壁菌门和变形菌门丰度相对较高
De,et al,2010年^[14]	非洲农村儿童	传统农业生活	15	16S rRNA	放线菌门和拟杆菌门丰度相对较高；含碳水化合物和木聚糖降解菌如普氏菌属、Xylanibacter、丁酸弧菌属和特征性密螺旋体属；短链脂肪酸相关菌丰度较高，但双歧杆菌丰度较低
Yatsunenko,et al,2012年^[15]	美国	工业化生活	316	16S rRNA	肠道菌群多样性较低；富含单糖代谢
Yatsunenko,et al,2012年^[15]	非洲马拉维、南美洲委内瑞拉	传统农业生活	215	16S rRNA	两者间肠道菌群的差异明显小于二者与美国人群间的差异；富含淀粉酶等多糖代谢
Schnorr,et al,2014年^[16]；Rampelli,et al,2015年^[17]*	意大利	工业化生活	16；11*	16S rDNA；鸟枪法测序	物种丰富度和多样性较低；富含单糖如葡萄糖、半乳糖和蔗糖及外毒素代谢
Schnorr,et al,2014年^[16]；Rampelli,et al,2015年^[17]*	非洲坦桑尼亚哈扎族人	狩猎-采集生活	27	16S rDNA；鸟枪法测序	普氏菌属、密螺旋体和未分类的拟杆菌门细菌丰度较高，拟杆菌属丰度较低，未检测到双歧杆菌；富含短链脂肪酸代谢
Clemente, et al,2015年^[18]	亚诺马米印第安人	半游牧式的狩猎生活	34	16S rRNA	物种多样性高；普氏菌属丰度较高，拟杆菌属丰度较低
Obregon,et al, 2015年^[19]	美国	工业化生活	23	16S rRNA、鸟枪法测序	物种丰富度较低；以放线菌门为主
Obregon,et al, 2015年^[19]	秘鲁	狩猎-采集和传统农业生活	56	16S rRNA、鸟枪法测序	以变形菌门为主；可检测到不属于致病性分支的密螺旋体属
Martínez,et al, 2015年^[20]	美国	工业化生活	22	16S rRNA	与美国人群相比，新几内亚人群α多样性较高而β多样性较低
Martínez,et al, 2015年^[20]	新几内亚	传统农业生活	40	16S rRNA	与美国人群相比，新几内亚人群α多样性较高而β多样性较低
Dehingia,et al, 2015年^[21]	印度	传统农业生活	193	16S rDNA、下一代基因测序	参与碳水化合物代谢的普雷沃氏菌科、瘤胃菌科、毛螺菌科及真杆菌科丰度较高
Zhang,et al, 2015年^[22]	中国多个省份与民族	传统农业生活	314	16S rRNA	门水平上，以厚壁菌门、拟杆菌门、变形菌门和放线菌门为主；属水平上，考拉杆菌属丰度最高；9个“核心”菌属在人群中共享，均与短链脂肪酸产生相关
Gomez,et al,2016年^[23]	俾格米人	狩猎-采集生活	28	16S rRNA	普雷沃氏菌科、密螺旋体属和梭菌科丰度较高
Gomez,et al,2016年^[23]	班图人	传统农业生活	29	16S rRNA	以厚壁菌门为主；糖和外源性物质代谢富集
Deschasaux,et al,2018年^[24]	荷兰阿姆斯特丹六个最大的民族	工业化生活	2 084	16S rRNA	门水平上，厚壁菌门丰度最高，其次为拟杆菌们；属水平上，普氏菌属、粪杆菌属、拟杆菌属丰度最高，其中摩洛哥人、土耳其人、加纳人的肠道菌群以普氏菌属为主，非洲苏里南人、南亚苏里南人以拟杆菌属为主，而丹麦人则以梭菌目为主
Liao,et al,2018年^[25]	居住在同一地区的瑶族、壮族和汉族人群	传统农业生活	47名汉族、28名壮族和59名瑶族成人	16S rDNA	拟杆菌属和普氏菌属在三个人群中丰度最高，其中巨单胞菌属和琥珀酸弧菌属分别是汉族和瑶族人群的特征性菌属
He,et al,2018年^[26]	中国广东地区	传统农业生活	7 009	下一代基因测序	拟杆菌门、厚壁菌门和变形菌门丰度最高
Ayeni,et al,2018年^[27]	非洲城镇尼日利亚	工业化生活	30	16S rRNA	拟杆菌属、双歧杆菌和粪杆菌属等丰度相对较高
Ayeni,et al,2018年^[27]	非洲农村巴萨	传统农业生活	18	16S rRNA	个体间差异相对较小；以纤维消化功能为主的细菌如普氏菌属、密螺旋体菌属、琥珀酸弧菌属、杆菌属和丁酸弧菌属等丰度较高

表2 不同地域/种族结直肠癌患者肠道菌群特征

作者，年份	地区	结直肠癌患者（例）/健康对照（例）	标本类型	测序方法	结直肠癌患者肠道菌群特征
Wang, et al, 2012年^[42]	中国	46/56	粪便	16S rRNA	脆弱拟杆菌、肠球菌属、埃希氏菌属、克雷伯菌属、链球菌属、消化链球菌属↑；氏菌属、毛螺菌科等短链脂肪酸产生相关菌↓
Wu, et al,2013年^[43]	中国	19/20	粪便	16S rRNA	拟杆菌属、梭杆菌属、弯曲杆菌、肠球菌科↑；氏菌属等短链脂肪酸产生相关菌↓
Ahn, et al, 2013年^[44]	美国	47/94	粪便	16S rRNA	梭杆菌属、卟啉单胞菌属↑、梭菌纲↑
Zackular, et al, 2014年^[45]	美国	30/30	粪便	16S rRNA	梭杆菌属、卟啉单胞菌属、肠杆菌科、紫单胞菌科↑；拟杆菌属、毛螺菌科等短链脂肪酸产生相关菌↓
Zeller, et al, 2014年^[46]	法国	91/358	粪便	宏基因组测序	具核梭杆菌、口炎消化链球菌、不解糖卟啉单胞菌↑
Feng, et al, 2015年^[47]	澳大利亚	41/55	粪便	宏基因组测序	多氏拟杆菌、普通拟杆菌、大肠杆菌、梭杆菌属↑；乳杆菌属、双歧杆菌属↓
Eklöf, et al, 2017年^[48]	瑞典	39/66	粪便	qPCR	Pks+大肠杆菌、具核梭杆菌↑
Liang, et al, 2017年^[49]	中国	203/236	粪便	qPCR	具核梭杆菌、哈氏菌属↑、克拉鲁斯拟杆菌、肠道罗斯拜瑞氏菌↓
Flemer, et al, 2017年^[50]	爱尔兰	59/56	粪便和组织	16S rRNA	拟杆菌属、氏菌属、瘤胃球菌属、颤杆菌克、卟啉单胞菌属、消化链球菌属、微小单胞菌属、梭杆菌属↑
Alomair, et al, 2018年^[51]	沙特阿拉伯	29/29	组织	宏基因组测序	脆弱拟杆菌、消化链球菌、微小单胞菌↑

表2 不同地域/种族结直肠癌患者肠道菌群特征

作者，年份	地区	结直肠癌患者（例）/健康对照（例）	标本类型	测序方法	结直肠癌患者肠道菌群特征
Wang, et al, 2012年^[42]	中国	46/56	粪便	16S rRNA	脆弱拟杆菌、肠球菌属、埃希氏菌属、克雷伯菌属、链球菌属、消化链球菌属↑；氏菌属、毛螺菌科等短链脂肪酸产生相关菌↓
Wu, et al,2013年^[43]	中国	19/20	粪便	16S rRNA	拟杆菌属、梭杆菌属、弯曲杆菌、肠球菌科↑；氏菌属等短链脂肪酸产生相关菌↓
Ahn, et al, 2013年^[44]	美国	47/94	粪便	16S rRNA	梭杆菌属、卟啉单胞菌属↑、梭菌纲↑
Zackular, et al, 2014年^[45]	美国	30/30	粪便	16S rRNA	梭杆菌属、卟啉单胞菌属、肠杆菌科、紫单胞菌科↑；拟杆菌属、毛螺菌科等短链脂肪酸产生相关菌↓
Zeller, et al, 2014年^[46]	法国	91/358	粪便	宏基因组测序	具核梭杆菌、口炎消化链球菌、不解糖卟啉单胞菌↑
Feng, et al, 2015年^[47]	澳大利亚	41/55	粪便	宏基因组测序	多氏拟杆菌、普通拟杆菌、大肠杆菌、梭杆菌属↑；乳杆菌属、双歧杆菌属↓
Eklöf, et al, 2017年^[48]	瑞典	39/66	粪便	qPCR	Pks+大肠杆菌、具核梭杆菌↑
Liang, et al, 2017年^[49]	中国	203/236	粪便	qPCR	具核梭杆菌、哈氏菌属↑、克拉鲁斯拟杆菌、肠道罗斯拜瑞氏菌↓
Flemer, et al, 2017年^[50]	爱尔兰	59/56	粪便和组织	16S rRNA	拟杆菌属、氏菌属、瘤胃球菌属、颤杆菌克、卟啉单胞菌属、消化链球菌属、微小单胞菌属、梭杆菌属↑
Alomair, et al, 2018年^[51]	沙特阿拉伯	29/29	组织	宏基因组测序	脆弱拟杆菌、消化链球菌、微小单胞菌↑

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Gut microbiome and colorectal cancer

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Gut microbiome and colorectal cancer