吸烟竟引发结直肠癌！中国3亿烟民，近一半会因吸烟早逝...

2022-05-31 Swagpp MedSci原创

GUT：香烟烟雾会导致肠道菌群失调，进而改变肠道代谢物且损害肠道的屏障功能，可能会激活结肠上皮细胞的致癌MAPK/ERK信号传导，诱发结直肠癌的发生。

今天是世界无烟日，这日期的选择还真有些讲究。最初，世界无烟日并没有被设定在5月31日，但考虑到6月1日是国际儿童节，所以将无烟日改定在儿童节前一天，也是为了起到一定的警示作用，希望下一代免受烟草的危害。

在我国，吸烟的群体不占少数。根据王辰院士团队5月3日在柳叶刀子刊《Lancet Regional Health-Western Pacific》发表的研究显示，我国的吸烟者总数约3.08亿，而近一半的吸烟者会因此提早死亡。此外，烟草依赖也是一种致命的慢性非传染性疾病，我国的患者人数高达1.835亿，超过冠心病、糖尿病、脑卒中等常见慢性疾病患病人数。

王辰院士在2022年世界无烟日主题活动发表演讲

吸烟，可谓是百害而无一利，对于健康的危害不胜枚举，是诱发肺癌、胃癌、肝癌等多种癌症的高危因素之一。根据BMJ子刊对2020-2040年中国大陆吸烟流行趋势的预测，男性吸烟相关癌症的死亡率将从2020年的337.2人/10万人（≈3.4/1000人），上升至2040年的485.6（≈4.9/1000人）；女性则从2020年的157.3上升至240.4/10万人，远高于非吸烟者。

近日，香港中文大学于君教授团队发现，吸烟还会增加结直肠癌的发生。研究者发现，香烟烟雾会导致肠道菌群失调，进而改变肠道代谢物且损害肠道的屏障功能，可能会激活结肠上皮细胞的致癌MAPK/ERK信号传导，诱发结直肠癌的发生。该论文发表于Gut上。

DOI: 10.1136/gutjnl-2021-325021

本实验中，研究者将雄性C57BL/6小鼠分为两组，一组小鼠每天2小时暴露于香烟烟雾中，另一组则置于洁净空气中，持续28周。

在实验之初，研究者给所有小鼠都注射了致癌物偶氮甲烷（AOM，广泛用作一种基质引起实验动物发生结肠肿瘤，从而研究癌症预防物和癌症形成机制），每周1次，连续6周，以有效诱导小鼠结肠癌。28周后，两组小鼠均牺牲，来观察结直肠肿瘤的情况。

实验具体操作

对比两组情况发现，暴露于香烟烟雾中会显著提高结肠肿瘤的发病率，香烟烟雾暴露组的结直肠肿瘤的数量和大小明显高于无烟组（p<0.01）。（见下图B）

进一步观察肠道的变化情况，研究者发现，与无烟对照组的小鼠相比，香烟烟雾暴露组的结直肠上皮细胞增殖相对比较活跃。具体表现为Ki-67阳性细胞数量显著上升，细胞增殖蛋白标记物，即增殖细胞核抗原（PCNA）的表达水平也明显升高。（见下图E和F）

香烟暴露组和无烟对照组的结直肠肿瘤情况对比

那么，吸入香烟烟雾是如何一步一步地导致结直肠癌的发生呢？

研究者使用鸟枪法宏基因组对小鼠的粪便进行分析发现，在基线没有显著差异的前提下，28周的香烟烟雾暴露使得实验组小鼠的肠道菌群组成发生明显改变，有20种肠道微生物的数量发生变化！

其中，E. lenta和头葡萄球菌（Staphylococcus capitis）数量增加，而肠道有益菌包括罗伊氏乳杆菌（Lactobacillus reuteri）、狄氏副拟杆菌（Parabacteroides distasonis）和多氏拟杆菌（Bacteroides dorei）则在香烟烟雾的暴露中被耗尽。

该实验结果提示，香烟烟雾改变了小鼠的肠道微生物群组成以及微生物的相互作用。此外，香烟烟雾组小鼠肠道中增长的菌落会与有益菌形成拮抗作用，导致肠道菌群生态网络的破坏。

香烟烟雾暴露导致肠道微生物的组成变化

肠道微生物群组成改变后，其相关代谢物自然会随之改变。与无烟对照相比，吸烟暴露组小鼠的粪便中有41种代谢物发生了改变，而这些改变的代谢物在不同的代谢组信号途径中被富集或耗尽。

比如，胆汁酸代谢物在实验组小鼠的结肠中显著增加，尤其是牛磺脱氧胆酸（TDCA），而TDCA是一种已知致癌物。为了确定肠道菌群和代谢物的潜在联系，研究者使用Spearman相关分析发现，前面提及的E. lenta与TDCA具有最显著的正相关，而两种有益菌，詹氏乳杆菌（L. jensenii）和卷曲乳杆菌（L. crispatus），则和TDCA呈负相关。因此，研究者认为，肠道微生物失调和代谢物的改变可能共同促成了结直肠肿瘤的发生。

此外，研究者还发现香烟烟雾明显降低了闭合蛋白3（Claudin-3）和紧密粘连蛋白1（ZO-1），但增加小鼠血清脂多糖（LSP）的水平，显示香烟烟雾会导致肠道屏障功能受损。

癌症相关基因分析显示，TDCA是激活MAPK/ERK途径的配体，MAPK/ERK信号通路的激活与TDCA水平存在正相关的关系，因此暴露于香烟烟雾组的小鼠表现出更强的致癌MAPK/ERK信号，进而促进结直肠癌的发生。

也就是说，香烟烟雾暴露导致肠道菌群丰度和组成的改变仅是第一步，但会产生“多米诺效应”——引发肠道菌群代谢物的改变，进一步导致肠道屏障功能受损以及致癌性MAPK/ERK信号传导，最终诱发结直肠癌。

为了证明香烟烟雾确实引发小鼠肠道菌群的失调，研究者还增加了一步——将暴露于香烟烟雾组小鼠的肠道微生物群移植至常规小鼠体内。同样，得到了相似的结果，即导致肠道屏障的损伤与致癌MAPK/ERK通路的增强，增加被移植小鼠发生结直肠肿瘤的可能性。

这项研究表明，吸烟会导致肠道微生物群组成的改变，进而诱发结直肠癌。相反与继续吸烟者相比，戒烟可以有效提高结直肠癌的特异性生存率。因此，研究者认为，戒烟能够重建健康的肠道菌群，是预防结直肠癌的实用方法之一。

众所周知，吸烟有害健康。但对于烟草依赖的人来说，戒烟的确不是一件容易的事儿。鉴于今天是世界无烟日，不如就从今天开始，从逐渐减少到最终远离，珍惜自己和身边人的身体健康。

参考资料

[1]Bai X, Wei H, Liu W, et alCigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolitesGut Published Online First: 06 April 2022. doi: 10.1136/gutjnl-2021-325021

[2]Li N, Wu P, Wang Z, Shen Y, Zhang L, Xue F, Han W, Chen Y, Du J, Zhao Y, Yang C, Hu Y, Gu W, Chen W, Guo X, Liu B, Jiang J, Xu N. Smoking-related cancer death among men and women in an ageing society (China 2020-2040): a population-based modelling study. Tob Control. 2021 Nov 1:tobaccocontrol-2020-056444. doi: 10.1136/tobaccocontrol-2020-056444. Epub ahead of print. PMID: 34725269.

[3]Liu Z, Li YH, Cui ZY, Li L, Nie XQ, Yu CD, Shan GL, Zhou XM, Qin R, Cheng AQ, Chung KF, Chen ZM, Xiao D, Wang C. Prevalence of tobacco dependence and associated factors in China: Findings from nationwide China Health Literacy Survey during 2018-19. Lancet Reg Health West Pac. 2022 May 4;24:100464. doi: 10.1016/j.lanwpc.2022.100464. PMID: 35538934; PMCID: PMC9079698.

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2022-06-01 crystal0564

#结直肠#

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2022-05-31 jing0309

感谢分享

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2022-05-31 萌宝嘟嘟

好东西谢谢分享

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2022-05-31 ms6000000960504356

#学习##期刊论坛#

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[GetPortalCommentsPageByObjectIdResponse(id=1453712, encodeId=c7ff1453e12b1, content=<a href='/topic/show?id=098ee8679ad' target=_blank style='color:#2F92EE;'>#结直肠#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=78679, encryptionId=098ee8679ad, topicName=结直肠)], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=9ace5575596, createdName=crystal0564, createdTime=Wed Jun 01 09:59:50 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223682, encodeId=3ea91223682df, content=感谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220313/1fccd8869aca4c2bbabb274c6aada833/8cdb5c5762b54b208703fcac43dcca47.jpg, createdBy=872f5678021, createdName=jing0309, createdTime=Tue May 31 19:31:29 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223533, encodeId=21c81223533a8, content=好东西谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0be2111725, createdName=萌宝嘟嘟, createdTime=Tue May 31 09:18:53 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223504, encodeId=712e1223504b8, content=<a href='/topic/show?id=23e3454e353' target=_blank style='color:#2F92EE;'>#学习#</a><a href='/topic/show?id=8f275032126' target=_blank style='color:#2F92EE;'>#期刊论坛#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=147, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=45473, encryptionId=23e3454e353, topicName=学习), TopicDto(id=50321, encryptionId=8f275032126, topicName=期刊论坛)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b0825417521, createdName=ms6000000960504356, createdTime=Tue May 31 08:19:16 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223502, encodeId=46cf12235029a, content=不错的文章, beContent=null, objectType=article, channel=null, level=null, likeNumber=101, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b0825417521, createdName=ms6000000960504356, createdTime=Tue May 31 08:19:07 CST 2022, time=2022-05-31, status=1, ipAttribution=)]
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