克罗恩病(CD，Crohn’s disease)是一种慢性炎症性肠病(IBD，inflammatory bowel disease)，在全球范围内影响着数百万人【1】。这种病常见于年轻人并会伴随一生。因此该病的患者需要长期的、甚至是昂贵的医疗和外科管理。因此这种疾病被认为是一个重要的公共卫生问题。组学技术的发展虽然可以为疾病诊断提供更为详尽的数据，但仍未能为克罗恩病提供确认的诊断指标。

  对此，法国科学家早在2003年于《柳叶刀》提出克罗恩病因学的假说：冷链假说【2】。该假说的主要观点认为，工业和家用制冷的发展导致人类频繁接触能够在寒冷中生长的细菌。遗传易感人群频繁低水平的接触这类细菌(特别是耶尔森氏菌)被认为会导致的肠道炎症加剧。该观点提出后，有部分研究也从不同角度为该假说提供了支撑证据【3.4】。

  该假说的提出者在2021年再次回顾该假说，并对假说提出后各方面的证据进行了总结(图1)【5】。在最新的总结中，值得关注的是作者指出慢性肠炎症(IBD)目前已经确定的200多个易感多态性遗传位点大多数都常见于克罗恩病和溃疡性肠炎【6】。并且经实验证实NOD2基因的突变与克罗恩病关系最密切。NOD2突变在欧洲血统中频繁出现，但在亚洲和非洲血统中很少出现【7.8】。在欧洲，多达10%的健康个体携带一种或多种CD相关的NOD2基因突变。这一特别高的频率表明，突变携带者的有益影响可能超过对病原体和CD的发展产生反应的突变的有害影响。由于假结核杆菌在基因上与鼠疫杆菌非常相似【9】，作者假设过去在鼠疫流行期间，NOD2突变可能为突变携带者提供了生存优势。通过结合考古学和欧洲近600年的黑死病流行记录，作者发现CD相关NOD2突变的当前频率[即鼠疫幸存者的后代]与欧洲和地中海国家过去鼠疫流行的强度相关。这一发现进一步支持了NOD2和耶尔森菌之间的联系【10】。并且最近发表在Nature的研究论文指出，如有史以来最大的一次死亡传染病流行(即第二次鼠疫大流行)不仅仅在当时造成了大量的人口死亡，而且塑造了今天人群的疾病易感性和免疫学疾病的易感性【11】。

  图1：冷链假说的图片摘要。

  参考文献：

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