In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric accumulation of connective tissue around bile ducts suggests that the cholangiocyte plays an integral role in PSC pathogenesis. However, what initiates changes in cholangiocyte phenotype and how cholangiocytes interact with cells in the peribiliary extracellular matrix like immune cells and stromal components is largely unknown. Over the last 10 years, genome-wide association studies in PSC have revealed >20 risk genes.2–5 A significant observation that can be derived from these data, which also applies to other non-Mendelian phenotypes, is that the predominant risk contribution is likely to come from one or more environmental sources, rather than the genetic aberrations. Indeed, in PSC, we estimate that <10% of the overall liability is accounted for by the genetic findings; with extrapolations into hypothetical, larger study populations, it is unlikely to exceed 30%–40%.6 7 Research dissecting the remaining environmental contribution to PSC and other complex diseases is methodologically challenging. The exposures of an organism throughout life as a whole have recently been referred to as the exposome8 and include a myriad of components of both the external (eg, xenobiotics) and internal (eg, gut microbes) milieu. There is a long tradition and effective means for detecting infectious exposures in medicine. Robert Koch in the late 19th century proposed criteria to identify a disease as infectious.9 These included (i) the organism is regularly associated with the disease, (ii) the organism can be isolated from the diseased host and grown in culture and (iii) the disease can be reproduced when the organism is introduced into a healthy susceptible host. With the development of nucleic acid sequence-based identification of microbes, as well as the …

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胆管细胞与原发性硬化性胆管炎的环境：联系在哪里？

在原发性硬化性胆管炎（PSC）中，肝内和肝外胆管周围的环形纤维化会导致进行性肝病，除肝移植外，没有其他有效的治疗方法。1胆管周围结缔组织的同心聚集表明胆管细胞起着不可或缺的作用在PSC发病机理中。然而，启动胆管细胞表型改变以及胆管细胞如何与胆管细胞外基质中的细胞（如免疫细胞和基质成分）相互作用的原因尚不清楚。在过去的10年中，在PSC中进行的全基因组关联研究揭示了> 20个风险基因。2–5从这些数据中可以得出的重要观察结果，也适用于其他非孟德尔表型，认为主要的风险贡献可能来自一种或多种环境来源，而不是遗传畸变。确实，在PSC中，我们估计遗传发现占总责任的不足10％。通过对假设的更大的研究人群进行推断，其可能性可能不会超过30％–40％。67剖析剩余的环境因素对PSC和其他复杂疾病的研究在方法上具有挑战性。最近，整个生命过程中生物体的暴露被称为暴露体8，其中包括外部环境（例如，异种生物）和内部环境（例如，肠道微生物）的多种成分。检测药物中的传染源有悠久的传统和有效的手段。罗伯特·科赫（Robert Koch）在19世纪后期提出了将一种疾病确定为传染病的标准。9这些标准包括（i）该生物经常与该疾病相关；（ii）该生物可以从患病宿主中分离出来，并在培养物中培养；以及（iii）当将有机体引入健康易感宿主中时，该疾病可以繁殖。随着基于核酸序列的微生物鉴定的发展，以及…