Gastroenterology ( IF 25.7 ) Pub Date : 2022-08-18 , DOI: 10.1053/j.gastro.2022.08.033 Beng San Yeoh 1 , Piu Saha 1 , Rachel M Golonka 1 , Jun Zou 2 , Jessica L Petrick 3 , Ahmed A Abokor 1 , Xia Xiao 4 , Venugopal R Bovilla 1 , Alexis C A Bretin 2 , Jesús Rivera-Esteban 5 , Dominick Parisi 6 , Andrea A Florio 7 , Stephanie J Weinstein 8 , Demetrius Albanes 8 , Gordon J Freeman 9 , Amira F Gohara 10 , Andreea Ciudin 11 , Juan M Pericàs 5 , Bina Joe 1 , Robert F Schwabe 12 , Katherine A McGlynn 8 , Andrew T Gewirtz 2 , Matam Vijay-Kumar 1
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Background & Aims
Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed.
Methods
We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber–enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case–control cohort.
Results
HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC.
Conclusions
PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber–enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.
中文翻译：
肠肝分流驱动的胆血症易患肝癌
背景与目标
每年夺去数百万人生命的肝细胞癌 (HCC) 的发病机制人们知之甚少。迫切需要识别风险因素和可改变的决定因素，并了解它们如何影响 HCC。
方法
我们在 C57BL/6 小鼠中寻找 HCC 的早期预后指标，我们发现当喂食富含可发酵纤维的饮食时，这些小鼠容易患上这种疾病。此类标记物用于对 HCC 发展的表型进行分型并询问其阶段。使用从 HCC/病例对照队列中前瞻性收集的血清测试了它们的人类相关性。
结果
小鼠的 HCC 倾向是由先天性门体分流 (PSS) 的存在决定的，这会导致血清胆汁酸 (BA) 显着升高。大约 10% 的各种来源的小鼠表现出 PSS/胆血症，但在喂食标准食物时缺乏明显的表型。然而，饲喂成分明确的饮食的 PSS/胆血症小鼠会出现 BA 和环氧合酶依赖性肝损伤，当饮食中富含可发酵纤维菊粉时，这种情况会加剧并一致进展为 HCC。这种胆汁淤积性 HCC 的进展与胆血症加剧和免疫抑制环境有关，这两者都是通过阻碍 BA 生物合成或中和白细胞介素 10 或程序性死亡蛋白 1 来预防 HCC 所必需的。人血清分析显示，BA 升高与HCC的未来发展。
结论
PSS 在 C57BL/6 小鼠中相对常见，会导致无症状胆血症，从而容易导致肝损伤和肝癌，特别是在喂食富含可发酵纤维的饮食时。人类静默 PSS/胆血症的发病率有待调查。无论如何，测量血清 BA 可能有助于 HCC 风险评估，可能提醒特定个体考虑饮食或 BA 干预措施。
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