Patients with Primary sclerosing cholangitis show signs of intestinal inflammation even in the absence of clinically manifest IBD

Primary Sclerosing Cholangitis (PSC) is a progressive liver disease frequently associated with Inflammatory Bowel Disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies, with the highest incidence of IBD reported in studies that use both endoscopy and histology to screen for intestinal inflammation. This raises the question whether all PSC patients show intestinal inflammation if screened thoroughly, but it only becomes clinically manifest in a subset of patients. To address this question, we collected intestinal biopsies of healthy controls, PSC, PSC-IBD and IBD patients. Using cytokine expression profiling, 16S sequencing, and in-depth histology and endoscopy scoring, we found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFN? in intestinal biopsies, suggesting that PSC patients have intestinal inflammation on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, while PSC-IBD patients presented with inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we also observed that PSC patients without IBD symptoms show signs of dysbiosis and exhibit a distinct microbial profile compared to healthy controls. In summary, we found multiple signs of intestinal inflammation in the majority of PSC patients even in the absence of clinically manifest IBD. Of note, the presence of IBD increases the risk for colorectal cancer. Thus, further studies evaluating the effect of anti-inflammatory therapies and shortened endoscopic screening intervals for colorectal cancer in PSC patients are needed.

原发性硬化性胆管炎（Primary Sclerosing Cholangitis, PSC）是一种常与炎症性肠病（Inflammatory Bowel Disease, IBD）伴发的进展性肝脏疾病。不同研究中，确诊同时合并IBD的PSC患者占比差异悬殊，其中同时采用内镜与组织病理学手段筛查肠道炎症的研究，报告的IBD发生率最高。这一现象引发了一个关键问题：若对所有PSC患者进行全面筛查，是否均会检出肠道炎症？但仅部分患者会出现临床显性的IBD症状。为解答这一问题，我们收集了健康对照者、PSC患者、PSC-IBD患者以及原发性IBD患者的肠道活检样本。通过细胞因子表达谱分析、16S测序、深度组织病理学评分与内镜评分，我们发现，绝大多数无临床显性IBD的PSC患者，其肠道活检样本中均存在免疫细胞浸润，且IL17A与干扰素γ（IFNγ）的表达水平显著升高，这提示PSC患者在分子层面存在肠道炎症。PSC患者的这类亚临床炎症主要局限于远端结肠；而PSC-IBD患者的炎症则可累及远端结肠，或结肠右侧及末端回肠。此外，我们还观察到，无IBD临床症状的PSC患者存在菌群失调（dysbiosis），且与健康对照者相比具有独特的微生物组特征。综上，我们发现，大多数PSC患者即便无临床显性IBD，也存在多种肠道炎症相关征象。值得注意的是，合并IBD会增加结直肠癌的发病风险。因此，亟需开展进一步研究，评估抗炎疗法对PSC患者的疗效，以及缩短结直肠癌内镜筛查间隔的合理性。