Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Gastroenterology. 2021 Apr;160(5):1784-1798.e0. doi: 10.1053/j.gastro.2020.12.058. Epub 2020 Dec 31.
BACKGROUND & AIMS: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).
Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.
Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.
The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
原发性硬化性胆管炎（PSC）患者的微生物群落组成发生改变，这种改变除了表型变化之外，还必然伴随着功能变化，进而影响宿主和疾病表型。因此，我们旨在比较 PSC 患者与健康对照（HC）和无 PSC 的炎症性肠病（IBD）患者的肠道微生物组的遗传潜力。
对来自两个队列（挪威队列和德国队列）的 136 例 PSC 患者（58%患有 IBD）、158 名 HC 和 93 名无 PSC 的 IBD 患者的粪便 DNA 进行宏基因组鸟枪法测序，共生成 170 亿对末端序列，然后使用 HUMAnN2 和 MetaPhlAn2 进行处理，并使用广义线性模型和随机效应荟萃分析进行分析。
与 HC 相比，PSC 患者的微生物基因较少（P<0.0001）。与 HC 相比，PSC 患者的梭菌属丰度增加， prevalence 增加，而真杆菌属和瘤胃球菌属等减少。PSC 患者与维生素 B6 合成和支链氨基酸合成相关的基因丰度存在显著差异（Q<0.05）。对来自独立的 PSC 患者和对照的血浆进行靶向代谢组学分析发现，PSC 患者的维生素 B6 和支链氨基酸浓度降低（P<0.0001），这与无肝移植生存率降低强烈相关（log-rank P<0.001）。在有无 IBD 的 PSC 患者之间未检测到分类或功能差异。
与 HC 相比，PSC 患者的肠道微生物组存在较大的功能差异，包括必需营养素的微生物代谢。与疾病过程相关的相关循环代谢物的改变表明，微生物功能可能与 PSC 疾病过程有关。
