粪便微生物群移植对系统性硬化症小肠黏膜的影响。

OBJECTIVES: In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling. METHODS: We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling. RESULTS: In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16. CONCLUSION: Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.

目的：在系统性硬化症（SSc）中，胃肠道（GIT）受累是一个主要关注点，目前尚无针对该疾病的改善病情和有限的对症治疗方法。粪便微生物群移植（FMT）为 SSc 患者的 GIT 疾病提供了一种新的治疗选择，最近的一项对照性试点试验显示出了临床前景。在此，我们旨在通过免疫组织化学和转录组分析研究 FMT 对 SSc 患者十二指肠活检的影响。

方法：我们分析了 9 名接受 FMT（n=5）或安慰剂（n=4）肠道输注的 SSc 患者在干预前（第 0 周）和干预后（第 2 周和第 16 周）获得的十二指肠活检。分析包括选择的免疫功能和纤维化标志物的免疫组织化学（IHC），以及整个活检转录组分析。

结果：接受 FMT 的患者在第 2 周时，黏膜中 podoplanin 和 CD64 表达细胞的数量较基线时减少。podoplanin（r=0.94）和 CD64 阳性细胞（r=0.89）的这种下降与患者报告的较低的 GIT 症状改善相关。第 2 周的全活检转录组分析显示，细胞和内质网应激反应、微绒毛和分泌小泡、血管和钠依赖性转运以及昼夜节律的关键途径显著富集。第 16 周时，我们发现与免疫球蛋白受体、T 细胞受体复合物和趋化因子受体结合活性以及对锌离子的反应相关的途径明显富集。我们发现包括基质金属蛋白酶-1 在内的 25 个基因在第 2 周和第 16 周均上调。

结论：结合选择性 IHC 和无偏基因表达分析，这项探索性研究强调了 FMT 在 SSc 合并 GIT 受累患者中具有针对器官相关疾病的潜在作用。

试验注册：ClinicalTrials.gov，http://clinicaltrials.gov，NCT03444220。