Moreau G Brett, Young Mary, Behm Brian, Tanyüksel Mehmet, Ramakrishnan Girija, Petri William A
Department of Medicine, University of Virginia, Charlottesville VA 22908.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville VA 22908.
medRxiv. 2024 Dec 1:2024.11.28.24318101. doi: 10.1101/2024.11.28.24318101.
Recurrent infection (CDI) is a major health threat with significant mortality and financial costs. Fecal Microbiota Transplantation (FMT) is an effective therapy, however the mechanisms by which it acts, particularly on the host, are poorly understood. Here we enrolled a prospective cohort of human patients with recurrent CDI (n=16) undergoing FMT therapy. Colonic biopsies were collected and bulk RNA sequencing was performed to compare changes in host gene expression pre- and two months post-FMT. Transcriptional profiles were significantly altered after FMT therapy, with many differentially expressed genes (~15% of annotated genes detected). Enrichment analysis determined that these changes were reflective of increased protein production post-FMT, with enrichment of pathways such as Ribosome Biogenesis, Protein Processing, and signaling pathways (Myc, mTORc1, E2F) associated with cell proliferation and protein biosynthesis. Histology of H&E-stained biopsies identified a significant increase in colonic crypt length post-FMT, suggesting that this treatment promotes cell proliferation. Crypt length was significantly correlated with enriched Myc and mTOR signaling pathways as well as genes associated with polyamine biosynthesis, providing a potential mechanism through which this may occur. Finally, signaling pathways upstream of Myc and mTOR, notably IL-33 Signaling and EGFR ligands, were significantly upregulated, suggesting that FMT may utilize these signals to promote cell proliferation and restoration of the intestine.
复发性艰难梭菌感染（CDI）是一种重大的健康威胁，会导致显著的死亡率和经济成本。粪便微生物群移植（FMT）是一种有效的治疗方法，然而其作用机制，尤其是对宿主的作用机制，目前仍知之甚少。在此，我们招募了一组接受FMT治疗的复发性CDI人类患者的前瞻性队列（n = 16）。采集结肠活检样本并进行批量RNA测序，以比较FMT治疗前和治疗后两个月宿主基因表达的变化。FMT治疗后转录谱发生了显著改变，有许多差异表达基因（检测到的注释基因的约15%）。富集分析确定这些变化反映了FMT治疗后蛋白质产生的增加，核糖体生物发生、蛋白质加工以及与细胞增殖和蛋白质生物合成相关的信号通路（Myc、mTORc1、E2F）等通路出现富集。苏木精和伊红（H&E）染色活检的组织学检查发现FMT治疗后结肠隐窝长度显著增加，表明这种治疗促进了细胞增殖。隐窝长度与富集的Myc和mTOR信号通路以及与多胺生物合成相关的基因显著相关，为这一过程可能发生的潜在机制提供了依据。最后，Myc和mTOR上游的信号通路，特别是IL-33信号通路和表皮生长因子受体（EGFR）配体，显著上调，表明FMT可能利用这些信号来促进细胞增殖和肠道恢复。
