BACKGROUND Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have led to markedly increased longevity of patients with cystic fibrosis, but new complications have emerged, such as early onset of colorectal cancer. Although the pathogenesis of colorectal cancer in cystic fibrosis remains unclear, altered host-microbe interactions might play a critical role. To investigate this, we characterized changes in the microbiome and host gene expression in the colonic mucosa of cystic fibrosis patients relative to healthy controls, and identified host gene-microbiome interactions in the colon of cystic fibrosis patients. METHODS We performed RNA-seq on colonic mucosa samples from cystic fibrosis patients and healthy controls to determine differentially expressed host genes. We also performed 16S rRNA sequencing to characterize the colonic mucosal microbiome and identify gut microbes that are differentially abundant between patients and healthy controls. Lastly, we modeled associations between relative abundances of specific bacterial taxa in the gut mucosa and host gene expression. RESULTS We find that 1543 genes, including CFTR, show differential expression in the colon of cystic fibrosis patients compared to healthy controls. These genes are enriched with functions related to gastrointestinal and colorectal cancer, such as metastasis of colorectal cancer, tumor suppression, p53, and mTOR signaling pathways. In addition, patients with cystic fibrosis show decreased gut microbial diversity, decreased abundance of butyrate producing bacteria, such as Ruminococcaceae and Butyricimonas, and increased abundance of other taxa, such as Actinobacteria and Clostridium. An integrative analysis identified colorectal cancer-related genes, including LCN2 and DUOX2, for which gene expression is correlated with the abundance of colorectal cancer-associated bacteria, such as Ruminococcaceae and Veillonella. CONCLUSIONS In addition to characterizing host gene expression and mucosal microbiome in cystic fibrosis patients, our study explored the potential role of host-microbe interactions in the etiology of colorectal cancer in cystic fibrosis. Our results provide biomarkers that may potentially serve as targets for stratifying risk of colorectal cancer in patients with cystic fibrosis.

中文翻译：

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囊性纤维化中肠道微生物组与宿主基因调控之间的相互作用。


背景囊性纤维化是白种人中最常见的常染色体隐性遗传病。它是由 CFTR 基因突变引起的，导致粘液水合作用不良以及呼吸、消化和生殖器官功能受损。医疗保健的进步使囊性纤维化患者的寿命显着延长，但新的并发症也出现了，例如结直肠癌的早发。尽管囊性纤维化引起的结直肠癌的发病机制尚不清楚，但宿主-微生物相互作用的改变可能发挥着关键作用。为了研究这一点，我们描述了囊性纤维化患者结肠粘膜相对于健康对照的微生物组和宿主基因表达的变化，并确定了囊性纤维化患者结肠中宿主基因-微生物组的相互作用。方法我们对囊性纤维化患者和健康对照的结肠粘膜样本进行 RNA 测序，以确定差异表达的宿主基因。我们还进行了 16S rRNA 测序，以表征结肠粘膜微生物组，并鉴定患者和健康对照之间丰度存在差异的肠道微生物。最后，我们模拟了肠道粘膜中特定细菌类群的相对丰度与宿主基因表达之间的关联。结果我们发现，与健康对照相比，囊性纤维化患者的结肠中有 1543 个基因（包括 CFTR）表现出差异表达。这些基因富含与胃肠道和结直肠癌相关的功能，如结直肠癌转移、肿瘤抑制、p53和mTOR信号通路。 此外，囊性纤维化患者的肠道微生物多样性下降，产生丁酸的细菌（例如瘤胃球菌科和丁酸单胞菌）的丰度减少，而其他类群（例如放线菌和梭状芽胞杆菌）的丰度增加。综合分析确定了结直肠癌相关基因，包括 LCN2 和 DUOX2，这些基因的表达与结直肠癌相关细菌（如瘤胃球菌科和韦荣球菌）的丰度相关。结论除了描述囊性纤维化患者的宿主基因表达和粘膜微生物组特征外，我们的研究还探讨了宿主-微生物相互作用在囊性纤维化结直肠癌病因学中的潜在作用。我们的结果提供了可能作为囊性纤维化患者结直肠癌风险分层目标的生物标志物。