Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Genome Med. 2020 Jan 28;12(1):12. doi: 10.1186/s13073-020-0710-2.
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.
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.
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.
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.
囊性纤维化是白种人中最常见的常染色体隐性遗传疾病。它是由 CFTR 基因突变引起的，导致粘液水合不良，并损害呼吸、消化和生殖器官功能。医疗保健的进步导致囊性纤维化患者的寿命明显延长，但出现了新的并发症，如结直肠癌的早期发病。尽管囊性纤维化中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起着关键作用。为了研究这一点，我们相对于健康对照组，对囊性纤维化患者的结肠粘膜中的微生物组和宿主基因表达进行了特征描述，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。
我们对囊性纤维化患者和健康对照组的结肠粘膜样本进行了 RNA-seq，以确定差异表达的宿主基因。我们还进行了 16S rRNA 测序，以描述结肠粘膜微生物组，并确定患者与健康对照组之间差异丰富的肠道微生物。最后，我们建立了特定肠道粘膜细菌分类群的相对丰度与宿主基因表达之间的关联模型。
我们发现 1543 个基因，包括 CFTR，在囊性纤维化患者的结肠中与健康对照组相比表现出差异表达。这些基因富集了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降低，产丁酸细菌（如 Ruminococcaceae 和 Butyricimonas）的丰度降低，而其他分类群（如 Actinobacteria 和 Clostridium）的丰度增加。综合分析确定了与结直肠癌相关的基因，包括 LCN2 和 DUOX2，其基因表达与结直肠癌相关细菌（如 Ruminococcaceae 和 Veillonella）的丰度相关。
除了对囊性纤维化患者的宿主基因表达和粘膜微生物组进行特征描述外，我们的研究还探讨了宿主-微生物相互作用在囊性纤维化中结直肠癌发病机制中的潜在作用。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的潜在目标的生物标志物。
