Journal Article

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

Niccum, David E., Khoruts, Alexander, Blekhman, Ran, Priya, Sambhawa, Dayama, Gargi

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Abundance / Analysis / Autosomal recessive inheritance / Bacteria / Biochemistry / Bioinformatics / Biological markers / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer / Cancer metastasis / Cancer Research / Colon - metabolism / Colon - microbiology / Colonoscopy / Colorectal cancer / Colorectal Neoplasms - etiology / Cystic fibrosis / Cystic Fibrosis - complications / Cystic Fibrosis - genetics / Cystic Fibrosis - microbiology / Cystic fibrosis transmembrane conductance regulator / Data smoothing / Development and progression / Digestive system / Dual Oxidases - genetics / Dual Oxidases - metabolism / Esters / Etiology / Etiology (Medicine) / Fibrosis / Gastrointestinal Microbiome / Gastrointestinal tract / Gene expression / Gene regulation / Generalized linear models / Genes / Genetic aspects / Genetic regulation / Genetic research / Genitalia / Gut microbiota / Health aspects / Host-microbe interactions / Human Genetics / Humans / Inflammation / Intestinal microflora / Intestinal Mucosa - metabolism / Intestinal Mucosa - microbiology / Lipocalin-2 - genetics / Lipocalin-2 - metabolism / Medical research / Medical screening / Medicine/Public Health / Metabolomics / Metastases / Microbiome / Microbiomes / Microbiota / Microorganisms / Mucosa / Mutation / p53 Protein / Patients / Pediatrics / RNA / rRNA 16S / Ruminococcaceae / Stem cells / Surveillance / Systems Biology / TOR protein / Transcriptome / Translating the microbiome in health and disease / Tumor proteins / Tumor suppression / Tumors