1. CFTR dysregulation drives active selection of the gut microbiome
- Author
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Samuel I. Miller, Hillary S. Hayden, Adeline M. Hajjar, Mitchell J. Brittnacher, Naseer Sangwan, Piper M. Treuting, Stacey M Meeker, Charles W. Frevert, Eli J. Weiss, Christopher E. Pope, Kevin S Mears, Anh T. Vo, Lucas R. Hoffman, Nicholas Tolley, Kyle R. Hager, and Jisun Paik
- Subjects
Male ,Cystic Fibrosis ,Pulmonology ,Physiology ,Cystic Fibrosis Transmembrane Conductance Regulator ,medicine.disease_cause ,Cystic fibrosis ,White Blood Cells ,Mice ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Biology (General) ,0303 health sciences ,Mutation ,T Cells ,030302 biochemistry & molecular biology ,Gastrointestinal Microbiome ,Animal Models ,Genomics ,Acquired immune system ,3. Good health ,Intestines ,Experimental Organism Systems ,Physiological Parameters ,Medical Microbiology ,Genetic Diseases ,Female ,medicine.symptom ,Anatomy ,Cellular Types ,Research Article ,QH301-705.5 ,Immune Cells ,Immunology ,Inflammation ,Mouse Models ,Microbial Genomics ,Biology ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Immune system ,Model Organisms ,Autosomal Recessive Diseases ,Virology ,medicine ,Genetics ,Animals ,Humans ,Microbiome ,Molecular Biology ,030304 developmental biology ,Nutrition ,Clinical Genetics ,Blood Cells ,Bacteria ,Body Weight ,Biology and Life Sciences ,Cell Biology ,RC581-607 ,medicine.disease ,Fibrosis ,Diet ,Gastrointestinal Tract ,Mice, Inbred C57BL ,Disease Models, Animal ,Animal Studies ,Dysbiosis ,Parasitology ,Immunologic diseases. Allergy ,Digestive System ,Spleen ,Developmental Biology - Abstract
Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome., Author summary It has been difficult to establish causal relationships between host genetics and the selection of the vast multitude of micro-organisms that live in and on us (i.e. the microbiota). Cystic fibrosis has been shown to be associated with changes in the fecal microbiome (the genetic constitution of the microbiota) although it was not evident whether mutation of CFTR, the gene mutated in CF, could drive this selection or whether the frequent use of antibiotics in this population was at fault. Here, by using a germfree (i.e. sterile, lacking all microbiota) mouse model of CF we clearly demonstrate that mutated CFTR alone can alter the microbiome. We also show an increase in an adaptive immune cell type (TH17 cells) in the mesenteric lymph nodes and spleens of CF mice compared to control mice. Our study provides new insights into the dominant role that CFTR plays in microbiome determination and suggests that therapies restoring CFTR function could also correct the microbial dysbiosis observed in CF.
- Published
- 2020