Pilot 13: Microbial colonization and adaptation to the CF gut

P.I.: Matthew Parsek, PhD
Professor, Microbiology

Disease of the intestinal tract is responsible for a substantial amount of the morbidity and mortality of cystic fibrosis (CF). The manifestations of CF intestinal disease result largely from pancreatic exocrine insufficiency, resulting in profound nutrient malabsorption and malnutrition, resulting in nutritional failure and intestinal obstruction. We and others recently showed that people with CF have significant alterations in the microbes present in their gastrointestinal (GI) tracts- the gut microbiota- relative to people without CF. This CF GI dysbiosis is characterized by a decreased abundance of many health-associated bacteria, and an increased abundance of other bacterial species that are potential pathogens and/or are associated with other, non-CF GI diseases. Furthermore, CF GI dysbiosis has been shown to correlate with both nutrient malabsorption and intestinal inflammation.

Until recently, most research in CF microbiology has focused on the bacteria that infect the respiratory tract. This effort has shown that CF respiratory pathogens change over time as they adapt to the CF airway, and in many cases these adaptive changes revealed important information about CF lung disease: The mechanisms of bacterial persistence and antibiotic resistance, associations with disease progression, and the physicochemical environment within the airway that selected for those adaptations. By comparison, much less is known about how bacteria adapt to the CF GI tract. We propose to use fecal specimens from adults participating in an ongoing observational study, the Mechanisms of Host Response to Ivacaftor/Lumacaftor (MRIL) study, in which samples are collected before and during treatment with a new CF treatment. Using microbiome data from those samples as a guide, we will identify the bacteria that most commonly colonize the GI tracts of people with CF, culture those species from the specimens, and sequence those isolates, and define their genetic differences (CF-specific adaptations) from reference genomes. We will also delineate the genetic changes that bacterial strains undergo upon treatment with ivacaftor/lumacaftor. This work will provide critical information regarding the mechanisms of bacterial colonization of the CF GI tract and the contribution of bacteria to CF GI disease.