Pilot 2: Describing the CF gut microbiome in infancy and early childhood

P.I.: Lucas Hoffman, MD, PhD
Associate Professor
Department of Pediatrics

Abstract: Disease of the lungs and intestinal tract are responsible for the majority of the morbidity and mortality of cystic fibrosis (CF). The manifestations of CF intestinal disease during early life primarily involve pancreatic exocrine insufficiency that causes nutrient malabsorption and, bulky stools that can result in intestinal obstruction. In people without CF, a complex relationship between gut microbiota, nutritional intake, nutrient absorption, and other measures of health has been demonstrated. GI tract microbes are known to be an important contributor to human nutrient metabolism. In CF, GI tract microbes may represent an important determinant of CF nutritional outcomes, which in turn can significantly impact severity of lung disease and overall longevity. The microbial constituents of the CF intestine, nor their relationship with clinical outcomes, have been well studied. Furthermore, some work has suggested a correlation between colonization of the airway and intestine in individual CF patients with a single microbial species (P. aeruginosa). Therefore the intestine may represent an important reservoir for airway infection. We hypothesize that the constituency of gut microbiota among children with CF (1) differs from that of children without CF, and (2) correlates with severity of malabsorption, vitamin deficiency, and nutritional state. To test these hypotheses, we propose a pilot study to establish methodology for studying gut microbiomes (as reflected by stool microbial content, defined with ultra high-throughput, cultureindependent molecular methods) among 10 infants and children with CF and age-matched non-CF controls. We will collect four stool samples per subject over a year to determine the within-subject variability of microbial characteristics and their relationship with the presence or absence of CF, with nutritional and clinical parameters (including weight, height, body mass index, growth rate of each of these parameters among both subject groups, and among CF subjects, serum vitamin levels, GI symptoms, and supplemental pancreatic enzyme dosage). Microbial species and gene content in stool samples will be defined using massively parallel next-generation DNA sequencing methods with which we have extensive experience. Estimates of the metabolic capability of the microbiome will be determined and correlated with these clinical parameters. Our goal in this pilot project is to apply these methods to collect sufficient preliminary data for a multicenter study of CF GI tract microbial species and gene content and their clinical relevance.