CF Research Translation Center and Research Development Program

University of Washington
UW Health Sciences, K-140
Genome Sciences, Box 357710
Seattle, WA 98195

Pilot 17 – Gastrointestinal dysbiosis as a modifier of CF infant somatic growth: A murine investigation

P.I.: Jisun Paik, PhD
Research Assistant Professor, Comparative Medicine

Luke Hoffman, MD PhD
Associate Professor, Pediatrics
Adjunct Associate Professor, Microbiology

Infants with the genetic disease cystic fibrosis (CF) tend to have early growth failure, including stunted growth. These inadequate growth outcomes correlate with later severity of lung disease and overall survival. Despite the opportunities for earlier diagnosis and interventions therapy afforded by newborn screening, 40% of infants with CF still fail to meet their growth goals by two years of age. While the reasons for this persistent growth failure are poorly understood, our preliminary data indicate that the GI microbiotathe bacteria that inhabit the GI tracts- of children with CF play an important role in early growth. In particular, we found that the fecal microbiota of infants with CF are depleted for bacteria known to be important for (1) most efficient nutrient and energy harvest, and (2) production of a class of molecules known as short-chain fatty acids (SCFAs). SCFAs regulate a variety of important host biological processes, including endocrine and metabolic activities. For example, SCFAs produced by gut microbes regulate the production of a growth hormone, insulin-like growth factor 1 (IGF-1), that is now known to be underproduced by people and animals with CF. Therefore, the relatively poor bone and somatic growth of children with CF may in part be due to insufficient GI SCFA abundance, which can be improved through nutritional supplements. Therefore, we propose to test this model in a CF mouse model, with the hypothesis that oral or probiotic supplementation of SCFAs will improve the linear growth and bone deposition of CF mice. Using an established model, we will compare the bone and somatic growth characteristics of germ-free and conventional mice with and without CF (Aim 1), and then investigate the effects of oral supplementation with SCFAs and with bacteria known to produce SCFAs, (Aim 2). To perform this study, we have combined the expertise a CF clinician and microbiologist, an expert in CF mouse models, and a specialist in the endocrinology of bone metabolism, the latter of whom is new to CF research. Our goal is to identify interventions that will normalize the growth of infants with CF, which is known to correlate with longterm outcomes.