Genetics, glycemic control and the microbiome in cystic fibrosis

Cystic fibrosis related diabetes (CFRD) is the most common non-pulmonary complication of
cystic fibrosis (CF), affecting up to 50% of adults. This diagnosis is linked to more pulmonary
exacerbations, worsening lung function, and increased mortality compared to those without
CFRD. Individuals with CFRD have more Pseudomonas Aeruginosa and Staphylococcus
Aureus pulmonary infections determined by culture based microbial analysis. However, the
specific microbiome seen in CFRD and how the microbiome changes with glycemic
manipulation is not understood. The development of CFRD may also be influenced by genetic
traits for insulin resistance and beta cell function, though studies evaluating this are limited.
Insulin is the only recommended treatment that has been shown to improve pulmonary
outcomes in CFRD; however, good glycemic control is difficult to achieve in this patient
population due to high carbohydrate intake, frequent hypoglycemia, and the added burden of
diabetes tasks. Artificial pancreas (AP) technology is a promising approach to controlling blood
glucose with greater accuracy and ease than conventional methods. We have funding to study
an AP device, the bionic pancreas (BP), in a randomized parallel design clinical trial in subjects
with poorly controlled CFRD (R01DK119699-01, PI:Putman). These subjects will be randomized
to usual care (UC) or the BP for 6 months, evaluating the impact of the BP not only on glycemic
control but also on CF-specific outcomes including nutritional status and pulmonary function.
We will leverage this funded trial to investigate novel clinical and genetic predictors of CFRD
and will use state-of-the-art microbiome analytic techniques to understand how glycemic control
impacts microbiome diversity in CF. Aim 1 will compare the microbiome in CFRD subjects
participating in this trial to biorepository samples from non-CFRD subjects and determine how
baseline glycemia influences the microbiome. Aim 2 will investigate genetic and clinical
predictors of baseline glycemia and response to the BP intervention in subjects with CFRD. Aim
3 will evaluate how strict glycemic control achieved with the BP impacts microbiome diversity
over 6 months, and if the change in lung function seen with improved glycemia is mediated
through the change in microbiome.
In summary, the research and mentoring plan proposed in this K23 application will test
innovative hypotheses about glycemic traits and the microbiome in patients with CFRD, will
broaden our understanding of CFRD, and will provide the necessary training and investigational
niche for Dr. Brenner to develop a successful, independent career in clinical research.

Grant Number: 5K23DK125839-05
NIH Institute/Center: NIH
Principal Investigator: Laura Brenner