Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis

Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations.
Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its
ability to act as a chloride channel. The recent development of a transgenic pig model of CF
has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become
colonized with a mixed microbial flora that likely initiates early inflammatory changes which
precede clinically apparent deterioration in lung function.

Because chronic infection and inflammation play central roles in CF disease progression and
exacerbations, many clinicians and researchers have focused on identifying pathogens
associated with CF infection and inflammation. Recent studies outside the area of CF,
however, have clearly demonstrated that "non-pathogens", such as the commensal flora carried
by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems
constantly. This interaction between "microbiome" and host genome is responsible for
appropriate development and function of protective inflammatory and immune responses.

We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical
role in initiating pathogenic inflammatory responses that subsequently lead to lung damage.
The acquired commensal flora may initially be identical to that of a non-CF infant, but may
be altered by the direct or indirect effects of CFTR mutation on the mucosal environment.
Such an altered flora is likely to encode different metabolic and regulatory functions, and
may directly influence host inflammatory responses. If so, a novel therapeutic opportunity
may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions
in a way that interrupts the insidious cycle of inflammation and damage that characterizes
CF.

We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and
evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2)
Determine the relationship between the microbiota and markers of inflammation in these two
cohorts; and (3) Determine whether early declines in lung function are associated with
inflammatory biomarkers or microbiome composition/function. This study is novel in its focus
on a rarely studied population, at a time when interventions might significantly impact
progression of this lethal disease and preserve pulmonary function. Its innovation lies in
applying state of the art technologies and methods to samples that can be collected simply
and non-invasively, thus increasing the likelihood that the findings of this study can be
translated into clinical practice.

Cystic Fibrosis participants:

Inclusion Criteria:

- laboratory diagnosis of Cystic Fibrosis

Exclusion Criteria:

- Major organ system disease other than Cystic Fibrosis

- History of prematurity

Non Cystic Fibrosis control participants:

Inclusion Criteria:

- Proof of a negative newborn CF screening test

Exclusion Criteria:

- Major organ system disease

- History of prematurity