Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis; Inflammation
Study type: Observational

Summary: 
      Cystic Fibrosis (CF) is a fatal, recessive genetic disorder characterized by progressive
      inflammation and lung damage. It is unclear whether current treatment strategies, which focus
      on detection and eradication of pathogenic microorganisms in the lung, are the best way to
      prevent the initiation of early inflammation and lung damage. This study asks how early
      acquisition of microbial flora occurs in infants with CF and healthy baby controls, and
      whether this process initiates or influences early inflammation and clinical disease
      progression in CF.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Infants and children up to the age of 4 with Cystic Fibrosis, and age-matched controls
        without cystic fibrosis will be eligible for this study. Participants will be recruited
        from the Cystic Fibrosis clinic and Primary Care Clinic of the Yale New Haven Hospital.
      
Biospecimen description: 
      Fecal samples