Asthma is the most common cause of chronic childhood disease in the United States, and is a major health problem, particularly in urban pediatric populations. Most asthma is diagnosed before the age of six, and most children with asthma are atopic with sensitization to at least one allergen. Bacterial gut colonization and Vitamin D exposure are two factors that vary in children with urbanization, may influence immune function at the intestinal and systemic levels, and may increase the risk of allergy and asthma. In a small pilot study we found that the anti-inflammatory immunomodulatory cytokine IL-10 was increased in the cord blood of children whose mothers had a higher proportion of anaerobes in the gut. Infant gut diversity was protective against atopic dermatitis in the first 6 months of life. However, there has been no adequate long-term follow-up study of the gut flora in human early life and the development of atopic diseases. In the only U.S. pre-birth Vitamin D asthma intervention trial (NIH Grant number: U01 HL091528, co-PIs: Litonjua &Weiss), we have a unique opportunity to evaluate the influences of gut colonization (maternal and child) on the risk of early life wheeze, atopic dermatitis, and allergic sensitization. Moreover, this proposed ancillary study will optimize the chance to evaluate whether gut colonization and vitamin D influences on allergy and asthma development are independent or linked. We propose to test the following primary hypotheses in a subset of 200 mother:child pairs: (1) Higher levels of maternal vitamin D during pregnancy will increase numbers of total and specific anaerobes (B fragilis, and Lactobacillus) in the maternal and child intestinal flora;(2) Increased numbers of anaerobes in the maternal intestinal flora, and in the child intestinal flora at 4 months of age will reduce the risk of wheeze, recurrent wheeze (>2 reports of wheeze in the previous year), atopic dermatitis (eczema), and sensitization to >1 allergen at 1 year of age. We will consider exposures to total anaerobes, as well as the specific anaerobes B fragilis, and Lactobacillus;To further explore whether there are common pathways through which intestinal flora and vitamin D influence allergy and wheeze, we will test the following three secondary hypotheses: 3) Higher levels of maternal vitamin D during pregnancy will reduce the risk of recurrent wheeze, atopic dermatitis and sensitization in part through increasing numbers of anaerobes in the maternal intestinal flora, and in the child intestinal flora at 4 months of age. (4) Increased numbers of total and specific anaerobes in maternal and child intestinal flora will increase the frequency and anti-inflammatory function of Foxp3+ and IL-10+ Treg cells in cord blood.(5) Maternal supplementation with vitamin D during pregnancy will increase the diversity/complexity of maternal and child fecal flora. This proposal is time-sensitive. As ascertainment of the composition of maternal intestinal flora is central to our hypotheses, it is critically important that this ancillary study be initiated early in the final year (2011) of the enrollment and delivery period of the parent clinical trial VDAART. PUBLIC HEALTH RELVEANCE: Asthma is a major public health problem and the most common cause of chronic childhood disease in the United States. Over a 40 year period, allergic asthma, allergic rhinitis (hay fever) and atopic dermatitis (atopic eczema) prevalence increased, and the high prevalence of asthma persists, particularly in urban pediatric populations in the United States. If we identify components of maternal or childhood intestinal microbial flora that are protective against allergy, wheeze or asthma, and that vary with vitamin D levels or diet, this could be translated into pharmacologic or dietary interventions that would be of great benefit to public health.

Public Health Relevance

Asthma is a major public health problem and the most common cause of chronic childhood disease in the United States. Over a 40 year period, allergic asthma, allergic rhinitis (hay fever) and atopic dermatitis (atopic eczema) prevalence increased, and the high prevalence of asthma persists, particularly in urban pediatric populations in the United States. If we identify components of maternal or childhood intestinal microbial flora that are protective against allergy, wheeze or asthma, and that vary with vitamin D levels or diet, this could be translated into pharmacologic or dietary interventions that would be of great benefit to public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108818-03
Application #
8448671
Study Section
Special Emphasis Panel (ZHL1-CSR-G (F2))
Program Officer
Noel, Patricia
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$400,713
Indirect Cost
$97,544
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115