By Nadia Rahman Fink
Chariman: Klaus Müller
Opponent: Erik Melén
Opponent: Maria Jenmalm
Elevated level of high sensitivity C-reactive protein (hs-CRP) is a marker of a low-grade inflammation and is associated with a range of chronic inflammatory diseases, including asthma and allergy. Hs-CRP has been associated with obesity, metabolic syndrome and cardiovascular disease, consequently exercise, diet and weight reduction have been proposed to alter level of inflammation – suggesting an extrinsic environmental influence. Most studies on childhood low-grade inflammation have been done in school- age children; still data from early life is ambiguous and sparse.
In pregnancy increased levels of hs-CRP is associated with obesity and pregnancy related conditions such as preeclampsia and gestational diabetes. During normal pregnancy maternal immunity is altered, and an anti-inflammatory environment is induced. Conversely CRP seems to be elevated during normal pregnancy but is not transferred directly across the placenta.
Only very little is known about the transfer of low-grade inflammation from mother to child. Genetic predisposition to inflammatory diseases is well known, and the heritability of hs-CRP level is estimated to be 25-45%. In line with this Genome Wide Associations Studies have found several Single Nucleotide Polymorphisms to be closely associated with CRP levels in adults, but only a minor part of the variance of CRP levels can be explained by these genetic factors. Accordingly intrauterine programming as well as environmental factors including the human microbiota has been speculated as facilitators of systemic low-grade inflammation in childhood.
The human microbiota consists of an ecological community of microorganism including bacteria, living in and on the human body. The human microbiota has become increasingly recognized as a relevant area of interest with potential immune modulatory effects, through active metabolites and direct microbe-host interactions. Pathogenic bacteria of the airways have already been proven connected to later development of childhood asthma. Airway microbial immune interactions could be a potential disease- mechanism in later development of inflammatory disease.
Objectives: To investigate development of systemic low-grade inflammation in early childhood, and specific host, genetic and environmental risk-factors.
This PhD consists of two studies:
Paper I: The aim of this study was to investigate the influence of airway microbiota on early life systemic inflammation. We examined whether the composition of three known pathogenic airway bacteria; Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae were associated with early life systemic low-grade inflammation in the COPSAC2010 cohort, and the high risk COPSAC2000 cohort.
In the COPSAC2010 cohort we found that pathogenic airway bacterial colonization age 1 and 3 months, was associated with levels of low-grade inflammation age 6 months. Prior infections and siblings at home were also found to influence levels of low-grade inflammation. The findings were replicated in the COPSAC2000 cohort, and further supported by a joined analysis of both cohorts. The conclusion of this study was that; asymptomatic neonates colonized with M. catarrhalis, H. influenzae and/or S. pneumoniae have elevated levels of systemic low-grade inflammation age 6 months.
Paper II: The aim of this study was to investigate if systemic low-grade inflammation tracks from mother to child. Investigations were done in the COPSAC2010 birth cohort, investigating levels of hs-CRP from mothers’ week 24 of pregnancy and week 1 post- partum in relation to levels of hs-CRP in their children age 6 months. We further investigated how anthropometric, genetic and environmental factors could determine levels of hs-CRP in mother and child. Smoking during pregnancy, high BMI, use of antibiotics, season and level of social circumstances were associated hs-CRP in the pregnant mothers. We found a CRP Genetic Risk Score significantly associated with increased levels of hs-CRP in the children, and moreover siblings, infections, BMI and airway bacteria likewise associated with increased levels of hs-CRP.
The conclusion of this study was that; levels of hs-CRP strongly correlated between pregnant mothers and their children, independently of the genetic, anthropometric and environmental risk factors investigated.
In conclusion: The two studies imply that elevated levels of low-grade inflammation may be a trait present in healthy neonates, determined very early in life and possibly induced by a combination of hereditary factors, fetal programming and early life environmental exposures including colonization with pathogenic airway bacteria.