Early Life Environment and Natural History of IBD
Early Life Environment and Natural History of IBD
Growing literature on genetics and the microbiome supported by data from prospective epidemiologic cohorts suggests an important role for the external environment in incidence and natural history of IBD. Identification of relevant environmental exposures offer the promise of providing clues towards the etiopathogenesis of these complex and disabling diseases, and importantly allow for development of interventions that modify these factors to improve disease outcomes. This study, for the first time examined the association between early life exposures and disease outcome in IBD. Our analysis showed that a history of being breastfed was inversely associated with risk of surgery in CD, while exposure to cigarette smoke during childhood increased this risk independent of current smoking status.
The role of breastfeeding in immunologically mediated diseases has been examined in several prior studies; most have focused on it as a risk factor for incident disease and not on subsequent natural history. The reduction in risk of IBD in those who were breastfed in infancy was proposed in support of the hygiene hypothesis, which linked the rise in incidence of autoimmune disease to improvement in environmental hygiene and reduced exposure to childhood infections. However, the association between a history of being breastfed and risk of incident CD or UC has been inconsistent in the literature. Several studies failed to identify such an association while a Danish cohort suggested a trend towards protective effect. A large population-based case control study by Gearry et al. including over 600 patients each with CD, UC, and healthy controls demonstrated a protective association between breastfeeding and both diseases. Indeed, Corrao et al. demonstrated that lack of breastfeeding during infancy provided the highest population attributable risk for CD in women.
Newly established inception cohorts of CD confirm dysbiosis early on in disease. Prior studies have shown that specific bacteria such as the firmicute Faecalibacterium prausnitzii may be protective against recurrence after surgical resection confirming the central role of enteric microbiota in the development of disease. No prior studies examined the effect of breastfeeding on course of IBD. However, considerable biological plausibility exists to this hypothesis. Breastfeeding exerts one of the strongest influences on the gut microbiome. In an elegant study, Penders et al. sequenced the microbiome of 1,032 infants in the Netherlands and found that those who were exclusively breastfed had reduced colonization with Clostridium difficile, Bacteroides, and Lactobacilli and higher frequency of the protective bifidobacteria. Other studies demonstrated similar changes in the enteric microbiome of breastfed infants. This has mechanistic implications for the findings of our present study as specific microbial colonization in infancy such as with C difficile has been associated with increased risk of allergy and atopic disorders. Thus it is plausible that early life factors that influence the establishment of the 'normal' microbiome may have persistent effects on immune reactivity, thereby also influencing natural history of chronic inflammatory diseases.
Considerable literature exists regarding the effect of cigarette smoke on CD and UC -. It is well recognized that current smoking is a risk factor for incident CD and more aggressive disease course. Passive exposure to cigarette smoke has a similar direction of effect though the magnitude of association is weaker than that existing for personal history of smoking. Our findings suggest that remote exposure even early on in childhood may exert a similar effect on natural history of CD. Several prior studies have suggested childhood exposure to be a risk factor for incident CD or UC but have not examined it as a risk factor for more aggressive subsequent course. There are a few possible ways through which early exposure to cigarette smoke may exert its effect. First, it may alter the intestinal microbiome composition. It has been consistently demonstrated that early life exposure may have greater and more sustained effects on the gut microbiome than exposures later on in adult life. Second, cigarette smoke may disrupt protective immune mechanisms by impairing recovery from oxidative stress through its effect on the mononuclear cells. Finally, it is possible that smoking may lead to epigenetic alterations that subsequently influence natural history of disease. All these avenues merit further exploration and may offer important clues to the effect of environment on disease.
There are a few implications of our findings. To our knowledge, it is one of the first studies to demonstrate an association between specific early life environmental influences and subsequent outcomes in CD. The large size of our cohort with detailed exposure and outcome information allowed for sufficient power to test our hypotheses. If confirmed in subsequent cohorts, such studies can offer intriguing clues to pathogenesis and highlight the role of the differentially distributed microbiome species as potentially modifiable targets to improve disease outcomes. Further studies are required to prospectively sequence the microbiome at diagnosis in patients with established disease, ascertain environmental exposures, and examine the association with subsequent disease course. Research is also necessary to examine if this is conditional on host genotype as genetics may influence susceptibility to the environment.
We readily acknowledge several limitations to our study. First, exposure to early life environmental influences was through self-report. However, it is unlikely that self-report of early life risk factors would be susceptible to recall bias. Recall bias owing to differential time since diagnosis is also unlikely as the duration of disease was similar between both groups, and adjusted for in our final multivariate models. Second, we did not have information on duration of breastfeeding, exclusivity of breastfeeding, or age at weaning. Such factors may modify the association between breastfeeding and disease outcomes and merit further exploration. Third, residual confounding is a possibility as in any observational study. Fourth, due to fewer events (surgery) in UC, the statistical power to detect associations may be lower. However, most associations except for daycare exposure did not demonstrate even a trend towards an association. We also did not have information on other factors that have been associated with aggressive disease course including steroid use at diagnosis.
Discussion
Growing literature on genetics and the microbiome supported by data from prospective epidemiologic cohorts suggests an important role for the external environment in incidence and natural history of IBD. Identification of relevant environmental exposures offer the promise of providing clues towards the etiopathogenesis of these complex and disabling diseases, and importantly allow for development of interventions that modify these factors to improve disease outcomes. This study, for the first time examined the association between early life exposures and disease outcome in IBD. Our analysis showed that a history of being breastfed was inversely associated with risk of surgery in CD, while exposure to cigarette smoke during childhood increased this risk independent of current smoking status.
The role of breastfeeding in immunologically mediated diseases has been examined in several prior studies; most have focused on it as a risk factor for incident disease and not on subsequent natural history. The reduction in risk of IBD in those who were breastfed in infancy was proposed in support of the hygiene hypothesis, which linked the rise in incidence of autoimmune disease to improvement in environmental hygiene and reduced exposure to childhood infections. However, the association between a history of being breastfed and risk of incident CD or UC has been inconsistent in the literature. Several studies failed to identify such an association while a Danish cohort suggested a trend towards protective effect. A large population-based case control study by Gearry et al. including over 600 patients each with CD, UC, and healthy controls demonstrated a protective association between breastfeeding and both diseases. Indeed, Corrao et al. demonstrated that lack of breastfeeding during infancy provided the highest population attributable risk for CD in women.
Newly established inception cohorts of CD confirm dysbiosis early on in disease. Prior studies have shown that specific bacteria such as the firmicute Faecalibacterium prausnitzii may be protective against recurrence after surgical resection confirming the central role of enteric microbiota in the development of disease. No prior studies examined the effect of breastfeeding on course of IBD. However, considerable biological plausibility exists to this hypothesis. Breastfeeding exerts one of the strongest influences on the gut microbiome. In an elegant study, Penders et al. sequenced the microbiome of 1,032 infants in the Netherlands and found that those who were exclusively breastfed had reduced colonization with Clostridium difficile, Bacteroides, and Lactobacilli and higher frequency of the protective bifidobacteria. Other studies demonstrated similar changes in the enteric microbiome of breastfed infants. This has mechanistic implications for the findings of our present study as specific microbial colonization in infancy such as with C difficile has been associated with increased risk of allergy and atopic disorders. Thus it is plausible that early life factors that influence the establishment of the 'normal' microbiome may have persistent effects on immune reactivity, thereby also influencing natural history of chronic inflammatory diseases.
Considerable literature exists regarding the effect of cigarette smoke on CD and UC -. It is well recognized that current smoking is a risk factor for incident CD and more aggressive disease course. Passive exposure to cigarette smoke has a similar direction of effect though the magnitude of association is weaker than that existing for personal history of smoking. Our findings suggest that remote exposure even early on in childhood may exert a similar effect on natural history of CD. Several prior studies have suggested childhood exposure to be a risk factor for incident CD or UC but have not examined it as a risk factor for more aggressive subsequent course. There are a few possible ways through which early exposure to cigarette smoke may exert its effect. First, it may alter the intestinal microbiome composition. It has been consistently demonstrated that early life exposure may have greater and more sustained effects on the gut microbiome than exposures later on in adult life. Second, cigarette smoke may disrupt protective immune mechanisms by impairing recovery from oxidative stress through its effect on the mononuclear cells. Finally, it is possible that smoking may lead to epigenetic alterations that subsequently influence natural history of disease. All these avenues merit further exploration and may offer important clues to the effect of environment on disease.
There are a few implications of our findings. To our knowledge, it is one of the first studies to demonstrate an association between specific early life environmental influences and subsequent outcomes in CD. The large size of our cohort with detailed exposure and outcome information allowed for sufficient power to test our hypotheses. If confirmed in subsequent cohorts, such studies can offer intriguing clues to pathogenesis and highlight the role of the differentially distributed microbiome species as potentially modifiable targets to improve disease outcomes. Further studies are required to prospectively sequence the microbiome at diagnosis in patients with established disease, ascertain environmental exposures, and examine the association with subsequent disease course. Research is also necessary to examine if this is conditional on host genotype as genetics may influence susceptibility to the environment.
We readily acknowledge several limitations to our study. First, exposure to early life environmental influences was through self-report. However, it is unlikely that self-report of early life risk factors would be susceptible to recall bias. Recall bias owing to differential time since diagnosis is also unlikely as the duration of disease was similar between both groups, and adjusted for in our final multivariate models. Second, we did not have information on duration of breastfeeding, exclusivity of breastfeeding, or age at weaning. Such factors may modify the association between breastfeeding and disease outcomes and merit further exploration. Third, residual confounding is a possibility as in any observational study. Fourth, due to fewer events (surgery) in UC, the statistical power to detect associations may be lower. However, most associations except for daycare exposure did not demonstrate even a trend towards an association. We also did not have information on other factors that have been associated with aggressive disease course including steroid use at diagnosis.