Epigenetics and the developmental origins of inflammatory bowel diseases

Abstract

The gut microbiota, the intestinal mucosa and the host immune system are among the large biological networks involved in the development of inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC). Host genetics and environmental factors can significantly modulate the interactive relationships among these biological systems and influence predilection toward IBD. High monozygotic twin discordance rates and the rapid rise in the prevalence of IBD indicate that environmental influences may be as important or even more important in their pathogenesis than genetic susceptibility. However, the nature and timing of environmental factors critical for inducing IBD remain largely unknown. The molecular mechanisms and the key biological component(s) that may be affected by such factors are also in question. Epigenetic changes, such as DNA methylation (the methylation of cytosines followed by a guanine in CpG dinucleotides) can be modified by environmental influences during finite developmental periods and have been implicated in the pathogenesis of IBD. Mucosal DNA methylation can also react to changes in the commensal microbiota, underscoring the intercalating relationships among the large biological systems involved in gastrointestinal disorders. Therefore, transient environmental influences during specific periods of development may induce critical change(s) in an isolated or concomitant fashion within the intestinal biomic networks and lead to increased susceptibility to IBD. The present review focuses on the emerging paradigm shift considering IBD to originate from critical environmental effects during pre- and postnatal development.

Figure 1)

Estimation of relative genetic contribution to common gastrointestinal diseases based on monozygotic (MZ) and dizygotic (DZ) twin concordance rates. CeD Celiac disease; CD Crohn disease; IBS Irritable bowel syndrome; UC Ulcerative colitis

Figure 2)

Upper panel Epigenetic mechanisms. A DNA methylation (and hydroxymethylation) can occur in cytosine-guanine dinucleotides (C^m pG). It usually negatively correlates ( ⊤ ) with transcription when present in gene promoter regions, but most commonly positively associates (→) with transcription when present within the gene. B Histone modification or post-translational modification (PTM) of histones correlates with gene transcription in a variable manner. C Noncoding RNAs (ncRNAs) can inhibit gene transcription and messenger RNA (mRNA) translation. They can also increase mRNA decay, thereby inducing pretranslational inhibition of gene expression. D Autoregulation provides a feedback loop for proteins to inhibit their own transcription. Lower panel Dynamic interaction between epigenetic mechanisms can provide a complex modulation of pretranslational gene expression

Figure 3)

Developmental plasticity, epigenetics and inflammatory bowel diseases (IBDs). Upper panel Developmental plasticity is higher during fetal development secondary to the massive molecular processes (intense cell division and differentiation) in flux. Therefore, environmental influences can significantly impact the fetus (thicker arrow) through the involvement of epigenetic mechanisms. Developmental plasticity progressively decreases postnatally (indicated by thinner arrows for environmental influences affecting pediatric development and adult aging). IBD presents in children (25%) and in young adults. Nevertheless, environmentally induced fetal changes are likely to contribute more to the onset of the disorders than postnatal modifications secondary to this decline in developmental (including epigenetic) plasticity. Lower panel Nongenetic mechanisms, which can be environmentally more labile than the genetic code, contribute more to common gastrointestinal disorders such as IBD and irritable bowel syndrome (IBS) than celiac disease or monogenic gastrointestinal diseases

Figure 4)

Prenatal (A) and postnatal (B) environmental influences can impact the interactive biological networks (genome and epigenome of the intestines and the associated immune system) involved in inflammatory bowel disease. The uterus, placenta, and/or amniotic fluid communicate maternal exposures toward the fetus in lack of a commensal microbiota during prenatal development. However, postnatally, environmental exposures directly affect the interactive communication between the intestinal microbiota and the epigenome of the various host systems involved in inflammatory bowel disease