As the underlying pathologies of common GI diseases are elucidated, it has become increasingly clear that many prevalent GI conditions first diagnosed in adult practice find their roots during development — from the prenatal period through childhood. Genetic variants or the presence of stressors during these key developmental stages play important roles in negative GI-health outcomes.
Irritable bowel syndrome (IBS) is a prime example of a common developmental GI condition in adults. IBS affects approximately 11 percent of the general population. Despite the fact that IBS is one of the most common problems treated by adult gastroenterologists, data supports the notion that IBS is the product of interactions that occur long before adulthood, with their foundation rooted in genetic variants or negative childhood exposures.
Although the precise genetic causes of IBS remain elusive, there is considerable evidence supporting their contribution to both IBS predisposition and pathogenesis. Clustering of IBS in families supports a heritable component as do twin studies that demonstrate a higher concordance among monozygotic compared to dizygotic twins. Twin studies have also revealed that differences can exist between IBS-discordant twins in utero; low birth weight has been associated with the development of IBS, as well as anxiety and depression.
Multiple studies have confirmed the strong association between the prevalence of early adverse life events, IBS diagnoses and IBS symptom severity.
These studies support the idea that hypothalamic–pituitary–adrenal axis dysfunction, which is hypothesized to be integral to IBS pathophysiology, may be the connection between impaired fetal development, IBS risk, and the association of IBS with anxiety and depression. Studies examining genetic abnormalities have focused primarily on single nucleotide polymorphisms on genes affecting neuronal function, the intestinal barrier and the serotonergic system and immunity.
Genetics, however, are usually not the sole determinant of chronic GI diseases, including IBS. Once considered innocent bystanders, environmental stressors that occur during fetal and child growth have also been found to profoundly influence intestinal development and adult GI function. Early adverse life events (EALs) encompass environmental stressors that occur during childhood, such as abuse and maternal neglect. Multiple studies have confirmed the strong association between the prevalence of EALs, IBS diagnoses and IBS symptom severity.
Although it is not known precisely how EALs are related to the eventual onset of IBS, there is data to suggest that the intestinal microbiota plays a role. The intestinal microbiota modulates both central and enteric nervous system (CNS and ENS, respectively) development, and EALs impact intestinal microbiota composition. Because the CNS and ENS are most vulnerable to influences such as the GI microbiome during early life, it is likely that deviations from an optimal intestinal-microbial community during this stage may disrupt normal ENS and CNS development and lead to brain-gut axis disease, including IBS. Further support that early-onset dysbiosis affects ENS development comes from studies showing that factors that impact the GI microbiota, such as childhood infection or antibiotic use, are linked to IBS symptomatology or diagnosis in children and adults.
Genetic predisposition and environmental influence likely don’t exist in isolation, and more research is needed to understand the interaction between the two. Though in their infancy, studies in epigenetics have begun to reveal links between pre- and post-natal environmental exposures and their impact on the epigenome. For example, epigenetic molecular mechanisms have been implicated in the stress-related dysregulation of the hypothalamic–pituitary–adrenal axis, which is of potential significance to the pathophysiology of IBS.
The concepts discussed here are not limited to IBS. They also apply to other complex, multifactorial diseases managed by gastroenterologists that have underpinnings rooted in development, including obesity, food allergy and IBD. A further understanding of which specific gene variants and/or developmental external factors contribute to long-term GI development and dysfunction will affect how gastroenterologists diagnose these diseases and, more importantly, when and how these conditions should be treated.
In most conditions, current therapy is overwhelmingly geared toward symptom reversal rather than prevention. In IBS, however, the increased plasticity of the ENS and CNS in development, with the CNS potentially influenced through the third decade of life, suggests that these may be opportune times for prevention of GI disease rather than reversal. As such, the next surge of IBS research may reveal preventative therapies, such as GI microbial manipulation, or aggressive psychotherapy as novel early prevention strategies for those at high risk for IBS, including individuals who experience high degrees of EALs or even primary presentations of anxiety or depression that are heavily associated with eventual IBS onset.
The implications of developmental intervention may expand way beyond the GI field. Studies over the past decade have shown direct correlations between the numbers of EALs and the prevalence of heart disease, diabetes, asthma and mental illness. Further, early-onset dysbiosis has also been associated with the onset of metabolic, psychiatric and immune disorders. Earlier intervention by microbial modulation and/or aggressive treatment of EALs with psychotherapy may thus provide a more holistic approach to overall disease prevention.
Dr. Margolis serves on editorial boards for the American Journal of Physiology and Neurogastroenterology and Motility, and is a councillor for the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.