The Gut Microbiome and the Triple Environmental Hit Concept of Inflammatory Bowel Disease Pathogenesis

The incidence of chronic inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC) have significantly increased in recent decades implicating environmental effects. The developmental origin of disease concept provides a theoretical framework by which the complex interplay between environmental factors and host cells, particularly during vulnerable time periods, ultimately cause disease, such as IBD. Epigenetics has been proposed as the underlying mechanism within this concept, turning environmental triggers into stable changes of cellular function. Adding further to the complexity of IBD is the gut microbiome, which is equally responsive to the environment, and can impact host cell function, where recent findings underscore the stochastic and individualized nature of such effects. We review the microbiome literature through a novel triple environmental hit concept (priming, modulation, and trigger) of IBD pathogenesis. We propose that there are at least 3 distinct stages during an individual's lifespan where random/stochastic events driven by environmental influences are necessary for ultimately developing IBD. By this means, we speculate that microbiome-directed therapeutics carry potential for individualized prevention and dynamic treatment of IBD.