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

Abstract

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.

Machine Learning Classification of Inflammatory Bowel Disease in Children Based on a Large Real-World Pediatric Cohort CEDATA-GPGE® Registry

“…Another possibility would be the inclusion of microbiome omics data. Kellermayer et al ( 32 ) have shown the correlation between this data and an inflammatory process in the intestines. The usage of this data could increase accuracy but also identify specific parameters that have an especially strong correlation to differing PIBD diagnosis.…”

An Immunologic Compatibility Testing Was Not Useful for Donor Selection in Fecal Microbiota Transplantation for Ulcerative Colitis

“…UC is an inflammatory bowel disease in which the dialogue between the gut microbiota and mucosal immunity is affected (2,21,22). FMT has been proposed as a useful tool for modifying the microbial gut ecosystem.…”

“…The interaction between the gut microbiota and immune system plays a relevant role in the etiopathogenesis of inflammatory bowel diseases, such as ulcerative colitis (UC) (1,2). A loss of immune tolerance to bacterial luminal antigens has been reported, triggering a local response (activation of dendritic cells), which spreads regionally and results in T-cell differentiation toward T helper (TH)-1, TH-2, TH-17 or regulatory T (Treg) phenotypes that ends in a "storm" of proinflammatory cytokines and chemokines, generating and perpetuating tissue damage (3).…”

“…A loss of immune tolerance to bacterial luminal antigens has been reported, triggering a local response (activation of dendritic cells), which spreads regionally and results in T-cell differentiation toward T helper (TH)-1, TH-2, TH-17 or regulatory T (Treg) phenotypes that ends in a "storm" of proinflammatory cytokines and chemokines, generating and perpetuating tissue damage (3). In fact, relevant differences in microbiota composition between inflamed and noninflamed intestinal mucosa have been reported in UC, according with the activity status of the disease (2,4). The genetic basis of UC indicates the protective role of various human polymorphisms in the interleukin (IL)-27 gene (5), as well as the predominant involvement of a TH-17 response, in close relationship with the intestinal microbiota (6,7).…”

Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in Humans

“…The preinjury high-risk state can be worsened further by risk modulating environmental changes such as dysbiosis resulting from early-life antibiotics exposure. 2 In this increased risk state, triggers (eg, NSAIDs, emulsifiers, or gastrointestinal infections) are hypothesized to cause barrier breaches igniting a flare. 1 , 3 The early responses to injury thus determine whether a trigger is harmful, as in UC, or can be contained, as in the healthy intestine.…”