Intestinal barrier dysfunction orchestrates onset of inflammatory host-microbiome cross-talk (in a human gut inflammation-on-a-chip)

These GEITP pages have frequently discussed the growing realization of the “brain-gut-microbiome” importance in clinical health and disease. Human intestinal inflammation involves complex processes: mucosal injury, impaired barrier function, recruitment and infiltration of immune cells, and subsequent inflammatory responses that include release of inflammatory cytokines [various substances (e.g. interferons, interleukins, and growth factors) secreted by certain immune-system cells and having an effect on other types of cells]. Compromised biomechanical dynamics in the gut is also closely associated with the pathophysiology (study of functional changes associated with, or resulting from, disease or injury) of gut inflammation.

Animal models and clinical studies of intestinal inflammation have shown that aberrant intercellular interaction –– among the epithelium, gut microbiome, and immune components –– is the major contributing factor that causes inflammatory pathogenesis in the gut. Indeed, the pathogenic manifestation in inflammatory bowel disease (IBD) has been characterized as “leaky gut”, “dysbiosed gut microbiome”, and “hyperactivated immunity”.

To identify the initiator of inflammatory host–microbiome cross-talk, authors [see attached article] used a “gut inflammation-on-a-chip” undergoing physiological flow and motions that recapitulates the pathophysiology of dextran sodium sulfate (DSS)-induced inflammation in mouse models. DSS treatment significantly impairs –– without cytotoxic damage –– epithelial barrier integrity, villous microarchitecture, and mucus production; these functions were rapidly restored after stopping the DSS treatment. Authors found that the direct contact of DSS-sensitized epithelium and immune cells increases oxidative stress, in which luminal (i.e. inside the gut) microbial stimulation provoked production of inflammatory cytokines and immune-cell recruitment.

By contrast, an intact intestinal barrier successfully suppressed oxidative stress and inflammatory cytokine production against physiological levels of lipopolysaccharide (LPS) or nonpathogenic Escherichia coli bacteria, in the presence of immune signaling. Probiotic treatment effectively decreased oxidative stress –– but, intriguingly, failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when probiotic treatment was given after the DSS-induced barrier disruption.

Authors concluded that maintenance of epithelial barrier function is necessary and sufficient to control physiological oxidative stress and proinflammatory cascades, signifying that “good fences make good neighbors.” Thus, the modular gut inflammation-on-a-chip model identifies the mechanistic contribution of barrier dysfunction mediated by intercellular host–microbiome cross-talk preceding onset of intestinal inflammation.

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