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

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          Abstract

          <p id="d3757323e161">Identification of the trigger of human intestinal inflammation can be a compelling clinical strategy for developing effective and target-specific antiinflammatory therapeutics. The pathomimetic “gut inflammation-on-a-chip” inspired by dextran sodium sulfate (DSS)-induced colitis models in mice enabled the independent uncoupling of complex inflammatory cross-talks and the combinatorial recoupling of individual contributing factors one at a time to identify the initiator of inflammatory responses. Our discovery suggests that an intact epithelial barrier is necessary to maintain the “homeostatic tolerance” in response to physiological host–gut microbiome cross-talks. We also expound an insight of probiotic therapy that the undamaged epithelial barrier is a prerequisite for eliciting the probiotic efficacy. Finally, the gut inflammation-on-a-chip verifies how microphysiological systems can be successfully implemented to dissect the mechanisms of gastrointestinal diseases. </p><p class="first" id="d3757323e164">The initiation of intestinal inflammation involves complex intercellular cross-talk of inflammatory cells, including the epithelial and immune cells, and the gut microbiome. This multicellular complexity has hampered the identification of the trigger that orchestrates the onset of intestinal inflammation. To identify the initiator of inflammatory host–microbiome cross-talk, we leveraged a pathomimetic “gut inflammation-on-a-chip” undergoing physiological flow and motions that recapitulates the pathophysiology of dextran sodium sulfate (DSS)-induced inflammation in murine models. DSS treatment significantly impaired, without cytotoxic damage, epithelial barrier integrity, villous microarchitecture, and mucus production, which were rapidly recovered after cessation of DSS treatment. We found that the direct contact of DSS-sensitized epithelium and immune cells elevates oxidative stress, in which the luminal microbial stimulation elicited the production of inflammatory cytokines and immune cell recruitment. In contrast, an intact intestinal barrier successfully suppressed oxidative stress and inflammatory cytokine production against the physiological level of lipopolysaccharide or nonpathogenic <i>Escherichia coli</i> in the presence of immune elements. Probiotic treatment effectively reduced the oxidative stress, but it failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when the probiotic administration happened after the DSS-induced barrier disruption. Maintenance of epithelial barrier function was necessary and sufficient to control the physiological oxidative stress and proinflammatory cascades, suggesting that “good fences make good neighbors.” Thus, the modular gut inflammation-on-a-chip identifies the mechanistic contribution of barrier dysfunction mediated by intercellular host–microbiome cross-talk to the onset of intestinal inflammation. </p>

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          Most cited references41

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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                October 22 2018
                : 201810819
                Article
                10.1073/pnas.1810819115
                6233106
                30348765
                d084d169-f5fa-4e0c-bda0-f421fb9fe96a
                © 2018
                History

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