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Early research has shown that proinflammatory cytokines (e.g., tumor necrosis factor- [TNF-] and interferon-) impair TJ integrity ( Regulatory Mechanisms of the TJ Barrier The innate immune system can sense pathogen-associated molecular patterns via pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing proteins (i.e., NOD1 and NOD2) ( in vitro ( in vitro and in vivo ( Endogenous machinery to suppress TJs is regulated by zonulin, a eukaryotic analog of the ZO toxin produced by Vibrio cholerae ( ex vivo ( The biological impact of zonulin on the intestinal epithelial barrier and the immune system has been defined in studies of zonulin-overexpressing mice, in which the mouse Hp1 gene is replaced with the human Hp2 (h Hp2 ) gene ( Hp2 knock-in enhanced intestinal permeability and promoted the development of dextran sodium sulfate (DSS)-induced colitis ( Hp2 knock-in mice also exhibited a proinflammatory immune response mediated by RORt + cells, especially IL7R + CD3 - RORt + (most likely, group 3) innate lymphoid cells in the small intestine ( Table 1 )

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