Postinfectious, diarrhea-predominant, irritable bowel syndrome (PI-IBS-D) is difficult to treat owing to its unknown pathophysiology. Extracellular vesicles (EVs) derived from human colon tissue and long noncoding RNAs (lncRNAs), such as growth arrest-specific 5 (GAS5), may play key roles in the pathophysiology of PI-IBS-D. To determine whether altered colonic EV lncRNA signaling leads to gastrointestinal dysfunction and heightened visceral nociception in patients with PI-IBS-D via the GAS5/miR-23ab/NMDA NR2B axis, we conducted translational studies, including those on (a) the role of colonic EV lncRNAs in patients with PI-IBS-D, human colonoids, and PI-IBS-D tissues; (b) i.p. injection of colonic EVs from patients with PI-IBS-D into Rab27a/b-/- mice (P-EV mice) to investigate whether colonic EVs drive visceral hypersensitivity in vivo via the GAS5/miR-23ab/NMDA NR2B axis; and (c) treatment of mice with oligo-miR-23 precursors and anti-GAS5 Vivo-Morpholinos for GAS5/miR-23ab/NMDA NR2B axis mechanisms. Colonic EVs from patients with PI-IBS-D, but not from control participants, demonstrated reduced miR-23a/b expression caused by enhanced GAS5 expression, which drives increased NR2B expression. Intraperitoneal injection of anti-GAS5-Vivo-Morpholino into P-EV mice increased miR-23 levels and decreased NR2B expression and VMR to CD. EVs are internal messengers that alter gastrointestinal function and increase visceral nociception in patients with PI-IBS-D. Strategies to deliver EVs to modulate GAS5/miR-23ab/NMDA NR2B axis signaling may lead to new and innovative treatments for patients with PI-IBS-D.
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