Intestinal epithelial claudin‐2‐dependent paracellular pores drive both diarrhea and survival in immune‐mediated colitis

Abstract

The tight junction protein claudin 2 (cldn2) creates paracellular pores that carry water and small cations. Intestinal cldn2 expression falls rapidly after weaning, but is increased in human and murine colitis. We used the CD4+CD45RBhi adoptive transfer (AT) colitis model and cldn2−/− mice to determine the impact of cldn2 upregulation on progression of immune‐mediated colitis. By day 30, cldn2+/+RAG1−/− (WT) AT recipients developed colitis associated with positive fecal occult blood test (FOBT, 47%), weight loss, diarrhea, and increased intestinal cldn2 expression. Appearance of FOBT (18% at d30), weight loss, and diarrhea were markedly delayed in cldn2−/−RAG1−/− (KO) mice. Although fecal water content was similar in WT (58±5%) and KO (54±1%) mice at baseline, disease‐associated increases were far greater in WT mice at day 23 (WT 70±1%; KO 58±1%) and 50 (WT 89±1%; KO 65±1%). Remarkably, 40% of cldn2 KO mice died by day 50, while all WT mice survived. These data indicate that development of diarrhea is enhanced by cldn2 upregulation that, in turn, facilitates paracellular water and cation flux to augment disease severity. Prevention of cldn2‐dependent diarrhea improves clinical status in early disease. However, KO mice ultimately display increased mortality, possibly due to loss of the innate flushing response. Thus, cldn2 upregulation in colitis may be both maladaptive (early) and adaptive (late).