Larazotide Acetate Protects the Intestinal Mucosal Barrier from Anoxia/Reoxygenation Injury via Various Cellular Mechanisms.
This study investigated the cellular mechanisms by which larazotide acetate (LA), a synthetic octapeptide in clinical development for celiac disease, protects the intestinal epithelial barrier. Researchers pretreated two intestinal epithelial cell lines — C2BBe1 (human) and IPEC-J2 (a "leaky" porcine line) — with LA before exposing them to anoxia/reoxygenation (A/R) injury, a model of ischemia-reperfusion stress. LA pretreatment significantly increased transepithelial electrical resistance (TEER), a measure of barrier integrity, and preserved the normal localization of tight junction (TJ) proteins. RNA sequencing identified enriched gene sets related to barrier regulation, small GTPase signaling, protein phosphorylation, cell proliferation, and migration. Consistent with transcriptomic findings, LA markedly reduced phosphorylation of myosin light chain-2 (MLC-2), suggesting modulation of the ROCK signaling pathway, which is known to influence TJ dynamics. LA also enhanced epithelial cell proliferation. Limitations include exclusive reliance on in vitro cell culture models with no animal or human data, and the use of a single, fixed LA concentration. The authors conclude that LA stabilizes tight junctions, reduces MLC-2 phosphorylation, and promotes epithelial renewal, supporting its broader potential in gastrointestinal conditions involving mucosal barrier disruption.