The study shows that the natural peptide LL‑37 helps gut lining cells move, grow protective mucus, and avoid cell death, which together strengthen the intestinal barrier. This was seen in lab-grown human gut cells, and the effects involve specific cell receptors and signaling pathways.

The human cathelicidin LL-37 is involved in innate immune responses, angiogenesis and wound healing. Functions in maintenance and re-establishment of intestinal barrier integrity have not been characterized yet. Following direct and indirect stimulation of human colonic HT-29 and Caco-2 cells with LL-37 the cellular viability, rate of apoptosis, proliferation and wound healing were determined. Expression of mucins and growth factors was quantified by real-time PCR and Western blotting. Direct application of LL-37 stimulated migration in Caco-2 cells expressing the proposed LL-37 receptor P2X7. Intestinal epithelial cell (IEC) proliferation was not altered. Indirectly, LL-37 significantly enhanced IEC migration via release of growth factors from subepithelial fibroblasts and IEC. Furthermore, LL-37 induced the expression of protective mucins in IEC and abated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis in IEC. LL-37 induced signaling is mediated in part by the P2X7 receptor, the epidermal growth factor receptor and the p38 mitogen-activated protein kinase (MAPK). LL-37 contributes to maintenance and re-establishment of the intestinal barrier integrity via direct and indirect pathways. These features, in addition to its known antimicrobial properties, suggest an important role for this peptide in intestinal homeostasis.