Food-Grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis

Abstract

Elafin, a natural protease inhibitor expressed in healthy intestinal mucosa, has pleiotropic anti-inflammatory properties in vitro and in animal models. We found that mucosal expression of Elafin is diminished in patients with inflammatory bowel disease (IBD). This defect is associated with increased elastolytic activity (elastase-like proteolysis) in colon tissue. We engineered two food-grade strains of lactic acid bacteria (LAB) to express and deliver Elafin to the site of inflammation in the colon to assess the potential therapeutic benefits of the Elafin-expressing LAB. In mouse models of acute and chronic colitis, oral administration of Elafin-expressing LAB decreased elastolytic activity and inflammation and restored intestinal homeostasis. Furthermore, when cultures of human intestinal epithelial cells were treated with LAB secreting Elafin, the inflamed epithelium was protected from increased intestinal permeability and from the release of cytokines and chemokines, both of which are characteristic of intestinal dysfunction associated with IBD. Together, these results suggest that oral delivery of LAB secreting Elafin may be useful for treating IBD in humans.

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…On day 7, DSS was replaced with normal drinking water for 3 d. PD1 n-3 DPA or vehicle (0.3 μg/100 μL in saline 0.01% EtOH) were administered intraperitoneally daily (from day 5 to day 10). At the end of day 8 or 10, the colon was removed, measured, and examined for the consistency of the stool found within, as well as the gross macroscopic appearance and length, as described previously (37,38). Samples harvested for histology were analyzed by light microscopy and scored (37,38).…”

“…At the end of day 8 or 10, the colon was removed, measured, and examined for the consistency of the stool found within, as well as the gross macroscopic appearance and length, as described previously (37,38). Samples harvested for histology were analyzed by light microscopy and scored (37,38). MPO activity was performed as previously described (39).…”

Gut microbiome and anticancer immune response: really hot Sh*t!

“…90 Elafin-overexpressing L. casei and L. lactis reduced colitis in mice and ex vivo in inflamed epithelial cells from human colitis. 91 L. gasseri genetically modified to overexpress superoxide dismutase decreased colitis in IL-10-deficient hosts. 92 Prebiotics refer to indigestible food ingredients that selectively promote the colonization of healthy commensals such as the dietary fiber inulin that promotes Bifidobacteria growth.…”

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

“…Thus, in pancreatitis, trypsin secretion by pancreatic acinar cells could constitute the major candidate in mediating pain related to this disease. Recently, increased elastolytic activity (elastase-like proteolysis) in colon tissue of IBD patients has been characterized [49]. This increase in activity was coupled with a decrease of mucosal expression of elafin (endogenous elastase inhibitor) in patients with IBD [49].…”

“…Recently, increased elastolytic activity (elastase-like proteolysis) in colon tissue of IBD patients has been characterized [49]. This increase in activity was coupled with a decrease of mucosal expression of elafin (endogenous elastase inhibitor) in patients with IBD [49]. In mouse colitis, macrophage cathepsins are activated during colitis, and Cat-S activates nociceptors to induce visceral pain via PAR 2 [50].…”