Oral delivery of pancreatitis-associated protein by Lactococcus lactis displays protective effects in dinitro-benzenesulfonic-acid-induced colitis model and is able to modulate the composition of the microbiota.

Antimicrobial peptides secreted by intestinal immune and epithelial cells are important effectors of innate immunity. They play an essential role in the maintenance of intestinal homeostasis by limiting microbial epithelium interactions and preventing unnecessary microbe-driven inflammation. Pancreatitis-associated protein (PAP) belongs to Regenerating islet-derived III proteins family and is a C-type (Ca+2 dependent) lectin. PAP protein plays a protective effect presenting anti-inflammatory properties able to reduce the severity of colitis, preserving gut barrier and epithelial inflammation. Here, we sought to determine whether PAP delivered at intestinal lumen by recombinant Lactococcus lactis strain (LL-PAP) before and after chemically induced colitis is able to reduce the severity in two models of colitis. After construction and characterization of our recombinant strains, we tested their effects in dinitro-benzenesulfonic-acid (DNBS) and Dextran sulfate sodium (DSS) colitis model. After the DNBS challenge, mice treated with LL-PAP presented less severe colitis compared with PBS and LL-empty-treated mice groups. After the DSS challenge, no protective effects of LL-PAP could be detected. We determined that after 5 days administration, LL-PAP increase butyrate producer's bacteria, especially Eubacterium plexicaudatum. Based on our findings, we hypothesize that a treatment with LL-PAP shifts the microbiota preventing the severity of colon inflammation in DNBS colitis model. These protective roles of LL-PAP in DNBS colitis model might be through intestinal microbiota modulation.

Protective effects of HTD4010, a Reg3α/PAP-derived peptide, in mouse model of acute pancreatitis via toll-like receptor 4 pathway.

Acute pancreatitis (AP) is one of the most common digestive tract diseases, but effective drug therapy is still lack. Regenerating gene protein 3α (Reg3α) administration significantly reduced the severity of AP in mice. HTD4010 is a new 15 amino acid long synthetic peptide and its biological activities are similar to Reg3α. This study aimed to explore whether HTD4010 could protect pancreatic acinar cells against necrosis and decrease the inflammatory response in AP, and thus to explore underlying mechanisms. It was shown that administration of HTD4010 alleviated significantly the severity of biliary AP (BAP), characterized as less degree of pancreatic histological damage and acinar cell injury (both apoptosis and necroptosis), lower levels of serum amylase and pro-inflammatory cytokines. Moreover, HTD4010 down-regulated the expression of toll-like receptor 4 (TLR4) protein, and TLR4 deficiency eliminated the protective effect of HTD4010 on BAP in mice. In conclusion, these results showed that HTD4010 could alleviate the severity of pancreatitis, reduce the acinar cells necrosis and inflammatory response possibly by TLR4 signaling pathway in AP.