Antimicrobial peptides and the gut microbiome in inflammatory bowel disease

Table 2 Antimicrobial peptides in preclinical models of inflammatory bowel disease

Ref.	Antimicrobial peptides (expression location)	Antimicrobial peptide delivery	Preclinical models (animal, human cell culture)	Key findings
Maeda et al[79]	Alpha defensins: Human neutrophil peptide-1 (HNP-1) murine colon	Genetic overexpression, intraperitoneal	Murine dextran sulfate sodium (DSS) colitis	Mild transgenic overexpression of HNP-1 reduces the susceptibility to DSS-induced colitis; Intraperitoneal injection of low-dose HNP-1 ameliorates DSS-induced colitis; The amelioration of colitis by low-dose HNP-1 may be explained by its indirect antimicrobial activity
Hashimoto et al[80]	Alpha defensins: Human neutrophil peptide-1 (HNP-1): Murine colon, human colon cells	Intraperitoneal	Murine dextran sulfate sodium (DSS) colitis, SCID mice, human colon cell cultures	Body weight and colon length significantly decreased, and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP-1-treated mice compared with PBS-treated mice. High concentrations of HNP-1 aggravate DSS-induced colitis, including upregulated expression of such macrophage-derived cytokines as IL-1β
Han et al[82]	Porcine β-defensin (pBD)2: Murine colon	Intrarectal	Murine dextran sulfate sodium (DSS) colitis, human colon cell cultures	Administration of pBD2 effectively attenuated colonic inflammation in mice with DSS induced colitis. pBD2 reduced the increased serum and colon levels of TNF-a, IL-6 and IL-8 all caused by DSS. The effects of pBD2 appeared to be through upregulation of the expression of genes associated with tight junctions and mucins
Koeninger et al[81]	Beta defensins: human beta defensin 2 (HBD-2): Murine colon	Subcutaneous	Murine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis, T cell transfer colitis model	Treatment improved disease activity index and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation
Koon et al[73]	Cathelicidin (LL-37): Murine colon	Genetic knockouts	Murine dextran sulfate sodium (DSS) colitis	Increased expression of cathelicidin in the colon of DSS-exposed mice; Compared with WT mice, cathelicidin KO mice developed a more severe form of DSS-induced colitis; Cathelicidin protects against induction of colitis in mice; Increased expression of cathelicidin in monocytes and experimental models of colitis involves activation of TLR9-ERK signaling by bacterial DNA
Fabisiak et al[83]	Cathelicidin (LL-37) KR-12 (active fragment of LL-37): Murine colon	Intraperitoneal	Murine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis, T cell transfer colitis model	LL-37 and KR-12 (1 mg/kg, ip, twice daily) showed a decrease in macroscopic and ulcer scores in the acute TNBS-induced model of colitis. KR-12 (5 mg/kg, ip, twice daily) reduced microscopic and ulcer scores in the semi-chronic and chronic TNBS-induced models of colitis compared with inflamed mice
Yoo et al[84]	Cathelicidin (LL-37): Murine colon	Intracolonic, intravenous	2,4,6-trinitrobenzenesulfonic acid (TNBS) Colitis,	Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice compared with vehicle administration. Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts
Tai et al[85]	Cathelicidin (LL-37): Murine colon	Genetic knockouts, intrarectal	Murine dextran sulfate sodium (DSS) colitis	Cathelicidin knockout mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS colitis. Intrarectal administration of plasmids encoding cathelicidin reversed colitis in cathelicidin knockout mice
Gubatan et al[21]	Cathelicidin (LL-37): Murine colon, human colon cells	Intrarectal	Murine dextran sulfate sodium (DSS) colitis, human colon cell cultures	Vitamin D-induced cathelicidin in human colonic epithelial cells suppressed Escherichia coli growth. Intrarectal cathelicidin reduced the severity of DSS colitis but did not mitigate the impact of colitis on microbial composition
Motta et al[91]	Elafin: Murine colon	Transgenic expression, adenoviral delivery	Murine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis	In mice given TNBS or DSS, transgenic expression of elafin protected against the development of colitis. Similarly, adenoviral delivery of Elafin significantly inhibited inflammatory parameters. Elafin modulated a variety of inflammatory mediators in vitro and in vivo and strengthened intestinal epithelial barrier
Ogawa et al[28]	RegIII (HIP/PAP): Murine colon	Endogenous expression	Murine dextran sulfate sodium (DSS) colitis	Epithelial expression of Reg III or HIP/PAP was induced under mucosal inflammation initiated by exposure to commensal bacteria or DSS as well as inflamed IBD colon
Jiang et al[93]	Donkey milk lysozyme (DML): Murine colon	Oral	Murine dextran sulfate sodium (DSS) colitis	DML ameliorated weight loss, colon damage and mucosal inflammation in DSS colitis mice. DML improved mechanical barrier function and increased gut microbiota composition diversity, promoting growth of probiotics and inhibiting pernicious bacteria
Reardon et al[92]	Secretory leukocyte peptidase inhibitor (SLPI): Murine colon	Genetic SLPI deficiency, oral	Murine dextran sulfate sodium (DSS) colitis, T cell transfer colitis model	Tslp−/− mice lead to endogenous SLPI deficiency which exacerbated DSS colitis. Treatment with recombinant SLPI (rSLPI) reduced DSS-induced mortality in Tslp−/− mice
Togawa et al[95]	Lactoferrin: Rat colon	Oral	Rat dextran sulfate sodium (DSS) colitis	DSS-induced colitis was attenuated by oral administration of lactoferrin in a dose-dependent manner. Reduced inflammation in response to lactoferrin was correlated with the significant induction of the anti-inflammatory cytokines and with significant reductions in the pro-inflammatory cytokines
Shanmugam et al[96]	Hepcidin: Murine colon	Endogenous expression	Murine dextran sulfate sodium (DSS) colitis, T cell transfer Colitis model	TNFα inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process