Copyright ©The Author(s) 2021.
World J Gastroenterol. Nov 21, 2021; 27(43): 7402-7422
Published online Nov 21, 2021. doi: 10.3748/wjg.v27.i43.7402
Table 1 Antimicrobial peptides in the gastrointestinal tract
Antimicrobial peptide class
Specific antimicrobial peptides
Tissue expression
Biologic function
α-defensins (human neutrophil peptides)[5-9]DEFAHuman defensin 5 and 6 (HD5 and HD6)Paneth cellsConfers resistance to oral challenge with enteric pathogens, regulates the intestinal microbiota by reducing levels of segmented filamentous bacteria, restricts infection by limiting intestinal epithelial cell invasion
β-defensins[5,10-13]DEFBHuman β-defensins 1–4 (hBD-1, hBD-2, hBD-3, and hBD-4)Intestinal epithelial cellsAntimicrobial activity (hBD-2-4) against bacterial pathogens including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes, antimicrobial activity (hBD-1) against gram-positive commensals
Cathelicidin[14-22]CAMPCathelicidin (LL-37/hCAP18)Colonic epithelial cells, neutrophils, monocytes, macrophages, mast cellsCationic peptide that directly disrupts bacterial cell membranes, deficiency increases susceptibility to infection with enterohemorrhagic E. coli (EHEC)
Regenerating (Reg) protein[23-29]REGRegIII; Hepatocarcinoma-intestine pancreas (HIP)/pancreatitis-associated protein (PAP)Paneth cells, intestinal epithelial cellsRegulates intestinal homeostasis by maintaining a physical separation between epithelial cells and the microbiota, selective for gram-positive bacteria through interaction with cell wall peptidoglycan
Lactoferrin[30]LTFLactoferrinEpithelial cellsSecreted iron binding protein, sequesters free iron required for bacterial growth
Lipocalin[31,129]LCN2Lipocalin-2 (neutrophil gelatinase-associated lipocalin, GAL)Neutrophils, granulocytes, macrophages, epithelial cellsBinds to bacterial siderophore enterobactin and inhibits bacterial growth by sequestering iron
Calprotectin[32]S100A8, S100A9CalprotectinIntestinal epithelial cells, neutrophilsChelates and sequesters metal co-factors (manganese, zinc, iron) during infection and inhibits bacterial growth
Hepcidin[33]HAMP, LEAP1Hepcidin antimicrobial peptideIntestinal epithelial cellsRegulates iron absorption and homeostasis, inhibits bacterial growth by limiting iron availability
Galectin[34,35]LGALSGalectin-3, Galectin-4, Galectin-8Intestinal epithelial cellsGalectins has bactericidal activity against bacteria expressing blood group antigen, Gal-8 targets damaged vesicles for autophagy during bacteria invasion
Lysozyme[36]LYZLysozymePaneth cellsEnzymatic degradation of bacterial membranes, preference towards Gram-positive pathogens
Elafin[37]PI3Elafin (peptidase inhibitor 3)Intestinal epithelial cellsBinds to bacterial lipopolysaccharide (LPS) and modulates innate immunity
Secretory Leukocyte Protease Inhibitor (SLPI)[38,39]SLPISLPIIntestinal epithelial cells, paneth cells, neutrophils, macrophagesProtease inhibitor binds to bacterial mRNA and DNA, dose-dependent bactericidal properties of SLPI against both Gram-positive and Gram-negative bacteria, has fungicidal properties
Table 2 Antimicrobial peptides in preclinical models of inflammatory bowel disease
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 colonGenetic overexpression, intraperitonealMurine dextran sulfate sodium (DSS) colitisMild 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 cellsIntraperitonealMurine dextran sulfate sodium (DSS) colitis, SCID mice, human colon cell culturesBody 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 colonIntrarectalMurine dextran sulfate sodium (DSS) colitis, human colon cell culturesAdministration 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 SubcutaneousMurine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis, T cell transfer colitis modelTreatment 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 colonGenetic knockoutsMurine dextran sulfate sodium (DSS) colitisIncreased 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 colonIntraperitonealMurine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis, T cell transfer colitis modelLL-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 colonIntracolonic, intravenous2,4,6-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 colonGenetic knockouts, intrarectalMurine dextran sulfate sodium (DSS) colitisCathelicidin 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 cellsIntrarectalMurine dextran sulfate sodium (DSS) colitis, human colon cell culturesVitamin 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 colonTransgenic expression, adenoviral deliveryMurine dextran sulfate sodium (DSS) colitis, 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitisIn 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 colonEndogenous expressionMurine dextran sulfate sodium (DSS) colitisEpithelial 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 colonOralMurine dextran sulfate sodium (DSS) colitisDML 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 colonGenetic SLPI deficiency, oralMurine dextran sulfate sodium (DSS) colitis, T cell transfer colitis modelTslp−/− 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 colonOralRat dextran sulfate sodium (DSS) colitisDSS-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 colonEndogenous expressionMurine dextran sulfate sodium (DSS) colitis, T cell transfer Colitis modelTNFα inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process
Table 3 Biomarker applications of antimicrobial peptides in patients with inflammatory bowel disease
Antimicrobial peptides
Type of IBD
Biomarker application
Key findings
Holgersen et al[110]Alpha defensins 5 and 6 (DEFA5/DEFA6)UCIBD diagnosis Marked upregulation of DEFA5 and DEFA6 in terminal ileal biopsies of inflamed ulcerative colitis relative to normal controls
Wehkamp et al[111]Alpha defensin (HD -5/6)UC/CDIBD diagnosis HD-5/6 both decreased in ileal Crohn's, and this correlated with a decrease in transcription factor Tcf-4, a known regulator of Paneth cell differentiation. Normal levels were observed in UC and colonic Crohn's
Yamaguchi et al[112]Alpha defensin (HNP1-3), beta-defensin (HBD-2)UC/CDDisease activityHNP-1-3 all elevated in IBD patients, while HBD-2 levels normal; serum HNP1-3 levels correlated with disease severity for Crohn's
Kanmura et al[113]Alpha defensin (HNP)UC/CDDisease activityFecal-HNP levels were markedly elevated in both UC and Crohn's, but slightly more so in Crohn's; F-HNP was significantly higher during flares of UC than remission. For UC, HNP levels correlated with Mayo endoscopic score
Cunliffe et al[114]Alpha defensin (HNP 1-3)UC/CDDisease activitySurface epithelial cells strongly immunoreactive for neutrophil defensins and lysozyme were seen in active ulcerative colitis and Crohn's disease (but not normal or inactive IBD) mucosal samples. Many of these cells coexpressed both antimicrobial proteins.
Tran et al[116]CathelicidinUC/CDDisease activityCathelicidin levels were significantly increased in IBD patients and were inversely correlated with CD activity. In moderate to severe IBD, higher cathelicidin levels before treatment correlated with better prognosis.
Krawiec et al[115]CathelicidinUC/CDIBD diagnosis Cathelicidin was significantly increased in patients with ulcerative colitis (1073.39 ± 214.52 ng/mL) and Crohn’s disease (1057.63 ± 176.03 ng/mL) patients compared to controls (890.56 ± 129.37 ng/mL) (P = 0.0003)
Gubatan et al[21]CathelicidinUCDisease activity, clinical relapseIn ulcerative colitis patients, serum 25(OH)D positively correlated with serum and colonic cathelicidin. Higher serum cathelicidin is associated with decreased risk of histologic inflammation and clinical relapse but not independent of 25(OH)D or baseline inflammation
Borkowska et al[118]LactoferrinUC/CDIBD diagnosis, disease activityFecal concentration of lactoferrin in children with IBD was significantly higher than in the controls. The sensitivity and specificity were 80.7% and 92.7%, respectively, and its positive and negative prognostic values were 96.8% and 63.3%, respectively
Sugi et al[119]Lactoferrin, lysozymeUC/CDDisease activityLactoferrin and lysozyme were significantly increased in the active phases of CD and UC relative to inactive. They both correlated with fecal Hb concentration in UC, and with alpha 1-AT concentration in CD
Sidhu et al[120]LactoferrinUC/CDIBD diagnosis, disease activityLactoferrin levels were significantly higher in IBD patients compared with IBS/healthy controls (P < 0.001). The sensitivity, specificity, positive and negative predictive values of lactoferrin in distinguishing active IBD from IBS/healthy controls were 67% and 96%, 87% and 86.8% respectively
Wang et al[121]LactoferrinUC/CDIBD diagnosisFL test has a high sensitivity (82%) and specificity (95%) for the discrimination of patients with IBD against non-IBD patients
Kane et al[122]LactoferrinUC/CDDisease activityFecal lactoferrin was 90% specific for identifying inflammation in patients with active IBD. Elevated fecal lactoferrin was 100% specific in ruling out IBS
Turner et al[123]LactoferrinUCIBD diagnosis Lactoferrin levels significantly were elevated in pediatric UC patients, but were not responsive to change or predictive of response to corticosteroids
Wang et al[132]ElafinCDDisease activity, intestinal stricturesHigh serum elafin levels were associated with a significantly elevated risk of intestinal stricture in CD patients. Serum elafin levels had weak positive correlations with clinical disease activity but not endoscopic disease activity
Zhang et al[133]ElafinUC/CDDisease activityThe expression of elafin mRNA in peripheral blood in active IBD patients is decreased, which may be correlated with the activity of IBD, and negatively correlated with corresponding disease activity score
Motta et al[130]ElafinUC Disease activityStudy identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. Study demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier and modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcript
Schmid et al[134]Elafin and SLPIUC/CDDisease activity Levels of mRNA and immunostaining of the antiproteases elafin and SLPI were enhanced strongly in inflamed versus noninflamed UC
Frol'ová et al[124]Galectin-3UC/CDDisease activitySerum concentrations were significantly increased in specimen of patients with active and remission-stage ulcerative colitis and Crohn's disease (relative to healthy controls)
Yu et al[125]Galectin-1, -3UC/CDIBD diagnosis Serum level of galectin-1 and -3, but not galectins-2, -4, -7 and -8, were significantly higher in IBD patients than in healthy people. None of the galectins however were able to distinguish active disease from remission in UC or CD
Tibble et al[97]CalprotectinCDIBD diagnosisThe cross-sectional study showed a sensitivity of 96% for calprotectin in discriminating between normal subjects and those with Crohn's disease. With a cutoff point of 30 mg/L fecal calprotectin has 100% sensitivity and 97% specificity in discriminating between active CD and irritable bowel syndrome
Moniuszko et al[100]CalprotectinUC/CDDisease activity, progressionRapid bedside FC test reliably detected disease flares in patients with both UC and CD. FC levels increased even with early signs of inflammations; values were lower in isolated small bowel disease for CD patients
Pous-Serrano et al[101]CalprotectinCDDisease activityFC was the only inflammatory marker significantly associated with the degree of histologic inflammation in surgical specimens
Scheopfer et al[102]CalprotectinCDDisease activityFC correlates more closely with endoscopic disease activity that CRP, blood leukocytes, and CDAI. It was the only marker that reliably discriminated inactive from mild, moderate, and highly active disease, underscoring its value in disease monitoring
Ferreiro-Iglesias et al[103]CalprotectinUC/CDRelapseIn IBD patients under Infliximab maintenance therapy, high FC levels allow predicting relapse within the following 2 mo. Long-term remission is associated with low calprotectin levels
Klingberg et al[104]CalprotectinCDIBD diagnosis, treatment monitoringFC was a useful predictor of the development of CD in patients with ankylosing spondylitis; NSAIDs increase FC levels; FC levels drop following TNF-blocker treatments
Godny et al[109]CalprotectinCDTreatment monitoringFC decreases following successful diet-based treatment of active CD
Karaskova et al[126]HepcidinUC/CDIBD diagnosisSerum hepcidin concentration was significantly decreased in IBD children compared with controls; levels did not differ significantly between patients with CD and UC
Martinelli et al[128]HepcidinUC/CDIBD diagnosis, iron deficiency MonitoringSerum hepcidin was significantly higher in IBD patients with active disease versus healthy and celiac patients. Hepcidin levels corresponded with iron malabsorption and other inflammatory biomarkers like ESR
Aksan et al[129]HepcidinUC/CDResponse to iron supplementationHigher hepcidin and other inflammatory markers correlated with decreased iron absorption follow supplementation
Zollner et al[127]LipocalinCDClinical and endoscopic activity Fecal lipocalin-2 levels of 78.4 and 0.56 μg/g in Crohn’s disease patients for clinical and endoscopic activity, respectively, corresponded well with fecal calprotectin levels in UC patients (R = 0.87, P < 0.001)