Antimicrobial Peptides: An Emerging Approach to Treating Colitis
Received Date: Feb 27, 2016 / Accepted Date: Mar 01, 2016 / Published Date: Mar 07, 2016
Antimicrobial peptides are endogenous peptides typically expressed on mucosal surfaces, such as the mouth, intestines, and respiratory tract. These mucosal surfaces are typically in close contact with the external environment and micro biota. Over the last decade, the role of antimicrobial peptides in colitis has become increasingly apparent, and some antimicrobial peptides show promise as future therapeutic approaches to treat colitis. Pharmaceutical companies and laboratories are developing clinically useful versions of antimicrobial peptides with high efficacy, robust chemical stability, and excellent safety profile.
Cathelicidin is a 37-amino acid antimicrobial peptide called LL-37 in humans and mCRAMP in mice . It may directly kill bacteria by pore formation on the cell membrane . On the other hand, cathelicidin mediates an anti-inflammatory effect by binding to endotoxin lipopolysaccharide and neutralizing its toxicity . Recent evidence shows that cathelicidin may bind to the bacterial sensor formyl peptide receptor-like 1 (FPRL1) and mediate its chemotactic activity in immune cells . In the colonic mucosa of inflammatory bowel disease patients, cathelicidin mRNA expression is increased in ulcerative colitis (UC) patients but not Crohn’s disease (CD) patients . However, this increase does not correlate with local inflammatory activities in the colonic tissues.
In mice, the lack of endogenous cathelicidin also contributes to exacerbation of DSS-mediated colitis . Intracolonic administration of cathelicidin peptide or oral administration of cathelicidinexpressing bacteria reduces colonic inflammation in mice after exposure to dextran sulfate (DSS) [7,8]. These findings suggest the protective role of cathelicidin in colitis.
Cathelicidin may also play a role in inhibiting colitis-associated intestinal fibrosis in Crohn’s Disease patients. Around 10-20% of Crohn’s disease patients develop stricture or intestinal fibrosis that has no established way for prevention or reversal . The current last resort option is surgery, which can affect the quality of life. A recent report shows that intracolonic cathelicidin peptide administration effectively inhibits intestinal fibrosis in mice caused by exposure to trinitrobenzene sulfonic acid and Salmonella . This study also reveals that cathelicidin can inhibit fibrogenic gene (collagen) expression in fibroblasts directly via an ERK-dependent mechanism. Another study demonstrates that cathelicidin can inhibit epithelialmesenchymal transition (EMT) . Inhibition of EMT eventually reduces the generation of fibroblasts, the cellular source of fibrogenesis.
Colonic expression of cathelicidin is also increased in C. difficile - infected patients. In mice infected with C. difficile , intracolonic administration of cathelicidin peptide inhibits colitis . Unfortunately, it is difficult to translate these important bench-side findings to clinical bedside application because cathelicidin can be degraded in body fluid and cause hemolysis [13-15]. Alternatively, N8 Medical Inc. has recently developed cathelicidin mimic CSA13 that shows superior antimicrobial capability [13,14]. Its non-peptide nature makes CSA13 resistant to degradation, and CSA13 does not cause a significant hemolysis in human red blood cells . However, its efficacy in colitis and its safety profile in vivo still need further investigations.
Lactoferrin is a glycoprotein originally found in milk . In IBD patients, fecal lactoferrin is a novel non-invasive biomarker of IBD with high sensitivity and specificity . Deficiency of lactoferrin augments azoxymethane- and DSS-mediated colitis-associated colorectal dysplasia in mice . Oral feeding of lactoferrin significantly reduces DSS-mediated colitis in rats . Despite promising preclinical findings, lactoferrin has not been used to treat IBD patients in clinical trials. The reason of this is that some IBD patients (13-29%) develop anti-lactoferrin autoantibodies . The clinical significance of the autoantibodies is unclear but may potentially neutralize the therapeutic effect of lactoferrin.
Elafin consists of 117 amino acids and possesses antimicrobial and anti-protease activities [22,23]. Colonic Elafin mRNA expression is increased in UC patients, but not CD patients and healthy control subjects . Another study shows that elafin is typically found in colonic epithelial cells of UC patients . In terms of therapeutic potential of elafin, elafin-expressing food grade lactic acid bacteria significantly inhibit DSS-mediated acute colitis and CD4CD45RBhimediated chronic colitis in mice . However, it is not known whether elafin is useful in clinical applications.
Clinical Applications Of Antimicrobial Peptides In Treating Colitis
Up to now, no clinical trial directly utilizes antimicrobial peptides in treating colitis. However, a Phase II randomized, double-blind, placebo-controlled clinical trial has shown the positive therapeutic role of butyrate in treating shigellosis . Butyrate enema induced LL-37 expression in the rectum and reduced shigellosis-mediated rectal tissue damage and inflammatory responses, suggesting the therapeutic effect of cathelicidin in colitis. On the other hand, another randomized double-blind controlled trial shows that bovine lactoferrin significantly reduces longitudinal prevalence and severity of diarrhea caused by norovirus, E. coli, and Shigella in children . An ongoing clinical trial has recruited 25,875 American men and women to study whether a vitamin D3 supplement can increase plasma cathelicidin levels and affect the risk of infectious diseases (NCT01758081). In fact, vitamin D2 supplement reduces C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) of adult IBD patients ; however, the LL-37 levels of these patients in this clinical trial were not reported.
In summary, antimicrobial peptides are novel and potentially useful approaches to treating various forms of colitis. One approach is to induce expression of cathelicidin by butyrate or vitamin D. Another approach may be the development antimicrobial peptide mimics. Some of the endogenous antimicrobial peptides may also serve as biomarkers for indicating disease activity of colitis.
- Ho S, Pothoulakis C, Koon HW (2013) Antimicrobial peptides and colitis. Curr Pharm Des 19: 40-47.
- Lee CC, Sun Y, Qian S, Huang HW (2011) Transmembrane pores formed by human antimicrobial peptide LL-37. Biophys J 100: 1688-1696.
- Golec M (2007) Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide. Ann Agric Environ Med 14: 1-4.
- De Y, Chen Q, Schmidt AP, Anderson GM, Wang JM, (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192: 1069-1074.
- Schauber J, Rieger D, Weiler F, Wehkamp J, Eck M, et al. (2006) Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 18: 615-621.
- Koon HW, Shih DQ, Chen J, Bakirtzi K, Hing TC, et al. (2011) Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology 141: 1852-1863.
- Tai EK, Wu WK, Wong HP, Lam EK, Yu L, et al. (2007) A new role for cathelicidin in ulcerative colitis in mice. Exp Biol Med (Maywood) 232: 799-808.
- Wong CC, Zhang L, Li ZJ, Wu WK, Ren SX, et al. (2012) Protective effects of cathelicidin-encoding Lactococcus lactis in murine ulcerative colitis. J Gastroenterol Hepatol 27: 1205-1212.
- Chang CW, Wong JM, Tung CC, Shih IL, Wang HY, et al. (2015) Intestinal stricture in Crohn's disease. Intest Res 13: 19-26.
- Yoo JH, Ho S, Tran DH, Cheng M, Bakirtzi K, et al. (2015) Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis. Cell Mol Gastroenterol Hepatol 1: 55-74.
- Cheng M, Ho S, Yoo JH, Tran DH, Bakirtzi K, et al. (2015) Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts. Clin Exp Gastroenterol 8: 13-29.
- Hing TC, Ho S, Shih DQ, Ichikawa R, Cheng M, et al. (2013) The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut 62: 1295-1305.
- Bucki R, Namiot DB, Namiot Z, Savage PB, Janmey PA (2008) Salivary mucins inhibit antibacterial activity of the cathelicidin-derived LL-37 peptide but not the cationic steroid CSA-13. J Antimicrob Chemother 62: 329-335.
- LeszczyÅ ska K, Namiot A, Fein DE, Wen Q, Namiot Z, et al. (2009) Bactericidal activities of the cationic steroid CSA-13 and the cathelicidin peptide LL-37 against Helicobacter pylori in simulated gastric juice. BMC Microbiol 9: 187.
- Travis SM, Anderson NN, Forsyth WR, Espiritu C, Conway BD, et al. (2000) Bactericidal activity of mammalian cathelicidin-derived peptides. Infect Immun 68: 2748-2755.
- Moscoso M, Esteban-Torres M, Menendez M, Garcia E (2014) In vitro bactericidal and bacteriolytic activity of ceragenin CSA-13 against planktonic cultures and biofilms of Streptococcus pneumoniae and other pathogenic streptococci. PLoS one 9: e101037.
- Vorland LH (1999) Lactoferrin: a multifunctional glycoprotein. APMIS 107: 971-981.
- Wang Y, Pei F, Wang X, Sun Z, Hu C1, et al. (2015) Diagnostic accuracy of fecal lactoferrin for inflammatory bowel disease: a meta-analysis. Int J Clin Exp Pathol 8: 12319-12332.
- Ye Q, Zheng Y, Fan S, Qin Z, Li N, et al. (2014) Lactoferrin deficiency promotes colitis-associated colorectal dysplasia in mice. PLoS one 9: e103298.
- Togawa J, Nagase H, Tanaka K, Inamori M, Nakajima A, et al. (2002) Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. J Gastroenterol Hepatol 17: 1291-1298.
- Roozendaal C, Horst G, Pogany K, van Milligen de Wit AW, Kleibeuker JH, et al. (1998) Prevalence and clinical significance of anti-lactoferrin autoantibodies in inflammatory bowel diseases and primary sclerosing cholangitis. Adv Exp Med Biol 443: 313-319.
- Sallenave JM, Silva A (1993) Characterization and gene sequence of the precursor of elafin, an elastase-specific inhibitor in bronchial secretions. Am J Respir Cell Mol Biol 8: 439-445.
- Greenhill C (2012) IBD: Elafin--a potential IBD therapy. Nat Rev Gastroenterol Hepatol 9: 686.
- Flach CF, Eriksson A, Jennische E, Lange S, Gunnerek C, et al. (2006) Detection of elafin as a candidate biomarker for ulcerative colitis by whole-genome microarray screening. Inflamm Bowel Dis 12: 837-842.
- Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, et al. (2007) Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn's disease. J Leukoc Biol 81: 907-915.
- Motta JP, Bermudez-Humaran LG, Deraison C, Martin L, Rolland C, et al. (2012) Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. Sci Transl Med 4: 158ra44.
- Raqib R, Sarker P, Mily A, Alam NH, Arifuzzaman AS, et al. (2012) Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis 12: 111
- Ochoa TJ, Chea-Woo E, Baiocchi N, Pecho I, Campos M, et al. (2013) Randomized double-blind controlled trial of bovine lactoferrin for prevention of diarrhea in children. J Pediatr 162: 349-356.
- Pappa HM, Mitchell PD, Jiang H, Kassiff S, Filip-Dhima R, et al. (2014) Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab 99: 3408-3417.
Citation: Ngoc Tran DH, Koon HW (2016) Antimicrobial Peptides: An Emerging Approach to Treating Colitis. J Colitis Diverticulitis 1:e002.
Copyright: © 2016 Ngoc Tran DH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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