• antimicrobial peptide
• bioengineering protein
• broiler
• growth performance
• intestinal health

• Antimicrobial peptide
• Cathelicidin LL-37
• Heat stroke
• Intestinal goblet cells
• Organ failure
• Systemic inflammation

Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.

• Antimicrobial peptides
• Inflammatory bowel disease
• Ulcerative colitis
• Crohn’s disease
• Gut microbiome
• Biomarkers

• Antimicrobial Peptides
• Colitis
• Gastrointestinal Microbiome
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Microbiota

Animal antimicrobial peptides (AMPs), known as broad-spectrum and high-efficiency antibacterial activity, are important effector molecules in innate immune system. AMPs not only have antimicrobial, antiviral and antitumor effects but also exhibit important effects in vivo, such as anti-inflammatory response, recruiting immune cells, promoting epithelial damage repair, and promoting phagocytosis of bacteria. However, research on the application of AMPs is incomplete and controversial. This review mainly introduces the classification of AMPs, biological functions, as well as the mechanisms of action, expression rules, and nutrition regulation from three perspectives, aiming to provide important information for the application of AMPs.

• antimicrobial peptides
• biological function
• classification
• expression mechanism
• nutrition regulation

• Dry eye
• diagnosis
• hyperemia
• inflammation
• lissamine green
• nerve receptors
• pain
• tear mucus
• vital staining

• Dysbiosis
• Gastrointestinal physiology
• Homeostasis
• Inflammation
• Microbiome
• Mucosa

The cathelin‐related antimicrobial peptide CRAMP protects the mouse colon from inflammation, inflammation‐associated carcinogenesis, and disrupted microbiome balance, as shown in systemic Cnlp^−/− mice (also known as Camp^−/− mice). However, the mechanistic basis for the role and the cellular source of CRAMP in colon pathophysiology are ill defined. This study, using either epithelial or myeloid conditional Cnlp^−/−mice, demonstrated that epithelial cell‐derived CRAMP played a major role in supporting normal development of colon crypts, mucus production, and repair of injured mucosa. On the other hand, myeloid cell‐derived CRAMP potently supported colon epithelial resistance to bacterial invasion during acute inflammation with exacerbated mucosal damage and higher rate of mouse mortality. Therefore, a well concerted cooperation of epithelial‐ and myeloid‐derived CRAMP is essential for colon mucosal homeostasis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

• CRAMP
• Camp
• Cnlp
• bacteria
• colon
• epithelial cell-derived CRAMP
• inflammation
• mucosa
• myeloid cell-derived CRAMP
• necrosis
• proliferation

Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal tract disorders with complex etiology, with intestinal dysbiosis as the most prominent factor. In this study, we assessed the anti-inflammatory and antibacterial actions of the human cathelicidin LL-37 and its shortest active fragment, KR-12 in the mouse models of colitis.

Mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) were used in the study. The extent of inflammation was evaluated based on the macro- and microscopic scores, quantification of myeloperoxidase (MPO) activity and microbiological analysis of stool samples.

A preliminary study with 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. We observed that 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. Furthermore, qualitative and quantitative changes in colonic microbiota were observed: KR-12 (5 mg/kg, ip, twice daily) decreased the overall number of bacteria, Escherichia coli and coli group bacteria. In the semi-chronic DSS-induced model, KR-12 attenuated intestinal inflammation as demonstrated by a reduction in macroscopic score and colon damage score and MPO activity.

We demonstrated that KR-12 alleviates inflammation in four different mouse models of colitis what suggests KR-12 and cathelicidins as a whole are worth being considered as a potential therapeutic option in the treatment of IBD.

• Cathelicidins
• Crohn’s disease
• Inflammatory bowel disease
• KR-12
• Ulcerative colitis

• Animals
• Anti-Bacterial Agents/pharmacology
• Anti-Inflammatory Agents/pharmacology
• Antimicrobial Cationic Peptides/chemistry
• Antimicrobial Cationic Peptides/pharmacology
• Cathelicidins/chemistry
• Cathelicidins/pharmacology
• Colitis/drug therapy
• Colitis/psychology
• Colon/pathology
• Dextran Sulfate
• Feces/microbiology
• Humans
• Inflammatory Bowel Diseases/chemically induced
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/psychology
• Male
• Mice
• Mice, Inbred BALB C
• Peptide Fragments/chemistry
• Peptide Fragments/pharmacology
• Peroxidase/metabolism
• Trinitrobenzenesulfonic Acid

• Uniwersytet Medyczny w Lodzi
• Uniwersytet Gdanski
• The Medical University of Lodz

Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and -negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.

• cathelicidin
• colitis
• colonic epithelium
• defensin
• host defense peptides

• MUC2
• MUC4
• MUC5AC
• Mucins
• colon and colorectal cancer
• glycans
• inflammatory bowel disease

• R01 CA206444 NCI NIH HHS
• RO1 CA183459 NIH HHS
• CA210637 NIH HHS
• R44 CA224619 NCI NIH HHS
• P50 CA127297 NIH HHS
• RO1CA206444 NIH HHS
• P50 CA127297 NCI NIH HHS
• UO1 CA200466 NIH HHS
• P01 CA217798 NCI NIH HHS
• R01 CA183459 NCI NIH HHS
• PO1 CA217798 NIH HHS
• R01 CA210637 NCI NIH HHS
• R43 CA235984 NCI NIH HHS

The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn’s disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.

• Enteroids
• Organoids
• Inflammatory bowel diseases
• Crohn’s disease
• Ulcerative colitis

• Biological Products/pharmacology
• Biological Products/therapeutic use
• Biopsy
• Drug Discovery/methods
• Drug Evaluation, Preclinical/methods
• Epithelial Cells
• Humans
• Immunosuppressive Agents/pharmacology
• Immunosuppressive Agents/therapeutic use
• Induced Pluripotent Stem Cells
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/cytology
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/immunology
• Organoids/drug effects
• Organoids/immunology
• Primary Cell Culture/methods

• antimicrobial peptides
• cancer
• defensins
• gastrointestinal diseases
• inflammation

• Animals
• Animals, Genetically Modified
• Antimicrobial Cationic Peptides/administration & dosage
• Antimicrobial Cationic Peptides/genetics
• Bone Marrow Cells/immunology
• Bone Marrow Cells/metabolism
• Cells, Cultured
• Chick Embryo
• Chickens/genetics
• Chickens/immunology
• Chickens/microbiology
• Immunity, Innate/genetics
• Immunomodulation/genetics
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/metabolism
• Microbiota/genetics
• Microbiota/immunology

• Immuno Valley ALTernatives to ANTibiotics (ALTANT) Animal Specific Immunomodulatory Antimicrobials (ASIA) program of the Dutch Ministry of Economic Affairs

• CRAMP
• allergic airway inflammation
• colitis
• mouse model
• oxazolone

• fermented foods
• gut mucosa
• infectious diseases
• innate immunity
• intestinal permeability

• Lactococcus lactis
• cathelicidin
• experimental colitis

• Entamoeba histolytica
• MUC2
• antimicrobial peptides
• mucin

• antimicrobial peptides
• competitive exclusion
• low pH
• mucus layer
• tight junctions

• cathelicidin (hcap18/ll37)
• esr
• hs-crp
• inflammatory bowel disease
• ulcerative colitis
• vitamin d

Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity.

• barrier function
• gut health
• host defense peptides
• innate immunity
• tight junction

Host defense antimicrobial peptides are key components of the human innate immunity that plays an indispensable role in human health. Cathelicidins are a family of antimicrobial peptides in mammals. LL-37, the only cathelicidin described so far in humans, plays a critical role in host defense against pathogen invasion, as well as regulating the functions of anti-inflammation, anti-tumorigenesis and tissue repair. Emerging evidence suggests that LL-37 is related to several kinds of gastrointestinal diseases, and its application to the diagnosis and treatment of gastrointestinal diseases has become a growing concern. This review aims to elucidate the structure and biological activity of LL-37 and discuss the recent progress in understanding the relationship between LL-37 and gastrointestinal diseases.

• Antimicrobial peptides
• LL-37
• Gastrointestinal diseases

• antimicrobial peptides
• bacteria
• microenvironment
• pathogenesis
• therapeutics

• F32 DC006320 NIDCD NIH HHS
• R01 DC013313 NIDCD NIH HHS
• R21 AI070825 NIAID NIH HHS

Protein kinases play a crucial role in the pathogenesis of inflammatory bowel disease (IBD), the two main forms of which are ulcerative colitis and Crohn’s disease. In this article, we will review the mechanisms of involvement of protein kinases in the pathogenesis of and intervention against IBD, in terms of their effects on genetics, microbiota, mucous layer and tight junction, and the potential of protein kinases as therapeutic targets against IBD.

• Inflammatory bowel disease
• Protein kinase
• Barrier function
• Microbiota
• Genetics

• Animal models
• Cancer
• Gastrointestinal diseases
• Inflammation

Mucosal surface of the intestinal tract is continuously exposed to a large number of microorganisms. To manage the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins (AMPs) that directly kill or inhibit the growth of microorganisms. Thus, AMPs are important components of innate immunity in the gut mucosa. They are frequently expressed in response to colonic inflammation and infection. Expression of many AMPs, including human β-defensin 2-4 and cathelicidin, is induced in response to invasion of pathogens or enteric microbiota into the mucosal barrier. In contrast, some AMPs, including human α-defensin 5-6 and human β-defensin 1, are constitutively expressed without microbial contact or invasion. In addition, specific AMPs are reported to be associated with inflammatory bowel disease (IBD) due to altered expression of AMPs or development of autoantibodies against AMPs. The advanced knowledge for AMPs expression in IBD can lead to its potential use as biomarkers for disease activity. Although the administration of exogenous AMPs as therapeutic strategies against IBD is still at an early stage of development, augmented induction of endogenous AMPs may be another interesting future research direction for the protective and therapeutic purposes. This review discusses new advances in our understanding of how intestinal AMPs protect against pathogens and contribute to pathophysiology of IBD.

• Antimicrobial peptide
• Antimicrobial protein
• Colitis
• Inflammatory bowel diseases

The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.

• Crohn’s disease
• animal models of intestinal inflammation
• gut immune homeostasis
• inflammatory bowel disease genetics
• innate immunity
• intestinal barrier function
• intestinal epithelial cells
• ulcerative colitis

• mucus
• adiponectin
• colon cancer
• inflammation
• goblet cells

• Adiponectin/deficiency
• Adiponectin/metabolism
• Animals
• Apoptosis/drug effects
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Cell Differentiation/drug effects
• Cell Differentiation/genetics
• Cell Line, Tumor
• Chronic Disease
• Colonic Neoplasms/etiology
• Colonic Neoplasms/pathology
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Gene Expression Regulation/drug effects
• Goblet Cells/drug effects
• Goblet Cells/metabolism
• Goblet Cells/pathology
• Humans
• Inflammation/complications
• Inflammation/pathology
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Mucus/drug effects
• Mucus/metabolism
• Receptors, Adiponectin/metabolism
• Tumor Necrosis Factor-alpha/pharmacology
• bcl-2-Associated X Protein/metabolism

• P20 RR017698 NCRR NIH HHS
• R25 GM076277 NIGMS NIH HHS
• P20 RR-017698 NCRR NIH HHS

Cathelicidins, are host defense peptides synthesized and stored in circulating leukocytes and numerous types of epithelial tissues in particular the gastrointestinal (GI) tract and skin. They have been known for their antimicrobial activities against a variety of microbes. Recently it was discovered that they have other significant biological functions and produce appealing pharmacological actions against inflammation and cancer in the GI tract through defined mechanisms. Experimental evidence shows that these actions could be tissue and disease specific and concentration dependent. This article reviews some of the physiological functions of cathelicidins and also their therapeutic potential in the treatment of inflammation and cancer and also the delivery system for this peptide as targeted therapy for various disorders in the GI tract both in animals and humans.

• Cathelicidin
• Gastrointestinal tract
• Cancer
• Inflammation
• Ulcer repair

• Animals
• Anti-Inflammatory Agents/metabolism
• Anti-Inflammatory Agents/therapeutic use
• Antimicrobial Cationic Peptides/metabolism
• Antimicrobial Cationic Peptides/therapeutic use
• Antineoplastic Agents/metabolism
• Antineoplastic Agents/therapeutic use
• Gastroenteritis/drug therapy
• Gastroenteritis/immunology
• Gastroenteritis/metabolism
• Gastroenteritis/pathology
• Gastrointestinal Agents/metabolism
• Gastrointestinal Agents/therapeutic use
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/immunology
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/pathology
• Gastrointestinal Tract/drug effects
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/metabolism
• Gastrointestinal Tract/pathology
• Humans
• Cathelicidins

This study investigated the role of the antimicrobial peptide cathelicidin in Escherichia coli O157:H7 infection and subsequent renal damage. Mouse and human cathelicidin, CRAMP and LL-37, respectively, killed E. coli O157:H7 in vitro. Intestines from healthy wild-type (129/SvJ) and cathelicidin-knock-out (Camp^−/−) mice were investigated, showing that cathelicidin-deficient mice had a thinner colonic mucus layer compared with wild-type mice. Wild-type (n = 11) and cathelicidin-knock-out (n = 11) mice were inoculated with E. coli O157:H7. Cathelicidin-deficient animals exhibited higher fecal counts of E. coli O157:H7 and bacteria penetrated the mucus forming attaching-and-effacing lesions to a much higher extent than in wild-type animals. Cathelicidin knock-out mice developed symptoms (9/11) as well as anemia, thrombocytopenia and extensive renal tubular damage while all cathelicidin-producing mice remained asymptomatic with normal laboratory findings. When injected with Shiga toxin intraperitoneally, both murine strains developed the same degree of renal tubular damage and clinical disease indicating that differences in sensitivity to infection between the murine strains were related to the initial intestinal response. In conclusion, cathelicidin substantially influenced the antimicrobial barrier in the mouse colon mucosa. Cathelicidin deficiency lead to increased susceptibility to E. coli O157:H7 infection and subsequent renal damage. Administration of cathelicidin or stimulation of endogenous production may prove to be novel treatments for E. coli O157:H7-induced hemolytic uremic syndrome.

• Animals
• Anti-Infective Agents/pharmacology
• Antimicrobial Cationic Peptides/pharmacology
• Escherichia coli Infections/prevention & control
• Escherichia coli O157/pathogenicity
• Fluorescent Antibody Technique
• Mice
• Mice, Knockout
• Microbial Sensitivity Tests
• Cathelicidins

• Dietary Proteins/pharmacology
• Endorphins/pharmacology
• Gene Expression/drug effects
• HT29 Cells
• Humans
• Intestinal Mucosa/metabolism
• Intestines/drug effects
• Mucin 5AC/genetics
• Mucins/genetics
• Mucins/metabolism
• RNA, Messenger/analysis