Antimicrobial Peptides in Gastrointestinal Diseases

Chi Hin Cho

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128143193
• eBook ISBN: 9780128143209
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Antimicrobial peptides (AMPs), including cathelicidins and defensins are host defence peptides that carry out multiple roles in the gastrointestinal (GI) tract. Antimicrobial Peptides in Gastrointestinal Diseases presents knowledge about the physiological functions and pharmacological actions of AMPs in inflammation, cancer, and further infection of the GI tract. The book provides coverage from the basic research to clinical application for GI diseases. Current research and development of AMPs is presented, opening the way for further work on these peptides, not only in the context of GI diseases, but also for similar pathologies in other organs. AMPs are key to the regulation of human microbiome and second line defence in the GI mucosa, prevent colonization of pathogens and modulation of innate response to invading pathogens, and modify immunological reactions during inflammatory processes and oncogenic development in the GI mucosa. More importantly, AMPs possess diversified anti-microbial actions against various infectious diseases in the GI tract. With these physiological functions and pharmacological actions, AMPs have significant potential as therapeutic agents for the treatment of inflammation, cancer and further infection in the GI tract.- Provides an overview of AMPs, particularly cathelicidin and defensin, in different diseases- Covers inflammation and ulcer repair in the stomach and colon and carcinogenesis in the GI tract- Presents AMP information and knowledge in a concise manner- Gives useful information on all aspects of AMPs- Promotes research on AMPs and their development as drugs, from bench, to clinical application

Chapter 1

Regulation of Cationic Antimicrobial Peptides Expression in the Digestive Tract

Tomasz Wollny^⁎; Ewelina Piktel^†; Bonita Durnaś^‡; Robert Bucki^{†,‡ ⁎} Holy Cross Oncology Center of Kielce, Kielce, Poland
^† Medical University of Bialystok, Bialystok, Poland
^‡ Jan Kochanowski University in Kielce, Kielce, Poland

Abstract

Recent advances in the field of intestinal natural antimicrobial peptides (AMPs) continuously highlight their important role in maintaining intestinal barrier homeostasis both in the presence of beneficial host microbiota and when challenged with external microbial pathogens. A variety of these peptides are constitutively produced in intestinal cells, while others are induced only during infection and inflammation. The understanding of mechanisms affecting the regulation of AMPs and interactions between microbial-dependent and -independent factors and host AMPs provide a way to introduce novel therapeutic strategies aimed at treating gastrointestinal tract disorders using stimulated induction of AMP production. This chapter focuses on a summary of recent reports presenting the emerging role of AMPs in the GI tract, provides an overview on the balance between intestinal cells and microbes, and discusses the molecular mechanisms governing AMP production during homeostasis, infection, and GI tract disorders.

Keywords

Defensins; Cathelicidin LL-37; Expression; Gastrointestinal tract diseases; Induction; Antibiotic therapy

Chapter Outline

• 1 Digestive Tract Microbiome as a Factor Regulating Expression of Cationic Antibacterial Peptides
• 2 Factors Regulating Expression of AMPs and Molecular Mechanisms Governing This Process
• 3 Regulation of AMPs’ Expression in Autoimmune Disorders Associated With the Gastrointestinal Tract
• 4 Stimulated Expression of AMPs in the Digestive Tract as a Potential New Method for Infection Treatment: A Great Alternative to Antibiotic Therapy
• 5 Conclusions
• References

1 Digestive Tract Microbiome as a Factor Regulating Expression of Cationic Antibacterial Peptides

The lumen of the human intestinal tract might be seen as a continuation of the external environment equipped with various antimicrobial mechanisms functioning as part of the host innate and adaptive immune responses [1]. The local defense system named GALT (gut-associated lymphoid tissue) consists of epithelial barriers and unique immune cells and structures located near the epithelium and lamina propria. A single layer of epithelium covered by mucus is composed of enterocytes whose main task is to absorb nutrients from the intestine and by other cell types with highly specialized roles. Goblet cells secrete mucus, Paneth cells are one of several cell types to produce antimicrobial peptides (AMPs) and M cells specialize in sampling and presenting antigens and delivering them to GALT. Together, the epithelium, covered by a thick mucus layer and substances such as AMPs and immunoglobulin A (IgA) creates a barrier protecting an internal human body milieu from bacterial infiltration. GALT can be divided into functionally distinct immune inductive and effector sites. The immune inductive sites (secondary lymphoid organs) responsible for the induction phase of the immune response consist of B and T lymphocytes existing as cell follicles or as aggregated forms called Peyer’s patches. The immune effector sites include various cells within the lamina propria, such as innate immune cells (macrophages, dendritic cells, and innate lymphoid cells), adaptive effector T cells, IgA-producing plasma cells, as well as the intraepithelial subpopulation of T cells [2,3]. In response to microbial antigens, immune cells are activated to produce various cytokines such as interleukins: IL-4, IL-5, IL-10, IL-13, IL-17, and IL-22, as well as interferons and TNF-α [4].

The intestinal tract is colonized by a large variety of microorganisms—bacteria, fungi, viruses, and parasites that slightly outnumber host cells. Most of the gut bacteria belong to the phyla Firmicutes (Gram-positive bacteria, mainly facultative anaerobes, such as Clostridia, Streptococcaceae, Staphylococcaceae, Enterococcaceae, or Lactobacillae), and Bacteroidetes (Gram-negative obligate anaerobes). Representatives of other phyla such as Proteobacteria, Fusobacteria, Actinobacteria, and Verrucomicrobia are also present in the intestinal tract but in significantly smaller number [3,5,6].

The endogenous gastrointestinal (GI) microbiota could itself be considered as a virtual organ, playing an important role in host health and disease [7]. Gut commensal microorganisms protect against pathogens by competing for nutrients and ecological niches and by producing antimicrobial substances. Commensals are also involved in immune system development, play metabolic functions (absorption of nutrients, vitamins, and short-chain fatty acids production), and maintain the integrity of the intestinal epithelial barrier. In return, the host provides places for commensals to live and allows for nutrient and energy acquisition. So, the relationship between human host and microbiota is mutually beneficial (symbiotic) [8].

The gut microbiota starts to establish early in life (even during gestation), continues after birth, and matures during the course of the first 2 years of life. In a healthy adult, it is quite stable and counts greater than 1000 species and has more than 150 times more genes than the host genome [9].

The majority of bacterial gut strains are present for decades, often for an entire adult life. Most likely, early colonizing microorganisms from parents and other family members are crucial through their metabolic products and impact on the immune system in shaping host health and susceptibility to some diseases [10]. The composition of the intestinal microbiota differs between individuals; however, a high level of diversity is observed at the species level but is low at the phylum level. Differences between stool and mucosa microbiota composition are also observed [5].

The diversity and quantity of gut commensal microorganisms is influenced by endogenous, host-derived factors such as genetic background, age, acid secretion, intestinal motility, immune response, as well as exogenous factors, such as diet, age, stress, antibiotic usage, proton pump inhibitor (PPI) usage, probiotics/prebiotics, and hospitalization [11,12].

Commensal bacteria and the gut immune system influence each other. The microbiota plays an important role in maturation of the immune system, stimulates the release of mucus from goblet cells, activates Paneth cells to secrete antimicrobial peptides, and teaches T-helper cells to be tolerogenic to nonpathogenic antigens and bacteria. A symbiotic relationship between host and microbiome leads to intestinal immune homeostasis. A lack of this balance increases the risk of developing infectious diseases in newborns as well as developing inflammatory, allergic, or some autoimmune diseases (e.g., type 1 diabetes) or obesity in later stages of life [13].

Alterations of the intestinal microbiota are associated with several immune-mediated inflammatory diseases including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis [12,14].

The coevolution of microbiota and host cells established several mechanisms to protect human tissues from microorganisms colonizing body surfaces. A thick inner mucus layer, antimicrobial peptides, and immunoglobulin A minimize the contact of microbiota with the epithelium and act as a first line of defense. If any commensal bacteria invade the epithelium and reach the lamina propria, the second line of defense is activated. Apart from intestinal macrophages, IL-22-producing innate lymphoid cells are crucial elements in preventing the systemic dissemination of commensal gut bacteria [6,15]. Interestingly, commensal microbiota, particularly Clostridial, and Bacteroidetes, might be involved in the development of resistance to fungal colonization, as recognized by Fan et al., using a mouse model of Candida albicans gastrointestinal colonization in antibiotic-treated adult mice [16]. It was demonstrated that the mechanism of such phenomenon includes the activation of HIF-1α, a ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• General Introduction of Antimicrobial Peptides and Gastrointestinal Diseases
• Chapter 1: Regulation of Cationic Antimicrobial Peptides Expression in the Digestive Tract
• Chapter 2: Antimicrobial Peptides in the Host-Microbiota Homeostasis
• Chapter 3: The Roles of Antimicrobial Peptides in the Regulation of Gastrointestinal Microbiota and Innate Immunity
• Chapter 4: Cathelicidin in Gastrointestinal Disorders
• Chapter 5: Antimicrobial Peptides as Potential Therapy for Gastrointestinal Cancers: Opportunities and Challenges
• Chapter 6: AMPs and Mechanisms of Antimicrobial Action
• Chapter 7: Host Defense Peptides as Innate Immunomodulators in the Pathogenesis of Colitis
• Chapter 8: Conclusion
• Index