Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches

Abstract

Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.

Keywords: Dysbiosis; Fecal Transplant; Personalized Therapy; Viruses.

Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Genetic and Environmental Factors that affect the Intestinal Microbiota

Key commensal microbes regulate activity of the immune response, including Treg cells, and mucosal homeostasis. Antigens from certain dysbiotic microbes activate T-helper 1 (TH1) and TH17 cells, leading to tissue injury. This mucosal injury leads to further uptake of microbial antigens, toll-like receptor (TCR) ligands and viable organisms that perpetuate immune responses.

Figure 2. Mechanisms of Barrier Function and Immune Regulation by the Intestinal Microbiota

A. Commensal bacterial and fungal species produce SCFAs and TLR ligands that activate protective epithelial and lamina propria innate cells, while microbial antigens, immunoregulatory proteins and secreted SFCAs stimulate adaptive regulatory cells. B. Products of microbial species expanded during dysbiosis injure epithelial cells and activate effector cells. Adherent and invasive E coli penetrate epithelial cells, proliferate within epithelial and antigen-presenting cells and produce antigens that stimulate TH1 and TH17 cells. These bacteria proliferate in the presence of ethanolamine, propanediol and iron liberated by the inflammatory process. Production of hydrogen sulfide by Bilophilia wadsworthia stimulate TH1 cells and segmented filamentous bacteria (SFB) specifically activate TH17 cells. Mucolytic enzymes and proteases produced by E. faecalis injure the mucosal barrier, which promotes uptake of injurious microbial products and viable organisms. Ag; Antigen, MHC; major histocompatibility complex, LPFA1; long polar fimbria A1, Fe; iron.

Figure 3. Microbial Profile, Genome, Transcriptome, Proteome, and Metabolome Features of Individuals With vs Without IBD

Arrows indicate whether these features are increased or reduced in patients with IBD compared to persons without IBD. Extensive data are available for bacterial 16S rRNA profiles of normal subjects and patients with IBD, however fungal 18S or ITS sequencing, shotgun metagenomic sequencing and metabolomic studies are only now beginning to be performed. Fecal metatranscriptome and proteomic studies of microbes and IBD are rudimentary. The sequence of 16S and ITS profiles leading to metabolomic studies is depicted because of timelines of applications of these –omic technique to intestinal bacteria and because microbial composition determines the genes present (metagenomic results). The available microbial genetic pattern, along with the environment and diet, help to determine which microbial genes are transcribed (metatranscriptomic profiles), the proteins produced and metabolites secreted under homeostatic vs. inflammatory conditions.

Figure 4. Treatment of IBD by Altering Microbial Composition or Function

A sustained remission of IBD might be achieved by sequential induction of remission using traditional corticosteroids and/or biologic therapies, followed by less toxic and more physiologic therapies that specifically target the microbiota. Alternatively, it may be possible to primarily treat inflammation by targeting the microbiota. The goal of this microbiota-centric therapy is to correct dysbiosis and restore normal microbial function, normalize the immune dysfunction and repair barrier defects. These goals could be accomplished by using traditional approaches (probiotics, antibiotics, diets, combinations of the above), developing methods (fecal microbial transplants; synthetic mixtures of defined microbes, perhaps personalized for an individual’s specific microbiota profile; highly selective antibiotics targeting key aggressive microbial species; and personalized diets), and still hypothetical novel approaches (bacteriophages targeting key aggressive bacteria; inhibiting bacterial attachment, promoting a more anaerobic environment; blocking bacterial receptors; stimulating protective mammalian pathways; using synthetic microbial metabolites or recombinant bacterial species).