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

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

Genetic Factors in Animal Models of Intestinal Inflammation

The critical importance of host genetic susceptibility in determining chronicity, aggressiveness and complications of intestinal inflammation is clearly demonstrated by studies of inbred rodents, transgenic rats and spontaneous mutants. Inbred Lewis rats challenged by purified bacterial cell wall polymers, indomethacin or small bowel bacterial overgrowth develop chronic granulomatous intestinal inflammation with fibrosis and extraintestinal manifestations, whereas Fischer (major histocompatibility complex identical to Lewis) and Buffalo rats identically stimulated demonstrate only self-limited enterocolitis with no chronic inflammation, fibrosis, granulomas or extraintestinal inflammation. Similar differential patterns of intestinal inflammation are apparent in inbred mouse strains challenged with trinitrobenzene-sulphonic acid, Citrobacter freundii or backcrossed with T cell receptor deficient (knockout) mice. The dominant role of genetic background in induction of intestinal inflammation is further documented by spontaneous colitis which develops in spontaneously mutant mice, cotton-top tamarins, human leukocyte antigen-B27/ β2 microglobulin transgenic rats and mice with targeted deletions of certain immunoregulatory cytokine and T lymphocyte genes. Identification of the immunological mechanisms of host genetic susceptibility and the genetic basis of spontaneous colitis should provide new insights into the pathogenesis of human inflammatory bowel disease

Genetic Factors in Animal Models of Intestinal Inflammation

The critical importance of host genetic susceptibility in determining chronicity, aggressiveness and complications of intestinal inflammation is clearly demonstrated by studies of inbred rodents, transgenic rats and spontaneous mutants. Inbred Lewis rats challenged by purified bacterial cell wall polymers, indomethacin or small bowel bacterial overgrowth develop chronic granulomatous intestinal inflammation with fibrosis and extraintestinal manifestations, whereas Fischer (major histocompatibility complex identical to Lewis) and Buffalo rats identically stimulated demonstrate only self-limited enterocolitis with no chronic inflammation, fibrosis, granulomas or extraintestinal inflammation. Similar differential patterns of intestinal inflammation are apparent in inbred mouse strains challenged with trinitrobenzene-sulphonic acid, Citrobacter freundii or backcrossed with T cell receptor deficient (knockout) mice. The dominant role of genetic background in induction of intestinal inflammation is further documented by spontaneous colitis which develops in spontaneously mutant mice, cotton-top tamarins, human leukocyte antigen-B27/ β2 microglobulin transgenic rats and mice with targeted deletions of certain immunoregulatory cytokine and T lymphocyte genes. Identification of the immunological mechanisms of host genetic susceptibility and the genetic basis of spontaneous colitis should provide new insights into the pathogenesis of human inflammatory bowel disease

Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics

AbstractCrohn's disease, ulcerative colitis, and pouchitis are caused by overly aggressive immune responses to a subset of commensal (nonpathogenic) enteric bacteria in genetically predisposed individuals. Clinical and experimental studies suggest that the relative balance of aggressive and protective bacterial species is altered in these disorders. Antibiotics can selectively decrease tissue invasion and eliminate aggressive bacterial species or globally decrease luminal and mucosal bacterial concentrations, depending on their spectrum of activity. Alternatively, administration of beneficial bacterial species (probiotics), poorly absorbed dietary oligosaccharides (prebiotics), or combined probiotics and prebiotics (synbiotics) can restore a predominance of beneficial Lactobacillus and Bifidobacterium species. Current clinical trials do not fulfill evidence-based criteria for using these agents in inflammatory bowel diseases (IBD), but multiple nonrigorous studies and widespread clinical experience suggest that metronidazole and/or ciprofloxacin can treat Crohn's colitis and ileocolitis (but not isolated ileal disease), perianal fistulae and pouchitis, whereas selected probiotic preparations prevent relapse of quiescent ulcerative colitis and relapsing pouchitis. These physiologic approaches offer considerable promise for treating IBD, but must be supported by rigorous controlled therapeutic trials that consider clinical disease before their widespread clinical acceptance. These agents likely will become an integral component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents

The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications

Dietary impacts on health may be one of the oldest concepts in medicine; however, only in recent years have technical advances in mass spectroscopy, gnotobiology, and bacterial sequencing enabled our understanding of human physiology to progress to the point where we can begin to understand how individual dietary components can affect specific illnesses. This review explores the current understanding of the complex interplay between dietary factors and the host microbiome, concentrating on the downstream implications on host immune function and the pathogenesis of disease. We discuss the influence of the gut microbiome on body habitus and explore the primary and secondary effects of diet on enteric microbial community structure. We address the impact of consumption of non-digestible polysaccharides (prebiotics and fiber), choline, carnitine, iron, and fats on host health as mediated by the enteric microbiome. Disease processes emphasized include nonalcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), IBD, and cardiovascular disease (CVD)/atherosclerosis. The concepts presented in this review have important clinical implications, although more work needs to be done to fully develop and validate potential therapeutic approaches. Specific dietary interventions offer exciting potential for nontoxic, physiologic ways to alter enteric microbial structure and metabolism to benefit the natural history of many intestinal and systemic disorders

Transient activation of mucosal effector immune responses by resident intestinal bacteria in normal hosts is regulated by interleukin-10 signalling

Interleukin-10 (IL-10) is a key regulator of mucosal homeostasis. In the current study we investigated the early events after monoassociating germ-free (GF) wild type (WT) mice with an E. coli strain that we isolated previously from the cecal contents of a normal mouse housed under specific pathogen free (SPF) conditions. Our results show that IFN-γ secreted by mesenteric lymph node (MLN) cells from both IL-10 deficient mice and WT mice, stimulated ex vivo with E. coli lysate, was dramatically higher at day 4 after monoassociation compared to IFN-γ secreted by cells from GF mice without E. coli colonization. Production of IFN-γ rapidly and progressively declined after colonization of WT but not IL-10 deficient mice. E. coli lysate-stimulated WT MLN cells also produced IL-10 that peaked at day 4 and subsequently declined, but not as precipitously as IFN-γ. WT cells that express CD4, CD8, and NKp46 produced IFN-γ; WT CD4-positive cells and B cells produced IL-10. Recombinant IL-10 added to E. coli-stimulated MLN cell cultures inhibited IFN-γ secretion in a dose-dependent fashion. MLN cells from WT mice treated in vivo with neutralizing anti-IL-10 receptor antibody produced more IFN-γ compared with MLN cells from isotype control antibody-treated mice. These findings show that a resident E. coli that induces chronic colitis in monoassociated IL-10 deficient mice rapidly but transiently activates the effector immune system in normal hosts, in parallel with induction of protective IL-10 produced by B cells and CD4(+) cells that subsequently suppresses this response to mediate mucosal homeostasis. This article is protected by copyright. All rights reserved

Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases

The authors present evidence published during the past two years of the roles of commensal and pathogenic bacteria in the pathogenesis of the inflammatory bowel diseases (IBD)

The role of mucosal immunity and host genetics in defining intestinal commensal bacteria

Dramatic advances in molecular characterization of the largely noncultivable enteric microbiota have facilitated better understanding of the composition of this complex ecosystem at broad phylogenetic levels. This review outlines current understanding of mechanisms by which commensal bacteria are controlled and shaped into functional communities by innate and adaptive immune responses, antimicrobial peptides produced by epithelial cells and host genetic factors

Gene expression patterns in experimental colitis in IL-10-deficient mice:

While others have described gene expression patterns in humans with inflammatory bowel diseases and animals with chemically-induced colitis, a genome-wide comparison of gene expression in genetically susceptible animals that develop spontaneous colitis has not been reported. We used microarray technology to compare gene expression profiles in cecal specimens from specific pathogen-free IL10-deficient (IL10−/−) mice with colitis and normal wild-type (WT) mice. RNA isolated from ceca of IL10−/− and WT mice was subjected to microarray analysis. Results were confirmed by real-time PCR and immunofluorescence microscopy of selected molecules. Expression of the selected genes in DSS-treated mice with colitis and epithelial cell lines activated with pathophysiologic stimuli was measured by real-time PCR. Histological inflammation of the colon and IL-12/23p40 secretion from intestinal explants were greater in IL10−/− and DSS-treated mice vs. WT and untreated mice. Microarray analysis demonstrated >10-fold induction of the following molecules in the ceca of IL10−/− mice: Mitochondrial ribosomal protein-L33, aquaporin-4, indoleamine-pyrrole-2,3- dioxygenase, and MHC class II with 63, 25, 20, and 12-fold increases, respectively. Cytochrome-P450, pancreatic lipase-related protein-2, and transthyretin were down-regulated in IL10−/− mice. MHC II was increased throughout the colon, and aquaporin-4 was increased in the basolateral aspect of cecal epithelial cells. MHC II mRNA was increased in epithelial cells treated with IFNγ, but not TNF or Toll-like receptor ligands. Although most upregulated genes in experimental colitis are immune-related, aquaporin-4 and mitochondrial ribosomal protein, which have not been previously associated with inflammation, were most highly upregulated