Julia Beisner; Eduard F Stange; Jan Wehkamp
Authors and Disclosures
Expert Rev Clin Immunol. 2010;6(5):809-818. © 2010 Expert Reviews Ltd.
Abstract and Introduction
Abstract
Inflammatory bowel diseases are characterized by chronic intestinal inflammation at different sites. Data from animal models as well as human patients including gene-association studies suggest that different components of the innate barrier function are primarily defective. These recent advances support the evolving hypothesis that intestinal bacteria induce inflammation predominantly as a result of a weakened innate mucosal barrier in genetically predisposed individuals. This article discusses our current understanding of the primary events of disease. Together, these findings should result in new therapeutic avenues aimed at restoring antimicrobial barrier function to prevent a bacterial-triggered inflammatory response.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the GI tract. The two major types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Whereas in UC inflammation is typically restricted to the colon, CD can affect any part of the GI tract, most commonly the small intestine and the colon.[1] Currently, classical anti-inflammatory and immunosuppressive drugs are commonly used in first-line therapy. The conventional therapies primarily target the mucosal inflammatory response and associated symptoms rather than treating the primary cause of the disease.
Although the precise etiology is still unknown, it is clear that complex mechanisms involving epithelial barrier function and innate and adaptive immunity play an important role in the disease pathogenesis. Research during the last few decades has mainly concentrated on the role of the adaptive immune system. In recent years this focus has shifted towards innate immunity, including antimicrobial host defense. Given the central role of the epithelium as a first line of defense against the luminal microbiota, the importance of the intestinal barrier has strongly attracted attention. Several studies have revealed that IBD patients show a compromised mucosal host defense and that clinical phenotypes of disease location are characterized by different defects of antibacterial immune function.[2] Data from animal models as well as gene-association studies suggest that different components of barrier function are primarily defective. These recent advances support the evolving hypothesis that intestinal bacteria induce inflammation predominantly as a result of a weakened innate mucosal barrier in genetically predisposed individuals. It is now widely accepted that these defects in the intestinal barrier play a central role in disease pathogenesis. A key question still remains as to whether the dysfunction of the intestinal barrier is a primary factor causing inflammation or rather is a consequence of the action of inflammatory mediators, although both concepts are not mutually exclusive. Understanding further mechanistic details will resolve the interplay between the innate and adaptive immune responses. This article aims to explain and discuss the current view and concepts for the primary events in disease pathogenesis.
Role of Luminal & Mucosal Bacteria in Pathogenesis
The mammalian gut harbors approximately 500–1000 different species of bacteria, which make up several trillions of microorganisms.[3,4] The two major types of IBD, CD and UC, occur in the areas of the GI tract with the highest concentration of bacteria. Moving distally from the duodenum, the microbial density increases in the lumen. The distal ileum contains up to 108 primarily anaerobic bacteria per gram of luminal contents,[5] whereas up to 1011–1012 bacteria per gram of luminal contents colonize the colon. Thus, the mucosal immune system has to keep a homeostatic balance between maintaining a tolerance towards the commensal microflora and at the same time protecting the host against microbial invasion. This balance is achieved through a complex network of innate and adaptive mucosal immune responses. It is interesting that the onset of disease often starts with a bacterial infection; it has been discussed for many years whether specific pathogens including Mycobacterium tuberculosis, rubella virus or other microbes might play a role in IBD. However, the variety of identified mucosal pathogens makes it unlikely that a specific microbe is the cause of disease and suggests that patients with CD are generally more susceptible towards microbial infections. Current concepts assume rather that the inflammation in the gut is a reaction towards the microflora that leads to disproportionate activation of immune responses and thus chronic inflammation of, and damage to, the intestinal mucosa.[2,6] Analysis of the enteric luminal flora in IBD patients revealed differences in the composition compared with healthy controls. Swidsinski et al.,[7] as well as other groups from France and the UK, demonstrated that mucosa-associated bacteria, especially anaerobic Bacteroides species and aerobic Enterobacteriaceae (Escherichia coli), are dramatically increased in IBD mucosa. Similarly, concentrations of adherent E. coli and enterococci are increased in the neoterminal ileum of CD patients after surgical resection.[8] In addition, early disease recurrence was associated with increased numbers of E. coli, Bacteroides and Fusobacterium. Another study by Darfeuille-Michaud described an increased number of adherent invasive E. coli strains in the ileal mucosa of patients with CD that may disrupt the intestinal barrier by synthesizing an α-hemolysin.[9] Fitting well with these observations, the adaptive immune responses target microbial antigens from the intestinal microflora, arguing against the 'old' concept of an autoimmune disease.[10] In summary, these findings show that the commensal flora may cause inflammation in the absence of adequate epithelial barrier function. Thus, an imbalance between the commensal flora and the epithelium of the host seems to be crucial in disease pathogenesis (Figure 1).[2]
Figure 1.
Proposed model for the role of intestinal bacteria and host defensins in the pathogenesis and disease progression of Crohn's disease. In Crohn's disease, the intestinal tract is characterized by a disturbed balance of host antimicrobial peptides and intestinal microbes. Owing to insufficient expression and function of antimicrobial defensin molecules, intestinal microbes are able to invade the mucosa. With further progression of disease, the bacterial influx provokes an inflammatory response. Reproduced with permission from [2].
Authors and Disclosures
Expert Rev Clin Immunol. 2010;6(5):809-818. © 2010 Expert Reviews Ltd.
Abstract and Introduction
Abstract
Inflammatory bowel diseases are characterized by chronic intestinal inflammation at different sites. Data from animal models as well as human patients including gene-association studies suggest that different components of the innate barrier function are primarily defective. These recent advances support the evolving hypothesis that intestinal bacteria induce inflammation predominantly as a result of a weakened innate mucosal barrier in genetically predisposed individuals. This article discusses our current understanding of the primary events of disease. Together, these findings should result in new therapeutic avenues aimed at restoring antimicrobial barrier function to prevent a bacterial-triggered inflammatory response.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the GI tract. The two major types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Whereas in UC inflammation is typically restricted to the colon, CD can affect any part of the GI tract, most commonly the small intestine and the colon.[1] Currently, classical anti-inflammatory and immunosuppressive drugs are commonly used in first-line therapy. The conventional therapies primarily target the mucosal inflammatory response and associated symptoms rather than treating the primary cause of the disease.
Although the precise etiology is still unknown, it is clear that complex mechanisms involving epithelial barrier function and innate and adaptive immunity play an important role in the disease pathogenesis. Research during the last few decades has mainly concentrated on the role of the adaptive immune system. In recent years this focus has shifted towards innate immunity, including antimicrobial host defense. Given the central role of the epithelium as a first line of defense against the luminal microbiota, the importance of the intestinal barrier has strongly attracted attention. Several studies have revealed that IBD patients show a compromised mucosal host defense and that clinical phenotypes of disease location are characterized by different defects of antibacterial immune function.[2] Data from animal models as well as gene-association studies suggest that different components of barrier function are primarily defective. These recent advances support the evolving hypothesis that intestinal bacteria induce inflammation predominantly as a result of a weakened innate mucosal barrier in genetically predisposed individuals. It is now widely accepted that these defects in the intestinal barrier play a central role in disease pathogenesis. A key question still remains as to whether the dysfunction of the intestinal barrier is a primary factor causing inflammation or rather is a consequence of the action of inflammatory mediators, although both concepts are not mutually exclusive. Understanding further mechanistic details will resolve the interplay between the innate and adaptive immune responses. This article aims to explain and discuss the current view and concepts for the primary events in disease pathogenesis.
Role of Luminal & Mucosal Bacteria in Pathogenesis
The mammalian gut harbors approximately 500–1000 different species of bacteria, which make up several trillions of microorganisms.[3,4] The two major types of IBD, CD and UC, occur in the areas of the GI tract with the highest concentration of bacteria. Moving distally from the duodenum, the microbial density increases in the lumen. The distal ileum contains up to 108 primarily anaerobic bacteria per gram of luminal contents,[5] whereas up to 1011–1012 bacteria per gram of luminal contents colonize the colon. Thus, the mucosal immune system has to keep a homeostatic balance between maintaining a tolerance towards the commensal microflora and at the same time protecting the host against microbial invasion. This balance is achieved through a complex network of innate and adaptive mucosal immune responses. It is interesting that the onset of disease often starts with a bacterial infection; it has been discussed for many years whether specific pathogens including Mycobacterium tuberculosis, rubella virus or other microbes might play a role in IBD. However, the variety of identified mucosal pathogens makes it unlikely that a specific microbe is the cause of disease and suggests that patients with CD are generally more susceptible towards microbial infections. Current concepts assume rather that the inflammation in the gut is a reaction towards the microflora that leads to disproportionate activation of immune responses and thus chronic inflammation of, and damage to, the intestinal mucosa.[2,6] Analysis of the enteric luminal flora in IBD patients revealed differences in the composition compared with healthy controls. Swidsinski et al.,[7] as well as other groups from France and the UK, demonstrated that mucosa-associated bacteria, especially anaerobic Bacteroides species and aerobic Enterobacteriaceae (Escherichia coli), are dramatically increased in IBD mucosa. Similarly, concentrations of adherent E. coli and enterococci are increased in the neoterminal ileum of CD patients after surgical resection.[8] In addition, early disease recurrence was associated with increased numbers of E. coli, Bacteroides and Fusobacterium. Another study by Darfeuille-Michaud described an increased number of adherent invasive E. coli strains in the ileal mucosa of patients with CD that may disrupt the intestinal barrier by synthesizing an α-hemolysin.[9] Fitting well with these observations, the adaptive immune responses target microbial antigens from the intestinal microflora, arguing against the 'old' concept of an autoimmune disease.[10] In summary, these findings show that the commensal flora may cause inflammation in the absence of adequate epithelial barrier function. Thus, an imbalance between the commensal flora and the epithelium of the host seems to be crucial in disease pathogenesis (Figure 1).[2]
Figure 1.
Proposed model for the role of intestinal bacteria and host defensins in the pathogenesis and disease progression of Crohn's disease. In Crohn's disease, the intestinal tract is characterized by a disturbed balance of host antimicrobial peptides and intestinal microbes. Owing to insufficient expression and function of antimicrobial defensin molecules, intestinal microbes are able to invade the mucosa. With further progression of disease, the bacterial influx provokes an inflammatory response. Reproduced with permission from [2].
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