The Gut Microbiota and Inflammatory Bowel Disease
Purpose of review Inflammatory bowel diseases (IBDs) reflect the cooperative influence of numerous host and environmental factors, including those of elements of the intestinal immune system, the gut microbiota, and dietary habits. This review focuses on features of the gut microbiota and mucosal immune system that are important in the development and control of IBDs.
Recent findings Gut innate-type immune cells, including dendritic cells, innate lymphoid cells, and mast cells, educate acquired-type immune cells and intestinal epithelial cells to achieve a symbiotic relationship with commensal bacteria. However, perturbation of the number or type of commensal microorganisms and endogenous genetic polymorphisms that affect immune responses and epithelial barrier system can ultimately lead to IBDs. Providing beneficial bacteria or fecal microbiota transplants helps to reestablish the intestinal environment, maintain its homeostasis, and ameliorate IBDs.
Summary The gut immune system participates in a symbiotic milieu that includes cohabiting commensal bacteria. However, dysbiotic conditions and aberrations in the epithelial barrier and gut immune system can disrupt the mutualistic relationship between the host and gut microbiota, leading to IBDs. Progress in our molecular and cellular understanding of this relationship has yielded numerous insights regarding clinical applications for the treatment of IBDs.
The intestinal tract is constitutively exposed to countless antigens, including dietary materials and commensal and pathogenic microorganisms. To deal with this barrage, the finely tuned host immune system discriminates between favorable and unfavorable antigens at mucosal sites; this mucosal immune system concurrently induces and regulates reciprocal responses that lead to antigenic tolerance and elimination. Because steady-state gut mucosal immunity relies on a fluctuating equilibrium, the disruption of intestinal homeostasis can lead to chronic remittent or progressive inflammatory disorders, especially inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis, and disruption of the intestinal mucosa.
Genetic polymorphisms associated with the host gut immune system and epithelial barrier predispose to the onset of IBDs. These include components involved in the innate and adaptive immune responses, maintenance of intestinal epithelial barrier function including autophagy, endoplasmic reticulum stress response, mucus secretion, and antimicrobial activity pathways that determine tolerance, train immune cells, and maintain the balance between T helper 17 (Th17) cells with effector function and regulatory T (Treg) cells with inhibitory task. For example, X-box binding protein 1 (Xbp-1) is a transcription factor whose functional impairment in intestinal epithelial cells (IECs) is implicated in the loss of Paneth and goblet cells, the initiation of intestinal inflammation, and the development of IBDs. Another Crohn's disease risk allele, autophagy-related 16-like 1 (Atg16L1) that relates to autophagosome formation and degradation of long-lived proteins, also regulate function of Paneth cells and intestinal homeostasis. In fact, granule formation and exocytosis of Paneth cells are severely impaired in mice lacking Atg16L1 and Crohn's disease patients homozygous for the Atg16L1. However, IBD-associated alleles are present in healthy individuals as well, thus suggesting the complexity of the etiologic mechanisms of IBDs.
In addition to IBD-predisposing genetic features, various environmental factors, especially commensal bacteria, are now known to be key triggers for the onset of IBDs. Commensal bacteria have a crucial role in calibrating the intestinal immune response and epithelial barrier system. For example, segmented filamentous bacteria (SFB) and Clostridia, two defined residents of the intestinal microbiota, drive the differentiation of Th17 and Treg cells, respectively, thus coordinating the effector and inhibitory arms of the gut immune system and achieving intestinal homeostasis. Conversely, environmental factors such as infection and antibiotic treatment that disrupt the dynamics of the healthy microbiota (that is, dysbiosis) can initiate the pathologic inflammatory cascade leading to IBDs (Fig. 1). In this review, we summarize the influences of the gut immune response, epithelial barrier system, and intestinal microbiota on IBDs and present potential opportunities for the translation of this knowledge into clinical therapies.
(Enlarge Image)
Figure 1.
Host (intrinsic) and environmental (extrinsic) factors interact to predispose the host to the development of inflammatory bowel diseases (IBDs). Intrinsic elements include genetic polymorphisms that affect epithelial barrier integrity and the positive and negative regulatory systems of intestinal immune cells. The intestinal immune system and epithelial barrier maintain the homeostasis of the gut microbiota and prevent the infection of pathogens. Extrinsic elements, especially those derived from commensal and pathogenic bacteria, both contribute to IBDs and modulate the intestinal immune system. Therefore, intrinsic and extrinsic sources interact to generate both physiologic and pathologic conditions of the digestive tract.
Abstract and Introduction
Abstract
Purpose of review Inflammatory bowel diseases (IBDs) reflect the cooperative influence of numerous host and environmental factors, including those of elements of the intestinal immune system, the gut microbiota, and dietary habits. This review focuses on features of the gut microbiota and mucosal immune system that are important in the development and control of IBDs.
Recent findings Gut innate-type immune cells, including dendritic cells, innate lymphoid cells, and mast cells, educate acquired-type immune cells and intestinal epithelial cells to achieve a symbiotic relationship with commensal bacteria. However, perturbation of the number or type of commensal microorganisms and endogenous genetic polymorphisms that affect immune responses and epithelial barrier system can ultimately lead to IBDs. Providing beneficial bacteria or fecal microbiota transplants helps to reestablish the intestinal environment, maintain its homeostasis, and ameliorate IBDs.
Summary The gut immune system participates in a symbiotic milieu that includes cohabiting commensal bacteria. However, dysbiotic conditions and aberrations in the epithelial barrier and gut immune system can disrupt the mutualistic relationship between the host and gut microbiota, leading to IBDs. Progress in our molecular and cellular understanding of this relationship has yielded numerous insights regarding clinical applications for the treatment of IBDs.
Introduction
The intestinal tract is constitutively exposed to countless antigens, including dietary materials and commensal and pathogenic microorganisms. To deal with this barrage, the finely tuned host immune system discriminates between favorable and unfavorable antigens at mucosal sites; this mucosal immune system concurrently induces and regulates reciprocal responses that lead to antigenic tolerance and elimination. Because steady-state gut mucosal immunity relies on a fluctuating equilibrium, the disruption of intestinal homeostasis can lead to chronic remittent or progressive inflammatory disorders, especially inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis, and disruption of the intestinal mucosa.
Genetic polymorphisms associated with the host gut immune system and epithelial barrier predispose to the onset of IBDs. These include components involved in the innate and adaptive immune responses, maintenance of intestinal epithelial barrier function including autophagy, endoplasmic reticulum stress response, mucus secretion, and antimicrobial activity pathways that determine tolerance, train immune cells, and maintain the balance between T helper 17 (Th17) cells with effector function and regulatory T (Treg) cells with inhibitory task. For example, X-box binding protein 1 (Xbp-1) is a transcription factor whose functional impairment in intestinal epithelial cells (IECs) is implicated in the loss of Paneth and goblet cells, the initiation of intestinal inflammation, and the development of IBDs. Another Crohn's disease risk allele, autophagy-related 16-like 1 (Atg16L1) that relates to autophagosome formation and degradation of long-lived proteins, also regulate function of Paneth cells and intestinal homeostasis. In fact, granule formation and exocytosis of Paneth cells are severely impaired in mice lacking Atg16L1 and Crohn's disease patients homozygous for the Atg16L1. However, IBD-associated alleles are present in healthy individuals as well, thus suggesting the complexity of the etiologic mechanisms of IBDs.
In addition to IBD-predisposing genetic features, various environmental factors, especially commensal bacteria, are now known to be key triggers for the onset of IBDs. Commensal bacteria have a crucial role in calibrating the intestinal immune response and epithelial barrier system. For example, segmented filamentous bacteria (SFB) and Clostridia, two defined residents of the intestinal microbiota, drive the differentiation of Th17 and Treg cells, respectively, thus coordinating the effector and inhibitory arms of the gut immune system and achieving intestinal homeostasis. Conversely, environmental factors such as infection and antibiotic treatment that disrupt the dynamics of the healthy microbiota (that is, dysbiosis) can initiate the pathologic inflammatory cascade leading to IBDs (Fig. 1). In this review, we summarize the influences of the gut immune response, epithelial barrier system, and intestinal microbiota on IBDs and present potential opportunities for the translation of this knowledge into clinical therapies.
(Enlarge Image)
Figure 1.
Host (intrinsic) and environmental (extrinsic) factors interact to predispose the host to the development of inflammatory bowel diseases (IBDs). Intrinsic elements include genetic polymorphisms that affect epithelial barrier integrity and the positive and negative regulatory systems of intestinal immune cells. The intestinal immune system and epithelial barrier maintain the homeostasis of the gut microbiota and prevent the infection of pathogens. Extrinsic elements, especially those derived from commensal and pathogenic bacteria, both contribute to IBDs and modulate the intestinal immune system. Therefore, intrinsic and extrinsic sources interact to generate both physiologic and pathologic conditions of the digestive tract.
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