Building an Intestine — Architectural Contributions of Commensal Bacteria
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《新英格兰医药杂志》
Bacterial cells within the intestine (commensal microflora) vastly outnumber the epithelial cells lining this organ. Like all bacteria, they release chemical signals with conserved patterns recognized by specific receptors — called toll-like receptors (TLRs) — of the innate immune system. It is therefore assumed that the healthy intestinal surface somehow defuses the threat of commensal bacteria to the lumen, where they thus reside undetected. A recent study by Rakoff-Nahoum and colleagues1 provides insight into how this happens: commensal bacteria interact with the intestinal surface and, to some degree, trigger TLR signaling (Figure 1). Surprisingly, this interaction is actually required to maintain the architectural integrity of the intestinal surface. Thus, it seems that the epithelium and resident immune cells do not simply tolerate commensal bacteria but are dependent on them.
Figure 1. Tickling Toll-like Receptors (TLRs).
Commensal bacteria secrete TLR ligands such as lipopolysaccharide and lipoteichoic acid, which interact in the normal intestine with a population of surface TLRs. The resultant basal signaling, which is normally ongoing, enhances the ability of the epithelial surface to withstand injury while also priming the surface for enhanced repair responses. Because many types of cells on the surface of the intestine — epithelial cells, lymphocytes between the epithelial cells, subepithelial mesenchymal cells, macrophages, and dendritic cells — express TLRs, it is not known whether this critical homeostatic mechanism is maintained by the cell populations that also respond by means of TLRs when the surface is breached. Either the disruption of TLR signaling or the removal of TLR ligands compromises the ability of the intestinal surface to withstand insult and effect repair.
The authors used mice deficient in a necessary downstream component of the TLR pathway, thereby preventing all TLR signaling. Such mice have a profoundly exaggerated response to intestinal injury. This effect is not a consequence of acute inflammation or the unrestrained overgrowth of commensal bacteria; rather, it results from the loss of TLR-dependent conditioning that allows the intestinal surface to maintain its normally resistant homeostasis. Rakoff-Nahoum et al. obtained further support for the validity of this hypothesis through a mirroring experiment: they found that depleting otherwise normal mice of intestinal microflora induced an equally profound injury. Reintroducing commensal bacteria into such mice, or simply adding the commensal-derived ligands for TLRs, prevented the injury. Thus, exposure of the intestinal surface to commensal-derived TLR ligands and the resulting activation of the TLR pathway are required for full health.
A second set of experiments revealed that preventing basal TLR activation thwarted the epithelial response to induced intestinal injury: the intestinal surface no longer produced substances critical to recovery, such as heat-shock proteins and tumor necrosis factor. An undefined degree of basal activation of the TLR pathways in the normal intestine is thus also responsible for priming this tissue so that it can respond to injury.
Bacteria have proved to be a rich source of information on the function of our own mammalian cells. Virulence factors have been identified in pathogens that cause a breathtaking array of human diseases, such as cholera, anthrax, and botulism. Elucidation of these mechanisms has led to highly targeted strategies in which specific signaling pathways of the mammalian cells were selectively affected by specific virulence factors. More recently, it has been recognized that common components of nonpathogenic organisms are also critical in signaling to mammalian cells. For example, it is now clear that nonpathogenic bacteria assist in epithelial development and surface differentiation and that these epithelial changes, in turn, provide inviting niches for the bacteria.2
The recognition that TLR signaling is activated by common bacterial products has also helped to shift the focus of study from how the intestinal mucosa becomes inflamed in disease to why surface inflammation is the exception rather than the rule.3 The study by Rakoff-Nahoum et al. helps to refine the new focus because, in addition to the previously known fact that commensals may quench as well as elicit inflammatory responses,3 it teaches us that basal commensal-dependent signaling is also critical to intestinal health and the ability of the luminal surface to respond to injury. The task now is to identify the specific signaling pathways activated by critical antigens of commensal bacteria, as has been achieved with those of pathogenic bacteria. Thus, we may discover how the physiologic state of the intestine is fine-tuned, discern the global context of TLR activation, and learn how the homeostatic balance of innate immunity is achieved.
The importance of context has also emerged from models of spontaneous intestinal injury and inflammation in mice deficient in various signaling molecules. A deficiency in any of numerous signaling molecules4 can induce intestinal inflammation — a precursor of inflammatory bowel disease — indicating that dysregulation of any one of multiple pathways involved in inflammation or repair disrupts the normal homeostatic mechanisms (which include microflora) and thereby results in disease. Thus, although microflora are required for homeostasis, they are also required for the full manifestations of inflammatory bowel disease induced in most genetic models. A better understanding of the context of different types of TLR activation will inform our approach to the treatment of inflammatory bowel disease.
Source Information
From the Department of Pathology, University of Chicago, Chicago.
References
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229-241.
Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science 2001;292:1115-1118.
Neish AS, Gewirtz AT, Zeng H, et al. Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination. Science 2000;289:1560-1563.
Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417-429.(James Madara, M.D.)
Figure 1. Tickling Toll-like Receptors (TLRs).
Commensal bacteria secrete TLR ligands such as lipopolysaccharide and lipoteichoic acid, which interact in the normal intestine with a population of surface TLRs. The resultant basal signaling, which is normally ongoing, enhances the ability of the epithelial surface to withstand injury while also priming the surface for enhanced repair responses. Because many types of cells on the surface of the intestine — epithelial cells, lymphocytes between the epithelial cells, subepithelial mesenchymal cells, macrophages, and dendritic cells — express TLRs, it is not known whether this critical homeostatic mechanism is maintained by the cell populations that also respond by means of TLRs when the surface is breached. Either the disruption of TLR signaling or the removal of TLR ligands compromises the ability of the intestinal surface to withstand insult and effect repair.
The authors used mice deficient in a necessary downstream component of the TLR pathway, thereby preventing all TLR signaling. Such mice have a profoundly exaggerated response to intestinal injury. This effect is not a consequence of acute inflammation or the unrestrained overgrowth of commensal bacteria; rather, it results from the loss of TLR-dependent conditioning that allows the intestinal surface to maintain its normally resistant homeostasis. Rakoff-Nahoum et al. obtained further support for the validity of this hypothesis through a mirroring experiment: they found that depleting otherwise normal mice of intestinal microflora induced an equally profound injury. Reintroducing commensal bacteria into such mice, or simply adding the commensal-derived ligands for TLRs, prevented the injury. Thus, exposure of the intestinal surface to commensal-derived TLR ligands and the resulting activation of the TLR pathway are required for full health.
A second set of experiments revealed that preventing basal TLR activation thwarted the epithelial response to induced intestinal injury: the intestinal surface no longer produced substances critical to recovery, such as heat-shock proteins and tumor necrosis factor. An undefined degree of basal activation of the TLR pathways in the normal intestine is thus also responsible for priming this tissue so that it can respond to injury.
Bacteria have proved to be a rich source of information on the function of our own mammalian cells. Virulence factors have been identified in pathogens that cause a breathtaking array of human diseases, such as cholera, anthrax, and botulism. Elucidation of these mechanisms has led to highly targeted strategies in which specific signaling pathways of the mammalian cells were selectively affected by specific virulence factors. More recently, it has been recognized that common components of nonpathogenic organisms are also critical in signaling to mammalian cells. For example, it is now clear that nonpathogenic bacteria assist in epithelial development and surface differentiation and that these epithelial changes, in turn, provide inviting niches for the bacteria.2
The recognition that TLR signaling is activated by common bacterial products has also helped to shift the focus of study from how the intestinal mucosa becomes inflamed in disease to why surface inflammation is the exception rather than the rule.3 The study by Rakoff-Nahoum et al. helps to refine the new focus because, in addition to the previously known fact that commensals may quench as well as elicit inflammatory responses,3 it teaches us that basal commensal-dependent signaling is also critical to intestinal health and the ability of the luminal surface to respond to injury. The task now is to identify the specific signaling pathways activated by critical antigens of commensal bacteria, as has been achieved with those of pathogenic bacteria. Thus, we may discover how the physiologic state of the intestine is fine-tuned, discern the global context of TLR activation, and learn how the homeostatic balance of innate immunity is achieved.
The importance of context has also emerged from models of spontaneous intestinal injury and inflammation in mice deficient in various signaling molecules. A deficiency in any of numerous signaling molecules4 can induce intestinal inflammation — a precursor of inflammatory bowel disease — indicating that dysregulation of any one of multiple pathways involved in inflammation or repair disrupts the normal homeostatic mechanisms (which include microflora) and thereby results in disease. Thus, although microflora are required for homeostasis, they are also required for the full manifestations of inflammatory bowel disease induced in most genetic models. A better understanding of the context of different types of TLR activation will inform our approach to the treatment of inflammatory bowel disease.
Source Information
From the Department of Pathology, University of Chicago, Chicago.
References
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229-241.
Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science 2001;292:1115-1118.
Neish AS, Gewirtz AT, Zeng H, et al. Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination. Science 2000;289:1560-1563.
Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417-429.(James Madara, M.D.)