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War and peace at mucosal surfaces
Nature Reviews Immunologyvolume 4, pages953–964 (2004)Cite this article
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Key Points
The intestine and its commensal microflora have established a homeostatic process of unresponsiveness that prevents intestinal inflammation and its deleterious clinical effects.
This process of microbial tolerance is an enigma that is just starting to be deciphered in molecular terms, with intestinal epithelial cells (IECs) having an important role at the interface between microorganisms and the mucosa.
'Tolerance' to bacteria is a consequence of a complex array of factors, which include the following: the lack of pathogenic factors in commensal microorganisms, which hampers their access to, and engagement of, the epithelial lining; a degree of 'blindness' of the intestinal epithelium to pathogen-associated molecular patterns, particularly resulting from the lack of expression of some important Toll-like receptors by IECs; and molecular crosstalk that actively maintains a situation of innate and adaptive immune tolerance between bacteria and host tissues.
This delicate balance is disrupted by invasive microorganisms that elicit a strong innate immune response, which thereby results in an inflammatory reaction, leading to disruption and destruction of the intestinal barrier.
The long co-evolution of bacteria (both commensal and pathogenic microorganisms) with their mammalian hosts, and the resultant reciprocal selective pressure, is likely to provide us with essential tools and concepts for deciphering the complex mechanisms that maintain the fragile balance between homeostasis and intestinal inflammation.
Abstract
That we live with numerous bacteria in our gut without any adverse effects is a remarkable feat by the body's immune system, particularly considering the wealth of sensing and effector systems that are available to trigger inflammatory or innate immune responses to microbial intrusion. So, a fine line seems to exist between the homeostatic balance maintained in the presence of commensal gut flora and the necessarily destructive response to bacterial pathogens that invade the gut mucosa. This review discusses the mechanisms for establishing and controlling the 'dialogue' between unresponsiveness and initiation of active immune defences in the gut.Si vis pacem, para bellum. (If you wish for peace, prepare for war.)
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Acknowledgements
I wish to thank D. Philpott and A. Phalipon for careful reading of this manuscript and for relevant comments. I also express my gratitude to all (present and past) members of Unité de Pathogénie Microbienne Moléculaire (Institut Pasteur, Paris, France). P.J.S. is a Howard Hughes Medical Institute scholar.
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Unité de Pathogénie Microbienne Moléculaire, U389 INSERM and Howard Hughes Medical Institute, Institut Pasteur, 28 Rue du Docteur Roux, Paris, 75724 cedex 15, France
Philippe J. Sansonetti
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Glossary
- MICROVILLI
Multiple extensions of the apical pole of intestinal epithelial cells that are caused by membranous evaginations around actin bundles. Together, these extensions form the brush border, which physically protects the apical pole, particularly against pathogens.
- BRUSH BORDER
Formed by the microvilli. It provides a large increase of the apical surface, thereby increasing the capacity of the epithelial surface for absorbing nutrients and exchanging water and electrolytes.
- PERISTALSIS
An activity of the intestinal muscular layer that leads to unilateral movement, promoting the movement of the intestinal content from proximal to distal zones.
- PATHOGEN-ASSOCIATED MOLECULAR PATTERNS
(PAMPs). Molecular motifs that are characteristic of prokaryotes and are thereby recognized by the mammalian innate immune system.
- PATTERN-RECOGNITION RECEPTORS
(PRRs). Host receptors (such as Toll-like receptors) that can sense pathogen-associated molecular patterns and initiate signalling cascades (involving the activation of nuclear factor-κB) that lead to an innate immune response.
- TYPE IV SECRETORY SYSTEM
A type of molecular syringe that Gram-negative bacteria have. It enables these bacteria to deliver DNA (by species such asAgrobacterium) and protein effectors (by species such asHelicobacter pylori) into eukaryotic cells.
- TYPE III SECRETORY SYSTEM
(TTSS). A molecular syringe that is prevalent in pathogenic and symbiotic Gram-negative bacteria. TTSSs can deliver effector molecules into eukaryotic target cells.
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Sansonetti, P. War and peace at mucosal surfaces.Nat Rev Immunol4, 953–964 (2004). https://doi.org/10.1038/nri1499
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