Review Article | Published:

Microbiota-mediated colonization resistance against intestinal pathogens

Nature Reviews Immunology volume 13, pages 790801 (2013) | Download Citation

Abstract

Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium, Gram-negative Enterobacteriaceae and Clostridium difficile. In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.

Key points

  • Antibiotic treatment disrupts the native intestinal microbiota and favours infection with and the proliferation of antibiotic-resistant intestinal pathogens. Clinically important antibiotic-resistant pathogens include vancomycin-resistant Enterococcus spp., various Enterobacteriaceae and Clostridium difficile.

  • The intestinal microbiota influences the development, the maintenance and the function of the innate and adaptive immune systems. Host immune function is decreased in the intestines following antibiotic therapy, and antibiotic-treated hosts are susceptible to intestinal infection.

  • Microbiota-derived bacterial populations and products that enhance immune defence against intestinal pathogens are being identified. However, the precise bacterial sources of many immunomodulatory molecules remain unclear and, conversely, the molecular mechanisms by which most probiotics restore immunity have yet to be elucidated.

  • In addition to indirectly enhancing colonization resistance by stimulating host immune defences, bacterial populations can directly suppress intestinal pathogens by competitive exclusion and by antimicrobial activities. The commensal populations that are responsible for direct antagonism of pathogens and indirect, immune-mediated colonization resistance may be closely related and difficult to distinguish.

  • Microbiota-derived bacterial populations and products, a subset of which enhance immune defence, can also promote intestinal inflammation, whereas other microbiota components restrain effector responses and promote tolerance.

  • Manipulation of the intestinal microbiota to prevent and to treat some intestinal infections, such as C. difficile, shows promise in human patients and animal models of infection. However, the specific contributions of the individual bacterial populations that constitute the consortia transferred in such studies remain mostly undefined.

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Acknowledgements

E.G.P. receives funding from US National Institutes of Health (NIH) grants RO1 AI42135 and AI95706, and from the Tow Foundation. C.G.B. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH (award number T32GM07739, which was awarded to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program).

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  1. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box number 9, New York, New York 10065, USA.

    • Charlie G. Buffie
    •  & Eric G. Pamer

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric G. Pamer.

Glossary

Innate lymphocytes

Lymphoid cells that are dependent on signalling through the common cytokine receptor γ-chain but that lack recombined antigen receptors. They have important roles in mucosal defence, epithelial homeostasis and lymphoid tissue development.

Endospores

Metabolically inactive bacterial forms that are resistant to chemical and physical stresses and that reactivate under specific environmental conditions.

Vegetative bacteria

Metabolically active bacterial forms.

Toxic megacolon

A potentially lethal complication of infectious colitis or inflammatory bowel disease that is characterized by mucosal inflammation, dilatation of the colon and systemic toxicity.

Paneth cell

Specialized epithelial cell that is found at the base of crypts in the small intestine and that expresses various antimicrobial proteins.

Cryptdins

Microbicidal peptides that are expressed in granules of phagocytic leukocytes and in secretory granules of Paneth cells.

Bacteroidetes

A major bacterial phylum of the intestinal microbiota that comprises physiologically diverse aerobic and anaerobic Gram-negative bacteria commonly associated with the degradation of complex carbohydrates.

Firmicutes

A major bacterial phylum of the intestinal microbiota that primarily comprises Gram-positive bacteria that have low guanine and cytosine DNA content. They are phenotypically diverse, commonly polyphyletic and are often distinguished by their ability to form endospores.

Actinobacteria

A bacterial phylum that is abundant in the intestinal microbiota and that is primarily composed of Gram-positive bacteria that have high guanine and cytosine content in their DNA and that are commonly associated with secondary metabolite production.

Proteobacteria

A bacterial phylum, which is abundant in the intestinal microbiota, that is composed of Gram-negative bacteria that can be distinguished by their collective morphological and metabolic diversity.

Segmented filamentous bacteria

(SFB). Gram-positive, spore-forming, non-culturable, Clostridia-related bacteria, provisionally named Candidatus Savagella (of the Clostridiaceae family), that closely adhere to the small intestinal epithelium in various vertebrates and that stimulate immune responses.

TRUC model

(Tbx21−/−Rag2−/− ulcerative colitis model). A mouse model of inflammatory bowel disease that resembles human ulcerative colitis, wherein conventionally-raised mice that lack T-bet and V(D)J recombination-activating protein 2 (RAG2) spontaneously develop an aggressive, highly penetrant, communicable form of colitis.

Type VI secretion system

(T6SS). A protein structure that is used by Gram-negative bacteria to translocate effector proteins that are commonly involved in virulence and bacterial competition into other prokaryotic and eukaryotic cells.

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DOI

https://doi.org/10.1038/nri3535

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