Review Article | Published:

Role of the gut microbiota in immunity and inflammatory disease

Nature Reviews Immunology volume 13, pages 321335 (2013) | Download Citation

Abstract

The mammalian intestine is colonized by trillions of microorganisms, most of which are bacteria that have co-evolved with the host in a symbiotic relationship. The collection of microbial populations that reside on and in the host is commonly referred to as the microbiota. A principal function of the microbiota is to protect the intestine against colonization by exogenous pathogens and potentially harmful indigenous microorganisms via several mechanisms, which include direct competition for limited nutrients and the modulation of host immune responses. Conversely, pathogens have developed strategies to promote their replication in the presence of competing microbiota. Breakdown of the normal microbial community increases the risk of pathogen infection, the overgrowth of harmful pathobionts and inflammatory disease. Understanding the interaction of the microbiota with pathogens and the host might provide new insights into the pathogenesis of disease, as well as novel avenues for preventing and treating intestinal and systemic disorders.

Key points

  • The gut microbiota is important for the development and functional maturation of the gut immune system, including gut-associated lymphoid tissue, T helper 17 cells, inducible regulatory T cells, IgA-producing B cells and innate lymphoid cells.

  • The gut microbiota prevents exogenous pathogen infection through direct (for example, competition for common nutrients and niches) and indirect (for example, enhancement of host defence) mechanisms.

  • Pathogens have evolved strategies to evade direct competition with the resident microbiota by eradicating bacterial competitors, localizing to niches that are distinct from those occupied by commensal bacteria and by using alternative resources.

  • Potential pathobionts can accumulate in a host with inherent genetic susceptibility or environmental factors that lead to the development of inflammatory bowel disease.

  • The gut microbiota regulates susceptibility to extra-intestinal autoimmune diseases, such as multiple sclerosis, type 1 diabetes, arthritis and allergy.

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Acknowledgements

This work is supported by grants from the US National Institutes of Health and the Bill & Melinda Gates Foundation, USA. N.K. is supported by a Research Fellowship from the Crohn's and Colitis Foundation of America.

Author information

Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, Michigan, USA.

    • Nobuhiko Kamada
    • , Sang-Uk Seo
    •  & Gabriel Núñez
  2. Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, Michigan, USA.

    • Grace Y. Chen

Authors

  1. Search for Nobuhiko Kamada in:

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gabriel Núñez.

Glossary

Gut-associated lymphoid tissues

(GALTs). Lymphoid structures and aggregates that are associated with the intestinal mucosa, specifically the tonsils, Peyer's patches, lymphoid follicles, appendix or cecal patch, and mesenteric lymph nodes. They are enriched in conventional and unconventional lymphocytes, and in specialized dendritic cell and macrophage subsets.

Germ-free mice

Mice that are born and raised in isolators, without exposure to microorganisms.

Peyer's patches

Collections of lymphoid tissue that are located in the mucosa of the small intestine. They have an outer epithelial layer consisting of specialized epithelial cells called M cells. Peyer's patches consist of a dome area, B cell follicles and interfollicular T cell areas. High endothelial venules are present mainly in the interfollicular areas.

Specific-pathogen-free mice

Mice raised in conditions whereby an increasing number of pathogens are excluded or eradicated from the colony. These animals are maintained in the absence of most of the known chronic and latent persistent pathogens. Although this enables better control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in constant contact with pathogens.

Pattern recognition receptors

(PRRs). Germline-encoded receptors (such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs)) that can sense pathogen- associated molecular patterns and initiate signalling cascades that lead to an innate immune response. They can be membrane-bound (such as TLRs and C-type lectin receptors (CLRs)) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation- associated protein 5 (MDA5) and NLRs).

Peripherally derived TReg cells

A subset of forkhead box P3 (FOXP3)+ regulatory T (TReg) cells that are induced in the periphery and mediate their suppressive effects through the secretion of cytokines such as interleukin-10 and transforming growth factor-β, which inhibit other T cells. Their role is to maintain self-tolerance.

Activation-induced cytidine deaminase

(AID). An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.

Follicular DCs

(FDCs). Specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells possess long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.

Type IV secretion system

(T6SS). An export system that is used by Gram-negative bacteria to deliver effector proteins to other cells in a cell contact-dependent manner.

Inflammasome

A molecular complex of several proteins, including a NOD-like receptor (NLR), the adaptor protein ASC and a caspase, that, upon assembly, cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18, thereby producing mature IL-1β and IL-18.

Aryl hydrocarbon receptor

(AHR). A cytosolic, ligand-dependent transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of regulatory T cells, T helper 17 (TH17) cells and intraepithelial intestinal T cells, and it is required for the secretion of interleukin-22 by TH17 cells. More recently, AHR has been shown to have crucial roles in the development and function of group 3 innate lymphoid cells, including lymphoid tissue inducer (LTi) cells and ILC3s.

Inflammatory bowel disease

(IBD). Immune-mediated inflammation of the bowel. There are two main forms: Crohn's disease, which is a granulomatous segmental inflammation affecting any part of the intestine; and ulcerative colitis, which is a mucosal inflammation involving the rectum and extending for a variable distance along the colon. In developed countries, the incidence of inflammatory bowel disease is approximately one in 50,000. It usually starts in early adult life and continues afterwards with a relapsing, remitting course.

SAMP1/yit mice

A mutant mouse strain that spontaneously develops a chronic intestinal inflammation that is mainly localized in the terminal ileum.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.

α-defensins

One subset of defensin proteins. Defensins and cathelicidins are members of a family of small antimicrobial polypeptides that are abundant in neutrophils and epithelial cells. They contribute to host defence by disrupting the cytoplasmic membrane of microorganisms.

Rag

Recombinase activating genes; Rag1 and Rag2 are expressed in developing lymphocytes. Mice that are deficient in either of these genes fail to produce B or T cells owing to a developmental block in the gene rearrangement that is necessary for receptor expression.

iNKT cells

Invariant natural killer (iNKT) cells; a population of cells that are thought to be particularly important in bridging the innate and adaptive immune responses. iNKT cells are typified by a capacity for self-recognition and rapid release of cytokines such as interferon-γ.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

K/BxN transgenic mice

Mice formed by crossing non-obese diabetic (NOD)/Lt mice with KRN T cell receptor-transgenic mice on the C57BL/6 background. As the KRN receptor on T cells recognizes a peptide from the autoantigen glucose-6-phosphate isomerase, these mice develop an arthritis that is mediated, and transferable, by circulating antibodies against glucose-6- phosphate isomerase.

NOD mice

Non-obese diabetic (NOD) mice spontaneously develop type 1 diabetes as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.

Hygiene hypothesis

This hypothesis originally stated that the increased incidence of atopic diseases in westernized countries was a consequence of living in an overly clean environment, which resulted in an understimulated immune system that responded inappropriately to harmless antigens. More recently it has been proposed that an absence of exposure to pathogens, in particular helminths, might predispose individuals to both increased allergy and autoimmune disease.

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DOI

https://doi.org/10.1038/nri3430

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