Immune adaptations that maintain homeostasis with the intestinal microbiota

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  • An Erratum to this article was published on 07 April 2015


Humans harbour nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of co-evolution have moulded this human–microorganism interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment. Although intestinal microorganisms carry out essential functions for their hosts, they pose a constant threat of invasion owing to their sheer numbers and the large intestinal surface area. In this Review, we discuss the unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota.

Key Points

  • The human intestine contains 100 trillion bacteria that make essential contributions to human metabolism and establish symbiotic relationships with their hosts. However, these organisms pose an ongoing threat of invasion owing to their enormous numbers.

  • The intestinal immune system has evolved unique immune adaptations that allow it to manage its high bacterial load. These immune mechanisms work together to ensure that commensal bacteria rarely breach the intestinal barrier and that any that do invade are killed rapidly and do not penetrate to systemic sites.

  • A key element of the mammalian intestinal strategy for maintaining homeostasis with the microbiota is to minimize contact between luminal microorganisms and the intestinal epithelial cell surface. This is accomplished by enhancing the physical barrier through the production of mucus, antimicrobial proteins and IgA.

  • A second layer of intestinal immune protection relies on the rapid detection and killing of bacteria that penetrate the epithelial cell surface. This occurs by several immune mechanisms, including bacterial uptake and phagocytosis by innate immune cells and a complex set of T cell-mediated responses.

  • A third immune barrier is presented by the mesenteric lymph nodes, which constitute an immune 'firewall' limiting penetration by commensal microorganisms to the systemic immune system. This allows induction of adaptive immune responses to resident bacteria to be confined to the mucosal immune compartment.

  • An increasing amount of evidence suggests that inflammatory bowel disease (IBD) arises from dysregulated control of host–microorganism interactions. In support of this hypothesis, several IBD risk alleles compromise intestinal immune mechanisms that maintain homeostasis with the microbiota.

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Figure 1: Immune mechanisms that limit bacteria–epithelial cell interactions.
Figure 2: Regulation of antimicrobial protein expression.
Figure 3: Production of IgA directed against intestinal bacteria.
Figure 4: CD4+ T cell subset differentiation.
Figure 5: Regulatory networks for intestinal CD4+ T cells.

Change history

  • 07 April 2015

    In figure 4 of the original article, the cytokines that promote the differentiation of T helper 2 (TH2) cells and TH17 cells were included in the wrong order. This has now been corrected in the online HTML and PDF versions of the article. Nature Reviews Immunology apologizes for this error.


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L.V.H. thanks the students and colleagues from her laboratory for the many discussions that contributed to the ideas in this manuscript. Work in L.V.H.'s laboratory is supported by the Howard Hughes Medical Institute, the US National Institutes of Health (DK070855), the Burroughs Wellcome Foundation and the Crohn's and Colitis Foundation. A.M. acknowledges K. McCoy, E. Slack, S. Hapfelmeier, M. Stoehl and M. Geuking.

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The microorganisms that are harboured by normal, healthy individuals. These microorganisms live in the digestive tract and at other body sites.


A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.


All the genetic material present in a population of microorganisms, consisting of the genomes of many individual organisms.

Goblet cell

A mucus-producing cell found in the epithelial cell lining of the intestine and lungs.


A class of antimicrobial peptide that has activity against Gram-positive and Gram-negative bacteria, fungi and viruses. α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells.

C-type lectin

An animal receptor protein that binds to carbohydrates, frequently in a Ca2+-dependent manner. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved among members of this family.

Paneth cells

A specialized epithelial cell lineage that produces most of the antimicrobial proteins in the small intestine.

Peyer's patches

Groups of lymphoid nodules present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. 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.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Plasma cell

A non-dividing, terminally differentiated, immobile antibody-secreting cell of the B cell lineage.


Process of transport of material across a cell monolayer by uptake on one side of the cell into a coated vesicle, which might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Germ-free mouse

A mouse that is born and raised in isolators, without exposure to microorganisms.

Germinal centre

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

Recombination-activating gene

(Rag). A gene expressed by developing lymphocytes. Mice that are deficient for either Rag1 or Rag2 fail to produce B or T cells owing to a developmental block in the gene rearrangement that is necessary for antigen receptor expression.

Severe combined immunodeficiency

(SCID). A phenotype of mice with a defect in DNA recombination. SCID mice lack B and T cells and do not reject tissue grafts from allogeneic and xenogeneic sources.

Intraepithelial CD8αα+ T cell

A type of T cell that is found in the intestinal epithelium. The CD8 molecule that they express is a homodimer of CD8α, rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes. It has been proposed that these cells are self-reactive T cells that have regulatory properties.

Lymphoid-tissue inducer cell

(LTi cell). A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue. LTi cells are required for the development of these lymphoid organs and are characterized by expression of the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt), interleukin-7 receptor-α and lymphotoxin-α1β;2.

Specific pathogen-free (SPF) mice

Mice kept in specific vivarium conditions whereby a 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 potential pathogens.

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