PerspectiveImmunology

Keeping the Gut Microflora at Bay

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Science  12 Mar 2004:
Vol. 303, Issue 5664, pp. 1624-1625
DOI: 10.1126/science.1096222

The gastrointestinal tract of human adults contains more than 400 different species of bacteria. Indeed, the total weight of microflora in the human gut has been estimated to be about 1 kg. Most of these bacteria are commensals that coexist peacefully with their host and remain harmless provided that they do not stray beyond the gut lumen. Some commensals may even confer health benefits upon their host by helping to digest dietary carbohydrate and by maintaining the appropriate balance among the different types of gut bacteria. The correct microbial balance helps to stimulate gut immunity and to prevent colonization by pathogenic bacteria that cause diarrhea and other intestinal disorders (1).

The intestinal epithelium provides a barrier against the invasion of host tissues by both pathogenic and nonpathogenic bacteria (2). However, pathogenic bacteria are able to breach the gut epithelium and the host's innate immune system in a number of ways, in some cases destroying gut epithelial cells (3). In contrast to bacterial pathogens, commensals have been presumed to reside in the gut lumen with little or no direct interaction with the epithelium. Recent studies, however, indicate that gut commensals do interact with the gut epithelium and can trigger innate and adaptive immune responses. In addition, commensals can influence epithelial cell proliferation, for example, by injecting factors into the gut epithelium that block β-catenin degradation (4). These microbes also enhance the nuclear export of NF-κB, the transcription factor that controls the production of proinflammatory chemokines by gut epithelial cells (5). On page 1662 of this issue, Macpherson and Uhr (6) reveal that the gut mucosa—comprising the gut epithelium, connective tissue layer (lamina propria), and gut-associated lymphoid tissues (GALT)—has developed an elegant system for keeping commensals in check. They report that commensals are prevented from breaching the gut mucosal barrier by an immunoglobulin A (IgA) antibody-mediated mucosal immune response. This immune response is triggered by presentation of commensal antigens to B cells in GALT by intestinal dendritic cells (DCs).

Cells of the innate immune system, such as dendritic cells and macrophages, provide broad nonadaptive (innate) protection against microorganisms that are newly encountered by the host. Activation of innate host defense depends on specific recognition of microbial signature molecules called pathogen-associated molecular patterns (PAMPs) (7). In the gut mucosa, monocytes and particularly DCs in the intraepithelial and subepithelial layers are specialized for detecting microbial pathogens. Both cell types recognize PAMPs through pattern-recognition receptors that are either secreted or expressed on the immune cell surface (8). These molecules include the Toll-like receptor (TLR) family in animals and the disease resistance-like receptor family (such as Nod1 and Nod2) in plants. Between them, human monocytes and DCs express all known TLRs, that is, TLR1 through TLR10 (9). The response of gut epithelial cells to microbial PAMPs depends on their expression of TLR3 and TLR5, and to a lesser extent TLR2 and TLR4 (10). In response to bacterial components, such as flagellin, gut epithelial cells release chemokines that recruit immune cells, in particular DCs, into the gut mucosa (11). Once DCs reach the epithelial layer of the gut, they express membrane proteins that allow them to pry open the tight junctions between the epithelial cells (see the figure). The DCs then send long extensions (dendrites) into the gut lumen and sample microbial antigens and other lumen antigens (12). These innate immune cells then return to lymphoid follicles deeper within the gut mucosa where they present antigens to B and T cells of the adaptive immune system. Thus, the gut epithelium acts as the gatekeeper of mucosal immunity, forming a link between the innate and adaptive immune systems.

Dendritic cell-mediated transport of commensal bacteria in the gut.

Commensal bacteria in the gut lumen are continuously sampled by cells of the innate immune system, such as dendritic cells (DCs) and M cells. M cells of the gut epithelium may import bacteria into the dome region of the GALT where DCs engulf the microbes. Alternatively, DCs may sample commensals directly by prying open the tight junctions between epithelial cells and projecting their dendrites into the gut lumen. DCs present antigenic peptides from captured microbes to B and T lymphocytes either locally in the GALT, or within the mesenteric lymph nodes that drain the gut submucosa. Presentation of microbial antigens to B cells triggers production of a commensal-specific IgA response that prevents the commensals from straying beyond the gut mucosa where they could elicit a systemic inflammatory response.

CREDIT: TAINA LITWAK

In the gut lumen, IgA is continuously produced in large amounts (>5 g per day), binding predominantly to commensal bacteria and to dietary antigens. MacPherson and his colleagues showed previously that the induction of commensal-specific IgA is independent of T helper cell activity and of the organization of lymphoid tissues, reflecting an evolutionarily primitive form of specific immune defense (13). In general, it is thought that antigenic stimulation within GALT induces the migration and homing of IgA+ lymphoblasts to the lamina propria of the gut mucosa where they differentiate into plasma cells and secrete IgA. An alternative pathway has been proposed in which IgM+ B cells in the lamina propria switch to production of the IgA isotype without the need for T cell help (14).

In their new work, MacPherson and Uhr (6) characterize the active transport of live commensals by DCs from the mouse gut lumen to the intestinal mesenteric lymph nodes. The DCs carrying their commensal load do not stray beyond these lymphoid tissues, preventing a systemic infection and ensuring a commensal-specific IgA response that is restricted to the gut mucosa. If commensal bacteria escape from the DCs, they become coated with IgA and are rapidly taken up and destroyed by Fcα/μ-bearing phagocytic cells (15). MacPherson and Uhr elegantly demonstrate that following surgical removal of mouse mesenteric lymph nodes, commensal microbes are able to invade the spleen, triggering a systemic immune response. Using fluorescent bacteria, the investigators identified DCs of the GALT as the cells containing commensals. These DCs may sample commensals in the gut lumen directly (see the figure). Alternatively, M cells of the gut epithelium may import commensal bacteria into the dome region of the GALT where they are taken up by DCs. The authors rule out participation by intraepithelial DCs of the intestinal villi in commensal uptake. However, it is possible that the majority of commensal-loaded DCs had departed the gut epithelium at the time of their analysis, that is, 5 hours after presentation of microbial antigens to local B cells and the triggering of a T cell-independent IgA response.

From the MacPherson and Uhr work, it appears that the mesenteric lymph nodes form a barrier that prevents the microflora from reaching the systemic compartment of the host immune system and from eliciting a damaging inflammatory response. The mesenteric lymph nodes also act as inductive sites, generating IgA antibodies that facilitate the destruction of commensal bacteria by phagocytes of the gut mucosa. These observations, as well as the recent elucidation of mechanisms that block inflammation in the gut, define new cellular targets for designing therapeutics to treat inflammatory bowel disease.

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