Germ-free mice have many immunological defects in the intestine, including smaller mesenteric lymph nodes and Peyer's patches, decreased numbers of interleukin-17 (IL-17)-producing T helper 17 (TH17) cells and defects in regulatory T (TReg) cells. In addition, germ-free mice have impaired immune responses to certain pathogens, including Shigella and Listeria species. These findings indicate that the intestinal microbiota might influence both pro- and anti-inflammatory responses.
Intestinal homeostasis depends on maintaining a proper balance between pro- and anti-inflammatory pathways that are mediated by TH17 and TReg cells, respectively. Improper regulation of inflammatory pathways can lead to diseases such as inflammatory bowel disease (IBD). IBD results from the breakdown in immune tolerance to gut bacteria. Indeed, spontaneous disease does not occur in many mouse models of experimental colitis, including IL-2- and IL-10-deficient mice, when raised under germ-free conditions.
Susceptibility to IBD is influenced by many factors, including genetic and dietary factors. However, recent studies have shown that the intestinal microbiota could be an important factor in driving disease.
Similar to observations made in animal models, changes in the microbiota of humans have been implicated in disease. Numerous studies have revealed a significant alteration in the microbiota of patients with IBD compared with healthy individuals, although whether changes in the intestinal microbiota are the cause or effect of disease still needs to be determined.
Several species of bacteria that peacefully reside in the intestine have been shown to have a protective role during IBD. These bacteria are referred to as probiotic bacteria and include species such as Lactobacillus casei and Bifidobacteria longum. The mechanisms by which these bacteria protect from disease are thought to involve modulation of TReg cell responses. A product of B. fragilis, polysaccharide A, elicits IL-10 production by CD4+ T cells and mediates protection from IBD, demonstrating that symbiotic intestinal bacteria have developed strategies to influence the host immune system.
Does harbouring certain strains of bacteria predispose an individual to disease or protect from it? As symbiotic bacteria seem to have evolved mechanisms to promote protection from potentially pathogenic bacteria in the microbiota, disease may result from the absence of these symbiotic organisms and their beneficial molecules. Therefore, dysbiosis (a shift in the composition of the intestinal microbiota) could be an underlying factor in the development of IBD.
Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
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We thank members of the Mazmanian laboratory for their critical review of the manuscript. We apologize to those whose work could not be mentioned owing to space limitations and the scope of the manuscript, in particular the vast clinical data on inflammatory bowel disease. J.L.R is a Merck Fellow of the Jane Coffin Child's Memorial Fund. S.K.M. is a Searle Scholar. Work in our laboratory is supported by funding from the National Institutes of Health, USA, Damon Runyon Cancer Research Foundation and the Crohn's & Colitis Foundation of America to S.K.M.
A symbiotic association in which both members benefit from the relationship.
An opportunistic organism that rarely comes into contact with the host, but causes acute or chronic disease following infection. Derived from the Greek word 'pathos', which means suffering.
The collective genomes of a microbiota.
The amalgam of microorganisms that make up a complex and diverse community living within a given anatomical niche (usually an environmentally exposed surface of the body).
- Inflammatory bowel disease
A chronic condition of the intestine that is characterized by severe inflammation and mucosal destruction. The most common forms in humans are ulcerative colitis and Crohn's disease.
- Gut-associated lymphoid tissue
Lymphoid structures and aggregates associated with the intestinal mucosa, specifically the tonsils, Peyer's patches, lymphoid follicles, appendix or caecal patch and mesenteric lymph nodes. They are enriched in conventional and unconventional lymphocytes and specialized dendritic cell and macrophage subsets. They provide the first line of defence against entry of pathogens across the mucosal barrier.
- Peyer's patches
Groups of lymphoid nodules that are 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.
- Mesenteric lymph node
(MLN). A lymph node that is located at the base of the mesentery. MLNs collect lymph (including cells and antigens) draining from the intestinal mucosa.
- Specific pathogen free
Conditions in which animals are reared and maintained in an environment with an unknown complex microbiota that is free from specific known pathogens.
- Isolated lymphoid follicles
Small lymphoid aggregates located in the anti-mesenteric wall of the small intestine, which contain B cells, dendritic cells, stromal cells and some T cells. They may contain germinal centres. They are thought to have a role in maintaining equilibrium between the immune system and the microbiota.
- Pattern recognition receptor
A host receptor (such as Toll-like receptors) that can sense pathogen-associated molecular patterns and initiate signalling cascades (which involve the activation of nuclear factor-κB) that lead to an innate immune response.
A microorganism that benefits from an association with no known effects on the host. Derived from the Latin phrase 'com mensa', meaning to share a table.
- Crohn's disease
A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract, but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is believed to result from an abnormal T cell-mediated immune response to commensal bacteria.
- Ulcerative colitis
A chronic disease that is characterized by inflammation of the mucosa and sub-mucosa of the large intestine.
- Regulatory T (TReg) cell
A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self tolerance and are characterized by expression of CD25 (the α-chain of the interleukin-2 receptor) and the transcription factor forkhead box P3 (FOXP3).
An opportunistic organism that maintains a prolonged and close association with the host, which benefits the parasite at the expense of the host.
A symbiont that does not normally elicit an inflammatory response but under particular conditions (environmentally induced) has the potential to cause dysregulated inflammation and lead to disease.
A mixture of bacteria consisting of four strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus and L. delbrueckii subspecies bulgaricus), three strains of Bifidobacterium (B. longum, B. breve and B. infantis) and Streptococcus salivarius subspecies thermophilus.
An organism that lives in association with a host (usually for a lifetime) without obvious benefit or harm to either member.
A constant and intimate relationship that occurs between dissimilar species, which was originally defined as 'living together'. Although it is often used to describe a beneficial relationship, symbiosis does not necessarily imply that either partner gains an advantage.
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Round, J., Mazmanian, S. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313–323 (2009). https://doi.org/10.1038/nri2515
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