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Skin
Intestines
Vagina
Fig. 1. The microbiome of various anatomical locations of the human body. regions of the body share similarities, they each have a unique site-specific “fingerprint”
Numerous bacterial species colonize the mouth, upper airways, skin, vagina, and made of many distinct microbes. Each site has a very high level of diversity, as shown by
intestinal tract of humans. The phylogenetic trees show the speciation of bacterial clades the individual lines on the dendrograms. Data are from the NIH-funded Human
from common ancestors at each anatomical site. Although the communities in different Microbiome Project; circles represent bacterial species whose sequences are known.
B
Treg
TH 17
Dysbiosis
(increased pro-
inflammatory
+ = Disease
bacteria)
C
Treg TH 17
Dysbiosis
(decreased anti- + = Disease
inflammatory
bacteria)
B cell TH 17 cell
Treg cell IL-10+ Treg cell
Fig. 2. How the microbiome and the human genome contribute to sclerosis, type I diabetes, rheumatoid arthritis, and Crohn’s disease contain a
inflammatory disease. In a simplified model, the community composition of spectrum of variants that are linked to disease by genome-wide association
the human microbiome helps to shape the balance between immune studies [reviewed in (63)]. Environmental influences, however, are risk factors
regulatory (Treg) and proinflammatory (TH17) T cells. The molecules produced in all of these diseases. Altered community composition of the microbiome
by a given microbiome network work with the molecules produced by the due to life-style, known as dysbiosis, may represent this disease-modifying
human genome to determine this equilibrium. (A) In a healthy microbiome, component. An increase in proinflammatory microbes (for example, SFBs in
there is an optimal proportion of both pro- and anti-inflammatory organisms animal models) may promote TH17 cell activity to increase and thus predispose
(represented here by SFBs and B. fragilis), which provide signals to the genetically susceptible people to TH17-mediated autoimmunity (B). Alterna-
developing immune system (controlled by the host genome), leading to a tively, a decrease or absence in anti-inflammatory microbes—for example, B.
balance of Treg and TH17 cell activities. In this scenario, the host genome can fragilis in animal models—may lead to an underdevelopment of Treg cell
contain “autoimmune-specific” mutations (represented by the stars), but subsets (C). The imbalance between TH17 cells and Tregs ultimately leads to
disease does not develop. (B and C) The genomes of patients with multiple autoimmunity.
D Modern adaptive
immune system
A Primordial adaptive
immune system
C Development of TH 17 cells
by pathobionts
TH 17
B cell TH 17 cell inducing cytokines
Fig. 3. A model for the coevolution of adaptive immunity with the microbiota. (such as SFBs) may have induced TH17 cell differentiation to increase mucosal
(A) The adaptive immune system develops under the control of the vertebrate defenses against enteric pathogens. (D) The modern adaptive immune system
genome to produce various cell types. The evolutionarily ancient molecule TGFb may have arisen from two distinct events: Tregs and TH17 cell types evolved
directs the differentiation of Foxp3+ Treg cells. Although the earliest mammals independently [(A) to (B) and (A) to (C)] or through the sequential development
contained a gut microbiota, bacteria may or may not have influenced features of TH17 cells from Treg cell precursors [(A) to (B) to (C) to (D)]. This may have
of the primordial adaptive immune system. (B) Over millennia of coevolution, been achieved by a combinatorial signal of TGFb, augmented by the addition of
commensal microbes (B. fragilis used as an example here) produced molecules IL-6 to promote TH17 cell evolution over time (inset). Together, the modulation
that networked with the primordial immune system to help expand various Treg of Tregs and TH17 cells by commensal microorganisms and pathobionts, re-
cell subsets (for example, IL-10–producing Foxp3+ Treg cells). This process may spectively, appears to shape the immune status of the host and thus represents a
have evolved to allow these microorganisms to colonize the gut by inducing possible risk factor for autoimmune diseases that appear to depend on balanced
antigen-specific tolerance to the microbiota. (C) Proinflammatory pathobionts Treg-TH17 proportions.
layers of mucosal defense while promoting the for disease among monozygotic twins are 20 to appropriate response to clear invading pathogens
unwanted side effect of autoimmune disease. The 40% on average, environmental factors are cru- by recognizing non-self molecules. The micro-
importance of TH17 cell–inducing microorganisms cial for the manifestations of symptoms (57). We biota presents a challenge to the adaptive im-
(such as SFBs) to animal models of autoimmunity predict that autoimmunity can result from the com- mune system because it contains an enormous
remains to be further established; caveats exist, such bination of an altered human genome and an foreign antigenic burden, which must be either
as the fact that animals from colonies devoid of altered microbiome (Fig. 2). Patients with auto- ignored or tolerated to maintain health. One hy-
SFBs can develop autoimmune disease. Also, it immunity likely have a genetic landscape that pothesis for how this occurs is “immunologic
remains to be determined how the microbiota may predisposes them to self-reactivity, and in some ignorance,” whereby spatial separation of bacteria
contribute to human autoimmunity. SFB coloniza- cases, certain gut bacteria may promote disease from the immune system or down-modulation of
tion of animals, however, does provide a model by activating the adaptive immune system. Po- innate immunity prevents overt inflammation
system for testing concepts linking specific gut tential future treatments for autoimmunity may (58). This notion rests on the inability of the in-
bacteria to nonintestinal immune disorders. The include treatment of dysbiosis, because whereas nate immune system to distinguish pathogens
identification of bacterial molecules required for the human genome is static and intransigent to from symbionts because they share similar mo-
SFBs to induce TH17 cell responses may reveal manipulation, the microbiome is conceivably lecular patterns (such as TLR ligands). Rather
why this particular microorganism is capable of more amenable to therapeutic alterations. Under- than ignorance, tolerance could also be induced
promoting the development of proinflammatory T standing the molecular mechanisms of how sym- by the microbiota, given the capacity of gut bac-
cells. Furthermore, studies that delineate the gene biotic microbes affect immune reactions to self teria to induce Treg lineage differentiation. Mol-
regulatory networks induced by SFB colonization antigens may provide insight into the causes, and ecules produced by our microbiome may be
may enhance our understanding of the evolutionary potential cures, for autoimmune diseases. considered “self,” because inflammatory bowel
forces that resulted in TH17 lineage development. disease is thought, in part, to involve a loss of
Autoimmune diseases such as MS, T1D, and Did the Microbiota Influence the Evolution tolerance to antigens of the microbiota. Therefore,
RA are associated with a spectrum of genetic poly- of Adaptive Immunity? it appears that we may tolerate the microbiota in
morphisms, as shown by recent genome-wide The adaptive immune system distinguishes be- the same way that we tolerate antigens encoded
association studies. Given that concordance rates tween self and foreign antigens and mounts an by our own genome. This then raises the question
A Gutsy Analysis
Efforts to sequence the human microbiome−−the genomes of all the microbes that inhabit our bodies−−have
demonstrated its enormous diversity. Analyses to probe the various functions of the microbiota, particularly of those that
reside in the gut, have revealed that our microbiota has a profound impact on the development and function of our
immune systems. Lee and Mazmanian (p. 1768) review how the microbiota influences the development of the adaptive
REFERENCES This article cites 62 articles, 11 of which you can access for free
http://science.sciencemag.org/content/330/6012/1768#BIBL
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