The human 'gut flora' consists of between 300 and 1,000 microbial species, and some 1014 microorganisms in total (about ten times the number of cells of the human body). We usually live in harmony with these microbes, and would be less healthy without them. For example, they synthesize essential vitamins and amino acids, and also degrade otherwise indigestible plant material, as well as certain drugs and pollutants.

On page 620 of this issue, Mazmanian et al.1 report that Bacteroides fragilis, a common bacterium of the lower gastrointestinal tract in mammals, can prevent intestinal inflammation in mice. Specifically, the authors show that polysaccharide A (PSA) of B. fragilis prevents gut inflammation induced by another bacterium, Helicobacter hepaticus, or by the chemical compound TNBS (2,4,6-trinitrobenzene sulphonic acid).

This is an exciting finding, not least given that the incidence of human intestinal inflammation and inflammatory bowel disease has increased steadily in the Western world since the early 1950s. These conditions, which include Crohn's disease and ulcerative colitis, are believed to stem in part from inappropriate immune responses to the gut microbiota2. In the healthy intestine, immune balance is regulated by different types of white blood cells called CD4+ T lymphocytes. These cells include CD4+ effector T lymphocytes (which help us fight pathogens by secreting various immune mediators called cytokines) and CD4+ regulatory T lymphocytes (which, through their production of the cytokines IL-10 and TGF-β, dampen the effector T cells when their action is no longer needed). When the balance between these types of T cell is disturbed, the immune response goes awry and intestinal inflammation occurs2.

Evidence in support of the theory that bacteria trigger gut inflammation came from the discovery that mutations in NOD2, a host immune-cell receptor involved in detecting bacterial peptidoglycan, are associated with an increased risk of Crohn's disease3,4. Furthermore, treatment with broad-spectrum antibiotics or probiotics (beneficial microbial species5) can improve health in patients with inflammatory bowel disease. Probiotics might inhibit the growth or invasion of pathogenic bacteria, or strengthen the gut-wall barrier. They may also stimulate the production of IgA (antibodies that are secreted into the gut lumen), and of IL-10 and TGF-β (ref. 5).

Mazmanian et al.1 used two experimental approaches. In the first, colitis was induced in mutant (Rag−/−) T-cell-deficient mice by infecting the animals with H. hepaticus and giving them CD4+ effector T cells. These effector cells start to respond to H. hepaticus, but in the absence of counterbalancing host regulatory T cells intestinal inflammation develops within a few weeks. The cytokine IL-23 plays a key role in this inflammatory response, and the disease is associated with a TH1/TH17 effector T-cell response to H. hepaticus6 (Fig. 1a). The second approach involves a chemical-induced colitis, in which the administration of TNBS to normal mice leads to acute inflammation within a few days.

Figure 1: Intestinal inflammation, and how B. fragilis PSA may prevent it in mice1.
figure 1

a, In mice that develop colitis, dendritic cells activated by H. hepaticus (Hh) produce pro-inflammatory cytokines (such as IL-23, IL-12, IL-6, TNF-α and IL-1β). They also present Hh antigen to CD4+ T cells that then differentiate into inflammatory TH1/TH17 CD4+ effector T cells; these cells are specific for Hh antigen, and produce the inflammatory cytokines IFN-γ and IL-17 (ref. 6). b, c, Dendritic cells jointly stimulated with Hh and B. fragilis PSA are less responsive, with reduced secretion of the pro-inflammatory cytokines TNF-α and IL-1β, and enhanced production of anti-inflammatory IL-10 (ref. 1). They present both Hh antigen and PSA to CD4+ T cells, and may either (b) produce only sub-optimal effector T-cell activation or (c) induce the differentiation of IL-10-producing CD4+ regulatory T cells. The antigen specificity (Hh antigen and/or PSA) of such regulatory T cells is unknown.

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In their new paper, Mazmanian et al.1 demonstrate that giving mice B. fragilis at the same time as the colitis-inducing agents improves the animals' health. A mutant of B. fragilis that lacks PSA could not prevent inflammation, implicating PSA in helping to maintain immune balance. Finally, colitis did not develop when purified B. fragilis PSA was administered together with H. hepaticus and effector T cells to the Rag−/− mice, or when this polysaccharide was given to the TNBS recipients. Together, these results provide direct evidence that PSA prevents intestinal inflammation in both model systems.

Bacteroides fragilis synthesizes at least eight distinct surface polysaccharides as part of its capsule, or coat7, PSA being the most abundant. Although CD4+ T cells normally recognize and respond to peptide fragments of proteins, PSA can be taken up by so-called antigen-presenting cells, such as dendritic cells, and presented to CD4+ T cells, resulting in T-cell activation7. Mazmanian et al.1 show that IL-10 secreted by T cells is essential for PSA to protect against colitis. But it is not yet clear whether PSA has induced 'true' IL-10-secreting regulatory T cells in the mice protected from colitis. Thus, although the authors demonstrate that PSA cannot prevent colitis when T cells cannot produce IL-10, this could be due to a more pathogenic nature of such IL-10-deficient effector T cells.

What about the molecular mechanism by which PSA prevents H. hepaticus-induced colitis? One possibility is that this sugar acts on dendritic cells, thereby altering their capacity to trigger an efficient effector-T-cell response (Fig. 1b). Support for this hypothesis comes from studies showing that T cells isolated from PSA-treated animals are hyporesponsive8.

Alternatively, is PSA inducing IL-10-secreting regulatory T cells (Fig. 1c)? Treatment with filamentous haemagglutinin (FHA) from Bordetella pertussis, the causative agent of whooping cough, can protect Rag−/− mice from colitis induced by CD4+ effector T cells9. T cells isolated from these FHA-treated mice produced IL-10 in vitro following polyclonal stimulation9, supporting the model shown in Figure 1c. It will be interesting to see whether the same observation (that IL-10 is produced by T cells isolated from disease-protected mice) applies in the H. hepaticus colitis model in which PSA prevents intestinal inflammation.

Moreover, do CD4+ T cells isolated from disease-free mice infected with B. fragilis plus H. hepaticus respond to B. fragilis and/or H. hepaticus antigens? If so, what cytokines do such bacterium-specific T cells produce? Has PSA skewed the T-cell immune response to H. hepaticus antigens away from a pro-inflammatory TH1/TH17-type response (Fig. 1a) towards IL-10 secretion (Fig. 1c)?

There is also the question of whether PSA can act against H. hepaticus-induced colitis not only when administered from the start of an experiment, but also when used to treat established disease. The long-term aim, of course, is to develop drugs to cure intestinal inflammation in humans. In this regard, treatment of patients suffering from inflammatory bowel disease with live eggs from the porcine whipworm, Trichuris suis, has produced promising results10. These effects are believed to be due to the induction by T. suis of regulatory T cells and factors such as IL-10, TGF-β and prostaglandin E2 that help maintain immune balance10. One view is that the apparent boons of modern life — antibiotics, vaccines and improved sanitation — have reduced the incidence of parasitic worms and other microbes, and therefore also of disease-protective molecules such as 'T. suis-like antigens' or PSA. That in turn may have altered the way our immune system responds to challenges, leading to the increased incidence of inflammatory diseases.

Ever-improving molecular techniques are providing tantalizing glimpses of the gut ecosystem11. With the launch of the Human Microbiome Project12, which plans to characterize the human microbiota and analyse its role in human health and disease, we are set to see considerable advances in understanding how host–microbial interactions may affect human health. When such information will translate into new therapeutic approaches is, however, anyone's guess.