Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–341.

In a recent issue of Science, Atarashi et al1 provided new insights about how indigenous microbial floras participate in the maintenance of intestinal homeostasis. The authors showed that the numbers of Foxp3+ regulatory T cells (Tregs), which are known to suppress activation of the immune system, were increased in the colonic lamina propria of newborn specific pathogen-free (SPF) mice. This increase was observed during the known timeframe of microbiota implantation following weaning. This accumulation was not observed with either germ-free (GF) or antibiotic-treated mice. Transplantation of fecal suspensions from SPF mice was sufficient to restore normal Foxp3+ Tregs in GF mice. Thus, the authors concluded that the gut microbiota drives accumulation of Foxp3+ Tregs in the colonic lamina propria.

Next, the authors individualized the group of bacteria driving Foxp3+ Tregs accumulation. They showed that treatment of mice with anti-Gram-positive antimicrobials (vancomycin) abrogated accumulation of Foxp3+ Tregs in the colon, while anti-Gram-negative antimicrobials (colistin) did not. Within the Gram-positive bacteria composing the microbiota, they further determined that chloroform-resistant spore-forming bacteria were responsible for mucosal Foxp3+ Tregs accumulation in the colon. They also showed that these spore-forming bacteria were mainly composed of 46 isolated strains of Clostridium spp. which belong to the defined clusters IV and XIVa according to taxonomic and phylogenetic considerations. Their luminal presence coincided with Tregs distribution in the cecum and in the proximal part of the colon of many commercially available SPF mice. Compared to other bacteria composing the microbiota such as Lactobacillus, segmented filamentous bacteria (SFB) or Bacteroides fragilis, the authors showed that Clostridium recolonization was the most efficient to boost Foxp3+ Tregs accumulation in mice with varying genetic backgrounds.

The authors then found a role for the epithelial environment in the mobilization of Fop3+ Tregs. Coculture of Clostridium with ex vivo murine colon or intestinal epithelial cells induced the production of various pro-Tregs differentiation molecules such as transforming growth factor beta (TGF-β) which were able to promote differentiation of splenic CD4+ T cells into Tregs. Furthermore, they characterized the subtype of Tregs mobilized by Clostridium spp. Mobilized Tregs expressed the antiinflammatory cytokine interleukin (IL)-10 and different phenotypic markers that led the authors to speculate that the colonic increase in this subset of Tregs was probably due to a shift of resident CD4+ T cells rather than a recruitment of systemic Tregs.

Finally, the authors generated mice that were abundantly colonized with Clostridium clusters IV and XIVa and displayed increased amounts of Tregs in the colon lamina propria. These Clostridium-hypercolonized/Tregs-abundant mice were shown to resist both dextran sodium sulfate- and oxazolone-mediated colitis. Therefore, the authors suggested that the Clostridium-host crosstalk in the gut may offer new therapeutic possibilities in human inflammatory bowel disease such as Crohn's disease (CD).


In CD, the increase of interferon-γ and tumor necrosis factor α promoted by Th17/Th1 cells participates in mucosal inflammation and gastrointestinal injury. Thus, the use of spore-forming Clostridium spp. to dampen an excessive immune Th17/Th1 response by enabling a digestive mucosal shift toward Tregs development could be an appealing approach, as suggested by Atarashi et al. Another spore-forming Gram-positive bacteria type closely related to the genus Clostridium, SFB, has been previously shown to promote expansion of Th17 cells rather than Tregs in the lamina propria of the small intestine.2 Th17 cells likely play an important protective role in the lining of the gastrointestinal tract by driving antimicrobial peptide synthesis, recruiting scavenging cells such as neutrophils, and facilitating Th1 cell development through cytokine expression. SFB could therefore be perceived as proinflammatory by promoting mucosal Th17 leading to an increased Th1-mediated immune response.

Taken together, these results suggest that luminal Clostridium cluster IV/XIVa and SFB may act as opposing triggers that influence the Tregs/Th17 balance and therefore gut homeostasis and disease: SFB as a trigger of Th17-mediated inflammation/antimicrobial response and Clostridium as a trigger of Treg-mediated suppression of Th17/Th1. It is difficult to interpret how this Treg/Th17 balance in the gut may be manipulated to offer treatment for patients suffering from inflammatory bowel disease. The idea of tipping the scale toward a Treg-dominant population to suppress inflammation is attractive, although in clinical practice there is evidence that this may not be effective. The use of recombinant IL-10, the major cytokine produced by Tregs, has been shown in a meta-analysis to be of no significant benefit in the treatment of patients with CD.3 Likewise, Th17/Th1 blockade by a human anti-IL-12 and anti-IL-23 monoclonal antibodies may not be effective4 and is being reassessed in an ongoing multicenter phase 3 trial. Although there are many possible explanations for these clinical results, one can speculate that blockade of the Th17 immune axis further weakens an already depressed immune response to luminal pathogens that is now known to exist in patients with CD.5–7 In this regard, although SFB may promote the accumulation of potentially proinflammatory Th17 cells into the gut, these immune cells may restore a weakened gut luminal defense against invading pathogens.

The effects of the balance of Tregs and Th17/Th1 lymphocytes in the gut caused by various strains of commensal gut luminal bacteria will need further study. The study by Atarashi et al is nonetheless very exciting. They have provided important data suggesting that strains of commensal bacteria may have a profound influence on the makeup of the gut host immune composition. These findings may strengthen the argument that luminal dysbiosis contributes to disease in patients with CD and is not solely a consequence of inflammation.


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  • 1
    Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011; 331: 337341.
  • 2
    Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009; 139: 485498.
  • 3
    Buruiana FE, Sola I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2010: CD005109.
  • 4
    Toedter GP, Blank M, Lang Y, et al. Relationship of C-reactive protein with clinical response after therapy with ustekinumab in Crohn's disease. Am J Gastroenterol. 2009; 104: 27682773.
  • 5
    Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005; 102: 1812918134.
  • 6
    Elphick D, Liddell S, Mahida YR. Impaired luminal processing of human defensin-5 in Crohn's disease: persistence in a complex with chymotrypsinogen and trypsin. Am J Pathol. 2008; 172: 702713.
  • 7
    Marks DJ, Harbord MW, MacAllister R, et al. Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet. 2006; 367: 668678.

Eric Kipnis XX* † ‡ § ¶, Rodrigue Dessein XX* † ‡ § ¶, * Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France, † CNRS, UMR 8204, Lille, France, ‡ Institut National de la Santé et de la Recherche Médicale, Lille, France, § University Lille Nord de France, Lille, France, ¶ C.H.R.U. de Lille, Lille, France.