news and views

Commensal cocktail suppresses gut inflammation

The sometimes remarkable therapeutic ben- Chloroform- Cecal Cecal treated feces contents contents efits of fecal transplantation—the transfer of Genomic stool from a healthy individual to a diseased analysis one—in patients with severe Clostridium Germ-free Germ-free Bacterial

difficile infection illustrate the ability of com- Selected icari mice mice colonies V mensal bacteria to counter dysfunctional human Treg-inducing bacteria intestinal physiology. As fecal transplantation Katie remains, however, a somewhat invasive and unpalatable procedure used in only the most focus on different anatomical sites. More specif- ongoing inflammation, has not been demon- severe cases, efforts are underway to develop ically, whereas human microbiota did not seem strated yet,” Fischbach states that “the field defined mixtures of human microbiota capable to reconstitute T cells in the small intestine, is very optimistic that this will be possible.” of more subtly tuning particular mediators of both studies detected robust effects of human Another reason for optimism is that mining gut inflammation. In a paper recently published microbiota on T cells in the colon. The mecha- of publicly available human microbiome data in Nature1, Kenya Honda and colleagues report nisms explaining this potential anatomical effect revealed that several of the strains in the doing just that. remain unclear. 17-strain cocktail were depleted in the micro- The mediator of interest is the regulatory T In terms of mechanism, the 17 strains stud- biomes of ulcerative colitis patients compared

(Treg) cell population, which suppresses inflam- ied by Honda and colleagues clearly act syn- with healthy humans. mation and is depleted in germ-free mice that ergistically because no single strain, or even Yet another question is what sorts of studies lack commensal bacteria. Having previously mixtures of 3 or 5 of the strains, had the same will be needed to bring a probiotic like this

observed a boost in the number of Treg cells in Treg-inducing effect. On a molecular level, the to the clinical market. This 17-strain mixture the colon of germ-free mice after these mice 17-strain cocktail seems to exert several effects differs from many existing probiotics in sev-

ingested chloroform-resistant, spore-forming on Treg cell differentiation. First, short-chain eral ways. For one, it consists of actual human bacteria from normal mouse feces, the team fatty acids in the cecal contents of colonized commensal microbes, rather than noncom-

searched for similar Treg-boosting bacteria in mice elicit production of transforming growth mensal strains, selected in part because they 2 the human gut microbiota . Sure enough, factor β—a known inducer of Treg cell differen- are easy to culture or package. For another, it ingestion of the chloroform-resistant fraction tiation and expansion—from intestinal epithelial contains multiple rather than a single bacte-

of human feces induced the appearance of Treg cells. Second, bacterial antigens in the cocktail rial strain. Both of these features may influ- cells in the colon of germ-free mice. To iden- seem capable of directly stimulating Treg cell ence its efficacy in humans and its chances of tify the particular bacterial strains driving Treg suppressive activity, at least in vitro. Even so, gaining regulatory approval. Bäckhed explains development, Honda and co-workers cloned further work is needed to measure the relative that “because there are big variations in the over 400 bacterial colonies from the guts of contributions of these and other mechanisms composition of the microbiome in different

these mice. Genomic analysis revealed that all to the Treg-potentiating effect of this probiotic individuals, a probiotic composed of just one clones were members of the genus Clostridium cocktail. “I have no doubt that multiple mecha- lactobacillus strain may be effective in some and none encoded strong virulence-related nisms are at play. I think it’s safe to say that the people but not all. A cocktail of several bacte- © 2013 Nature America, Inc. All rights reserved. America, Inc. © 2013 Nature genes. A mixture of only 17 of these clostridia most important molecules involved in this activ- ria has a larger likelihood of effectively treating

strains was sufficient to recapitulate the Treg ity have not yet been discovered,” says Michael a larger portion of the human population. Also, cell–promoting effect of the entire chloroform- Fischbach from the University of California, if all of the strains in the cocktail are commen- npg resistant feces fraction and to reduce the San Francisco. sal bacterial strains known not to be harmful, severity of experimentally induced allergic In fact, if defined molecular ‘active principles’ including five strains instead of one strain will

diarrhea and colitis. This effect was robust, accounting for the Treg-potentiating effect of the not likely markedly increase risk.” as it was observed in mice of different genetic 17-strain mixture are identified, it is possible Nevertheless, by sequencing the genomes of backgrounds and in rats. that administration of the purified molecules, all bacterial strains in the 17-strain cocktail, Fredrik Bäckhed at the University of rather than the bacteria themselves (by means of Honda and colleagues may already be one step Gothenburg, Sweden, concludes that “this an enema, for example), would be sufficient to ahead of the regulatory process. According to

is a really important study because the field boost Treg cell numbers. Also unclear is whether Fischbach, “For any therapeutic products that is a little bit stuck, in that most mechanistic this bacterial cocktail will be able to exert clini- will be mixtures of purified bacterial strains, the studies are done in mice, and most correlative cally meaningful therapeutic effects if adminis- genome sequences will need to be known, at studies are done in humans. This particular tered in a scenario of ongoing severe intestinal the very least to rule out the presence of cryptic study is a step forward because it represents inflammation. This is because, although Honda toxins. The question is how much additional an intermediate between mouse and man.” and colleagues demonstrated beneficial effects characterization of these strains will be required This study might also be considered surpris- on experimental allergic diarrhea and colitis, to bring something safe to the clinic.” ing in light of a previous report that mouse, but the probiotic was administered just before or not human, fecal microbiota induced matura- at the same time as disease onset, in a more Christine Borowski, Senior Editor, Nature Biotechnology tion and expansion of T cells in the intestines prophylactic than therapeutic regimen. Although of germ-free mice3. However, a closer look confirming that “the principle that a therapy like 1. Atarashi, K. et al. Nature doi:10.1038/nature12331 (10 July 2013). reveals that the different overall conclusions this will be able to turn things around, in other 2. Atarashi, K. et al. Science 331, 337–341 (2011). of these two studies are likely related to their words induce Treg differentiation in the face of 3. Chung, H. et al. Cell 149, 1578–1591 (2012).

nature biotechnology volume 31 number 9 september 2013 813