In shaping our immune systems, some 'friendly' bacteria may play inordinate role
(15 October 2009: VIDYYA MEDICAL NEWS SERVICE) -- Out of the trillions of "friendly" bacteria - representing hundreds of species -that make our intestines their home, new evidence in mice suggests that it may be a very select few that shape our immune responses. The findings detailed in two October 16th reports appearing in the journals Cell and Immunity, both Cell Press publications, offer new insight into the constant dialogue that goes on between intestinal microbes and the immune system, and point to a remarkably big role for a class of microbes known as segmented filamentous bacteria (SFB).
"It's the first example of a commensal bacteria that can induce accumulation in the gut of a highly specific branch of the immune system," said Dan Littman of the Howard Hughes Medical Institute and the New York University School of Medicine, who led the study reported in Cell. "We're headed into an exciting new area, and we hope more pieces of how the microbial-host interaction contributes to health will begin to fall into place."
"Our study provides the surprising result that among the hundreds of bacterial species composing the gut microbiota -- only a very small number, the prototype of which is SFB -- can efficiently stimulate the post-natal physiologic maturation of the immune barrier," added Valérie Gaboriau-Routhiau of INSERM in France, who led the Immunity report. "A unique feature of SFB appears to be its capacity to simultaneously stimulate a large spectrum of intestinal immune responses -- innate and adaptive, pro-inflammatory and regulatory -- which complete and balance each other."
Notably, those SFBs stimulate particular types of helper T cells, known as Th17 cells, the studies show.
In Littman's case, the findings by his group were something of an accidental discovery. They were studying T cells in the intestine and were getting some inconsistencies in their results. Those inconsistencies could be traced to differences in the gut floras of mice obtained from different sources, and specifically, they found, in the presence or absence of SFB.
Introduction of SFB, but not other bacteria, stimulated the production of Th17 cells in mice who were otherwise deficient in them, they show. The bacteria also set in motion a pro-inflammatory gene program. That SFB-induced immune response protected the mice from becoming ill with an intestinal pathogen, supporting a role for the SFBs in setting up the intestine's immunity barrier.
Gaboriau-Routhiau similarly found in studies of conventional and germ-free mice that colonization of the gut induced a broad spectrum of pro-inflammatory and T cell responses, including the emergence of Th17 cells. That occurred despite the fact that most bacteria, in combination or on their own, didn't lead to such a reaction. Rather, that function appeared limited to a restricted number of bacteria, her team reports, the prototype of which is the SFB. All on its own, SFB could largely recapitulate the coordinated maturation of T cell responses normally induced by the whole mouse microbiota.
Gaboriau-Routhiau suspects that SFBs may have some special attributes that explain their importance.
"For us, it was first a surprise to observe so little redundancy in the role of commensal bacteria on stimulating immune responses," Gaboriau-Routhiau said. "One striking feature of SFB, which makes it very different from the vast majority of the members of the microbiota, is its capacity to adhere to epithelial cells notably in the ileum, a property normally more the prerogative of pathogens." The ileum is the final section of the small intestine and is distinguished by many folds, giving it a very substantial surface area.
The findings also suggest how such commensal bacteria might sometimes go from beneficial inhabitants, helping to fend off nasty bugs, to ones that may tip the balance of the immune system toward the development of inflammatory, autoimmune disease, such as Crohn's disease, psoriasis and even arthritis, according to the researchers. Indeed, the Th17 cells observed in the new studies have been noted in recent years because of their importance in autoimmune diseases, Littman explained. Animals with defects in those Th17 cells generally don't develop autoimmune disease or develop disease that is less severe, earlier studies showed.
"Th17 cells make cytokines that can be highly protective in the case of infection," he said. "At the same time, in the wrong context or in the wrong amount [they can lead to disease]. You need to have the right balance."
Given the bacterial diversity found within our guts, the new results show how much there still is to learn about this important aspect of the immune system. While probiotic products on the market today don't have the benefit of such a thorough understanding, says Littman, there is little doubt that down the road we may be able to manipulate our immune system in beneficial ways with microbes. Alternatively, he said, some of the molecular products of those bacteria – particular sugars or peptides, for instance – might ultimately serve as useful therapies on their own.
The researchers include Ivaylo I. Ivanov, New York University School of Medicine, New York, NY; Koji Atarashi, Osaka University, Osaka, Japan, Nicolas Manel, New York University School of Medicine, New York, NY; Eoin L. Brodie, Lawrence Berkeley National Laboratory, Berkeley, CA, Tatsuichiro Shima, Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan, Ulas Karaoz, Lawrence Berkeley National Laboratory, Berkeley, CA; Dongguang Wei, Carl Zeiss SMT, Inc., Nanotechnology Systems Division, Peabody, MA; Katherine C. Goldfarb, Lawrence Berkeley National Laboratory, Berkeley, CA; Clark A. Santee, Lawrence Berkeley National Laboratory, Berkeley, CA; Susan V. Lynch, University of California San Francisco, San Francisco, CA; Takeshi Tanoue, Osaka University, Osaka, Japan; Akemi Imaoka, Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan; Kikuji Itoh, University of Tokyo, Tokyo, Japan; Kiyoshi Takeda, Osaka University, Osaka, Japan; Yoshinori Umesaki, Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan; Kenya Honda, Osaka University, Osaka, Japan, Japan Science and Technology Agency, Saitama, Japan; and Dan R. Littman, New York University School of Medicine, New York, NY, Howard Hughes Medical Institute.
The researchers include Vale´ rie Gaboriau-Routhiau, INRA, U910, Unite´ Ecologie et Physiologie du Syste`me Digestif, Domaine de Vilvert, Jouy-en-Josas, France, INSERM, Universite´ Paris, Paris, France; Sabine Rakotobe, INRA, U910, Unite´ Ecologie et Physiologie du Syste`me Digestif, Domaine de Vilvert, Jouy-en-Josas, France, INSERM, Universite´ Paris, Paris, France; Emelyne Le´ cuyer, INRA, U910, Unite´ Ecologie et Physiologie du Syste`me Digestif, Domaine de Vilvert, Jouy-en-Josas, France, INSERM, Universite´ Paris, Paris, France; Imke Mulder, University of Aberdeen, Aberdeen, UK; Annai¨g Lan, University of Aberdeen, Aberdeen, UK; Chantal Bridonneau, INRA, U910, Unite´ Ecologie et Physiologie du Syste`me Digestif, Domaine de Vilvert, Jouy-en-Josas, France; Violaine Rochet, INRA, U910, Unite´ Ecologie et Physiologie du Syste`me Digestif, Domaine de Vilvert, Jouy-en-Josas, France; Annamaria Pisi, University of Bologna, Bologna, Italy; Marianne De Paepe, INSERM, Universite´ Paris, Paris, France; Giovanni Brandi, Ge´ rard Eberl, University of Bologna, Bologna, Italy; Johannes Snel, NIZO Food Research, The Netherlands; Denise Kelly, University of Aberdeen, Aberdeen, UK; and Nadine Cerf-Bensussan, INSERM, Universite´ Paris, Paris, France.
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