Gut Immune Maturation Depends on Colonization with a Host-Specific Microbiota

Chung, Hachung; Pamp, Sünje Johanna; Hill, Jonathan A.; Surana, Neeraj K.; Edelman, Sanna; Troy, Erin B.; Reading, Nicola C.; Villablanca, Eduardo J.; Wang, Sen; Mora, J. Rodrigo; Umesaki, Yoshinori; Mathis, Diane; Benoist, Christophe; Relman, David A.; Kasper, Dennis L.

doi:10.1016/j.cell.2012.04.037

Cited by 1,036 publications

(914 citation statements)

References 66 publications

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“…In our recently published comprehensive analysis of the immunomodulatory capacity of taxonomically diverse commensal microbes, none of 28 bacteria assessed for small-intestinal expression of Reg3γ caused significant induction 18 . We previously showed that HMb mice have ileal levels of Reg3γ expression similar to those in GF mice and lower than those in MMb mice 12 . We now found that Reg3γ expression in HMb MMb-1d mice is restored to levels comparable to those in MMb mice, with no change observed in MMb HMb-1d mice (Fig 4A).…”

Section: Main Textmentioning

confidence: 87%

“…MMb and HMb mice have been bred and maintained at this facility in separate vinyl isolators since their initial characterization 12 . Experimental manipulation of gnotobiotic mice was performed in sterile cages (Innovive; San Diego, CA) in which animals received autoclaved food and water.…”

Section: Methodsmentioning

confidence: 99%

“…qPCR for Reg3γ was performed as previously described 12 . The distal 1.5 cm of small intestine was harvested from the indicated mice, frozen immediately in liquid nitrogen, and stored at −80°C until needed.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we generated and characterized gnotobiotic mice colonized with a mouse microbiota (MMb) or a human microbiota (HMb) 12 . We have now explored how these mice differ in susceptibility to colitis, using a chemically induced model of inflammatory bowel disease (IBD).…”

Section: Main Textmentioning

confidence: 99%

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Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

215

177

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Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota1,2. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis1–5. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalog of differentially abundant microbes and allow for subsequent mechanistic studies1,4. Herein, we demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harboring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe–phenotype triangulation may be more broadly applicable to human microbiome studies.

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Section: Main Textmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

See 2 more Smart Citations

Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

215

177

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“…For example, germ free mice colonized with clostridial species clusters IV and XIVa promote regulatory T cell expansion [1,2] while mice colonized with SFB promote Th17 cells [4]. However, the role of SFB in shaping immune response is much broader than mere induction of one specific subset and it contributes to full maturation of gut immune response [22] and induction of a wide range of T cell responses comprising of Th17, Th1, Th2 and Treg cells [23]. This might explain why SFB colonization is associated with protection in some experimental models of disease such as the NOD mouse model of type 1 diabetes [24,25], while it is pathogenic in other experimental settings such as EAE and arthritis [26,27].…”

Section: Maturation Of Cellular Immune Responsementioning

confidence: 99%