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MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells.

ABSTRACT: T regulatory cells that express the transcription factor Foxp3 (Foxp3(+) T(regs)) promote tissue homeostasis in several settings. We now report that symbiotic members of the human gut microbiota induce a distinct T(reg) population in the mouse colon, which constrains immuno-inflammatory responses. This induction—which we find to map to a broad, but specific, array of individual bacterial species—requires the transcription factor Rorγ, paradoxically, in that Rorγ is thought to antagonize FoxP3 and to promote T helper 17 (T(H)17) cell differentiation. Rorγ's transcriptional footprint differs in colonic T(regs) and T(H)17 cells and controls important effector molecules. Rorγ, and the T(regs) that express it, contribute substantially to regulating colonic T(H)1/T(H)17 inflammation. Thus, the marked context-specificity of Rorγ results in very different outcomes even in closely related cell types.

SUBMITTER: Sefik E

PROVIDER: S-EPMC4700932 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells.

Sefik Esen E Geva-Zatorsky Naama N Oh Sungwhan S Konnikova Liza L Zemmour David D McGuire Abigail Manson AM Burzyn Dalia D Ortiz-Lopez Adriana A Lobera Mercedes M Yang Jianfei J Ghosh Shomir S Earl Ashlee A Snapper Scott B SB Jupp Ray R Kasper Dennis D Mathis Diane D Benoist Christophe C

Science (New York, N.Y.) 20150813 6251

T regulatory cells that express the transcription factor Foxp3 (Foxp3(+) T(regs)) promote tissue homeostasis in several settings. We now report that symbiotic members of the human gut microbiota induce a distinct T(reg) population in the mouse colon, which constrains immuno-inflammatory responses. This induction—which we find to map to a broad, but specific, array of individual bacterial species—requires the transcription factor Rorγ, paradoxically, in that Rorγ is thought to antagonize FoxP3 an ...[more]

PMID: 26272906

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Project description:BackgroundA dysbiosis in the intestinal microbiome plays a role in the pathogenesis of several immunological diseases. These diseases often show a sex bias, suggesting sex differences in immune responses and in the intestinal microbiome. We hypothesized that sex differences in immune responses are associated with sex differences in microbiota composition.MethodsFecal microbiota composition (MITchip), mRNA expression in intestinal tissue (microarray), and immune cell populations in mesenteric lymph nodes (MLNs) were studied in male and female mice of two mouse strains (C57B1/6OlaHsd and Balb/cOlaHsd). Transcriptomics and microbiota data were combined to identify bacterial species which may potentially be related to sex-specific differences in intestinal immune related genes.ResultsWe found clear sex differences in intestinal microbiota species, diversity, and richness in healthy mice. However, the nature of the sex effects appeared to be determined by the mouse strain as different bacterial species were enriched in males and females of the two strains. For example, Lactobacillus plantarum and Bacteroides distasonis were enriched in B6 females as compared to B6 males, while Bifidobacterium was enriched BALB/c females as compared to BALB/c males. The strain-dependent sex effects were also observed in the expression of immunological genes in the colon. We found that the abundance of various bacteria (e.g., Clostridium leptum et rel.) which were enriched in B6 females positively correlated with the expression of several genes (e.g., Il-2rb, Ccr3, and Cd80) which could be related to immunological functions, such as inflammatory responses and migration of leukocytes. The abundance of several bacteria (e.g., Faecalibacterium prausnitzii et rel. and Coprobacillus et rel.- Clostridium ramosum et rel.) which were enriched in BALB/c males positively correlated to the expression of several genes (e.g., Apoe, Il-1b, and Stat4) related to several immunological functions, such as proliferation and quantity of lymphocytes. The net result was the same, since both mouse strains showed similar sex induced differences in immune cell populations in the MLNs.ConclusionsOur data suggests a correlation between microbiota and intestinal immune populations in a sex and strain-specific way. These findings may contribute to the development of more sex and genetic specific treatments for intestinal-related disorders.

Project description:UnlabelledLongitudinal sampling for intestinal microbiota in wild animals is difficult, leading to a lack of information on bacterial dynamics occurring in nature. We studied how the composition of microbiota communities changed temporally in free-ranging small primates, rufous mouse lemurs (Microcebus rufus). We marked and recaptured mouse lemurs during their mating season in Ranomafana National Park in southeastern mountainous rainforests of Madagascar for 2 years and determined the fecal microbiota compositions of these mouse lemurs with MiSeq sequencing. We collected 160 fecal samples from 71 animals and had two or more samples from 39 individuals. We found small, but statistically significant, effects of site and age on microbiota richness and diversity and effects of sex, year, and site on microbiota composition, while the within-year temporal trends were less clear. Within-host microbiota showed pervasive variation in intestinal bacterial community composition, especially during the second study year. We hypothesize that the biological properties of mouse lemurs, including their small body size and fast metabolism, may contribute to the temporal intraindividual-level variation, something that should be testable with more-extensive sampling regimes.ImportanceWhile microbiome research has blossomed in recent years, there is a lack of longitudinal studies on microbiome dynamics on free-ranging hosts. To fill this gap, we followed mouse lemurs, which are small heterothermic primates, for 2 years. Most studied animals have shown microbiota to be stable over the life span of host individuals, but some previous research also found ample within-host variation in microbiota composition. Our study used a larger sample size than previous studies and a study setting well suited to track within-host variation in free-ranging mammals. Despite the overall microbiota stability at the population level, the microbiota of individual mouse lemurs can show large-scale changes in composition in time periods as short as 2 days, suggesting caution in inferring individual-level patterns from population-level data.

Dataset Information

MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells.

Publications

MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells.

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