The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

SUMMARY The host gut microbiota varies across species and individuals but is relatively stable over time within an individual. How the host selectively shapes the microbiota is largely unclear. Here, we show that fecal microRNA (miRNA)-mediated inter-species gene regulation facilitates host control of the gut microbiota. MiRNAs are abundant in mouse and human fecal samples and present within extracellular vesicles. Cell-specific loss of the miRNA-processing enzyme, Dicer, identified intestinal epithelial cells (IEC) and Hopx-positive cells as predominant fecal miRNA sources. These miRNAs can enter bacteria, such as F. nucleatum and E. coli, specifically regulate bacterial gene transcripts and affect bacterial growth. IEC-miRNA deficient (Dicer1ΔIEC) mice exhibit uncontrolled gut microbiota and exacerbated colitis and WT fecal miRNA transplantation restores fecal microbes and ameliorates colitis. These findings identify both a physiologic role by which fecal miRNA shapes the gut microbiota and a potential strategy for manipulating the microbiome.

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (T reg cells) and interleukin 17 (IL-17)-producing helper T cells (T H 17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced T reg cells (iT reg cells). We found that AhR activation promoted the differentiation of CD4 + Foxp3 − T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-β1 induced Foxp3 + iT reg cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3 + iT reg cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT reg cells could be induced in human autoimmune disorders.In healthy people, the immune response is controlled by several subsets of regulatory T cells (T reg cells) that are generated in the thymus (natural T reg ) and also in the periphery in response to various tolerogenic stimuli (induced T reg cells (iT reg cells) 1 . One of these subsets is a population of CD4 + T cells characterized by expression of the transcription factor Foxp3 (A002750) 1 . In mice, Foxp3 is a specific marker for T reg cells, and forced expression of Foxp3 (refs. 2,3 ) or its induction with transforming growth factor-β1 (TGF-β1) 4 promotes the differentiation of functional Foxp3 + T reg cells. In humans, however, Foxp3 expression is not always linked to regulatory function: activated T cells transiently express Foxp3 (refs. 5,6 ), and neither forced overexpression of Foxp3 (ref. 7 ) nor its induction with TGF-β1 (ref. 8 ) results in the differentiation of suppressive Foxp3 + T reg cells. Thus, additional signals beyond those controlled by Foxp3 are required for the generation of human functional Foxp3 + T reg cells.Correspondence should be addressed to F.J.Q. (fquintana@rics.bwh.harvard.edu). 3 Present address: Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.Accession codes. UCSD-Nature Signaling Gateway (http://www.signaling-gateway.org): A002750, A000229 and A003947.Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONS COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. NIH Public Access RESULTS AhR activation induces T cells that produce IL-10AhR participates in the differentiation of mouse Foxp3 + T reg cells [14][15][16][17][18] . To investigate whether AhR contributes to the differentiation of human T reg cells, we isolated naive CD4 + T cells from peripheral blood mononuclear cells obtained from healthy donors and activated them with anti-CD3, anti-CD28 and IL-2 with or without the AhR ligand TCDD ( Supplementary Fig. 1). Naive ...