The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.

The human gut is populated with as many as 100 trillion cells, whose collective genome, the microbiome, is a reflection of evolutionary selection pressures acting at the level of the host and at the level of the microbial cell. The ecological rules that govern the shape of microbial diversity in the gut apply to mutualists and pathogens alike.

In vertebrates, including humans, individuals harbor gut microbial communities whose species composition and relative proportions of dominant microbial groups are tremendously varied. Although external and stochastic factors clearly contribute to the individuality of the microbiota, the fundamental principles dictating how environmental factors and host genetic factors combine to shape this complex ecosystem are largely unknown and require systematic study. Here we examined factors that affect microbiota composition in a large (n = 645) mouse advanced intercross line originating from a cross between C57BL/6J and an ICR-derived outbred line (HR). Quantitative pyrosequencing of the microbiota defined a core measurable microbiota (CMM) of 64 conserved taxonomic groups that varied quantitatively across most animals in the population. Although some of this variation can be explained by litter and cohort effects, individual host genotype had a measurable contribution. Testing of the CMM abundances for cosegregation with 530 fully informative SNP markers identified 18 host quantitative trait loci (QTL) that show significant or suggestive genomewide linkage with relative abundances of specific microbial taxa. These QTL affect microbiota composition in three ways; some loci control individual microbial species, some control groups of related taxa, and some have putative pleiotropic effects on groups of distantly related organisms. These data provide clear evidence for the importance of host genetic control in shaping individual microbiome diversity in mammals, a key step toward understanding the factors that govern the assemblages of gut microbiota associated with complex diseases.16S rDNA | pyrosequencing | quantitative trait loci mapping | microbiome phenotyping | population

BackgroundIllumina's second-generation sequencing platform is playing an increasingly prominent role in modern DNA and RNA sequencing efforts. However, rapid, simple, standardized and independent measures of run quality are currently lacking, as are tools to process sequences for use in downstream applications based on read-level quality data.ResultsWe present SolexaQA, a user-friendly software package designed to generate detailed statistics and at-a-glance graphics of sequence data quality both quickly and in an automated fashion. This package contains associated software to trim sequences dynamically using the quality scores of bases within individual reads.ConclusionThe SolexaQA package produces standardized outputs within minutes, thus facilitating ready comparison between flow cell lanes and machine runs, as well as providing immediate diagnostic information to guide the manipulation of sequence data for downstream analyses.

SummaryThe instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, where self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3+ regulatory T(Treg) cells1. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, in order to prevent immunopathology such as inflammatory bowel disease2–4. Here, we show that encounter with commensal microbiota results in the peripheral generation of Treg cells, rather than pathogenic effectors. We observed that colonic Treg cells utilized T cell antigen receptors (TCRs)different from those used by Treg cells in other locations, implying an important role for local antigens in shaping the colonic Treg cell population. Many of the local antigens appeared to be derived from commensal bacteria based on the in vitro reactivity of common colon Treg TCRs. Interestingly, these TCRs did not facilitate thymic Treg cell development, implying that manycolonic Treg cells arise instead via antigen-driven peripheral Treg cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimeras and a TCR transgenic linerevealed that microbiota indigenous to our mouse colony was required for the generation of colonic Treg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo Treg cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of Treg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.