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Ley, R.

Publications and source records attributed to Ley, R..

3 recordsLinked to original sources
bioRxiv2019

Interactions between the gut microbiome and mucosal immunoglobulins A, M and G in the developing infant gut

ObjectiveInteractions between the gut microbiome and immunoglobulin (Ig) A in infancy are important for future health. IgM and IgG are also present, however, their interactions with the microbiome in the developing infant are less understood.\n\nDesignWe employed stool samples sampled 15 times in infancy from 32 healthy subjects at 4 locations in 3 countries (from the TEDDY study). We characterized patterns of microbiome development in relation to levels of IgA, IgG and IgM. For 8 infants from a single location, we FACS-sorted microbial cells from stool by Ig status. We used 16S rRNA gene profiling on full and sorted microbiomes to assess patterns of antibody coating in relation to age and other factors.\n\nResultsAll antibodies decreased in concentration with age, but were augmented by breastmilk feeding regardless of infant age. Levels of IgA correlated with the relative abundances of OTUs belonging to the Bifidobacteria and Enterobacteriaceae, which dominated the early microbiome, and IgG levels correlated with Haemophilus. The diversity of Ig-coated microbiota was influenced by breastfeeding and age, but birth mode. IgA and IgM coated the same microbiota, while IgG targeted a different subset. Blautia generally evaded antibody coating, while members of the Bifidobacteria and Enterobacteriaceae were high in IgA/M.\n\nConclusionIgA/M have similar dynamics with respect to microbiome development with age, and their interactions with the microbiome are influenced by breastfeeding status. IgG generally does not coat the commensal microbiota.\n\nSummaryWhat is already known on this subject? O_LISecretory IgA coats ~50% of microbiota in the gut\nC_LIO_LIIgM and IgG are less prevalent and coat a lower fraction in the adult, dynamics in the infant gut are not well characterized.\nC_LIO_LIBreastmilk is a source of IgA to the infant gut and decreases with time.\nC_LIO_LIIgA coating of microbial cells in infant gut microbiome decreases over time.\nC_LI\n\nWhat are the new findings? O_LIBreastfeeding augments the IgA coating of the microbiome at all ages.\nC_LIO_LIIgA and IgM coat many of the same cells, whereas few are coated by IgG alone.\nC_LIO_LIBifidobacteria, Enterobacteriaceae, Ruminococcus gnavus are enriched in IgA/M-coated cell fraction, Blautia is enriched in uncoated fraction.\nC_LIO_LIIgG levels correlated with Haemophilus.\nC_LI\n\nHow might it impact on clinical practice in the foreseeable future? O_LIIg-coated fraction of the gut microbiome could serve as a useful tool for tracking development of the infant gut microbiome, and/or identifying aberrations to immune sensing of the microbiome.\nC_LI

microbiology↗
bioRxiv2019

Gut microbiota influence B cell function in a TLR5-dependent manner

Toll-like receptor (TLR) 5-deficient mice display aberrantly low levels of flagellin-specific antibodies (Flic-IgA) secreted into the gut, combined with excess bacterial flagellin in the gut, and together these attributes define microbiome dysbiosis (T5-dysbiosis). How TLR5 signaling deficiency results in T5-dysbiosis is unclear. Here, we address the role of B cells in T-dysbiosis. We observed that B cells do not express TLR5, and that B cell transplantation from TLR5-/- mouse donors into B-cell deficient mice resulted in a slight reduction in Flic-IgA levels compared to B-cells from WT donors. Bone marrow transplants from WT and TLR5-/- donors into recipients of both genotypes confirmed that TLR5 signaling by non-hematopoietic cells is required for T5-dysbiosis. We observed TLR5 deficiency was associated with an expanded population of IgA+ B cells. TLR5-/- mice tended to have higher richness for the IgA gene hypervariable region (CDR3 gene) variants. Transplantation of microbiomes from TLR5-/- and WT microbiomes donors into germfree mice resulted in a higher proportion of IgA-secreting B cells, and higher overall fecal IgA and anti-Flic IgA for TLR5-/- microbiome recipients. This observation indicated that the TLR5-/- mouse microbiome elicits an anti-flagellin antibody response that requires TLR5 signaling. Together these results indicate that TLR5 signaling on epithelial cells influences B cell populations and antibody repertoire.

immunology↗
bioRxiv2019

GeNet: Deep Representations for Metagenomics

We introduce GeNet, a method for shotgun metagenomic classification from raw DNA sequences that exploits the known hierarchical structure between labels for training. We provide a comparison with state-of-the-art methods Kraken and Centrifuge on datasets obtained from several sequencing technologies, in which dataset shift occurs. We show that GeNet obtains competitive precision and good recall, with orders of magnitude less memory requirements. Moreover, we show that a linear model trained on top of representations learned by GeNet achieves recall comparable to state-of-the-art methods on the aforementioned datasets, and achieves over 90% accuracy in a challenging pathogen detection problem. This provides evidence of the usefulness of the representations learned by GeNet for downstream biological tasks.

bioinformatics↗