Biology subjects

Ley, R.

Publications and source records attributed to Ley, R..

11 recordsLinked to original sources

bioRxiv2026

Extensive genomic diversity in Desulfovibrio species reveals species-specific functional traits associated with disease

Desulfovibrio spp. are associated with inflammatory diseases and human health, yet limited representative genomes and isolates hinder our understanding of their role in disease. Here, we assembled a comprehensive database of 2,658 Desulfovibrio genomes across 90 diseases and 32 countries, including 24 human isolates. Genomic analyses showed extensive species diversity and revealed disease-associated functional traits, including flagellin and virulence genes (i.e. ureases). Flagellin-mediated Toll-like receptor 5 activation was species-specific and D. desulfuricans flagellin downregulated TGF-beta signalling in murine small intestinal organoids, suggesting impaired immune tolerance. Additionally, we investigated genomic capacity for hydrogen sulfide (H2S) production, a main Desulfovibrio metabolite. While health- and disease-associated Desulfovibrio spp. mainly encoded dissimilatory sulfate reduction, tetrathionate metabolism-encoding bacteria were exclusively detected in inflammatory bowel diseases, including Proteus mirabilis and Morganella morganii. Overall, our study provides a comprehensive genomic Desulfovibrio resource and identifies new links associating strain variation, functional traits and H2S-production with inflammatory diseases.

genomics↗

bioRxiv2025

Fidelity in co-diversified symbiosis

Obligate co-dependence can arise in symbiosis, yielding heritable partnerships. These interactions are considered to be highly specific, but partner fidelity is difficult to quantify owing to the experimental constraints of symbiont exchange between host species. Here, we overcome this challenge by leveraging the unique transmission dynamics of Stammera capleta, the obligate digestive symbiont of tortoise beetles (Chrysomelidae: Cassidinae). Despite its extracellular localization, S. capleta possesses a drastically reduced genome ([~]0.25 Mb) and is vertically transmitted through egg-associated spheres. Manipulating these spheres allowed us to experimentally exchange S. capleta between beetle species to determine their impact on host development. We show that non-native S. capleta can successfully colonize the symbiotic organs of a novel host, but that the interaction outcome correlates with genetic relatedness to the native symbiont. Genetically distant species trigger a more pronounced transcriptional response and can only partially rescue host development. While more closely related symbionts proliferate similarly to the native one and induce a comparable host response, they fail to propagate to the next generation, underscoring how transmission fidelity, host-symbiont compatibility, and local adaptation can further specificity within a Paleocene-aged partnership.

evolutionary biology↗

bioRxiv2025

D- and L-lactate consumers in the human gut are taxonomically, biochemically, and energetically different

The human gut microbiota routinely produces D- and L-lactate during fermentation; however, the microbial fate of these stereoisomers, particularly the neurotoxic D-lactate, remains poorly understood. Given that D-lactate is an unavoidable byproduct of digestion, understanding its microbial turnover is essential for linking gut metabolism to host health. Here, we used chemostat bioreactors (pH 7.0, 37{degrees}C, and a solids retention time [SRT] of 4 d) to simulate gut-relevant, transient nutrient conditions and to enrich for lactate-consuming communities. DL-lactate-consuming consortia were enriched from a human-derived microbiota and then inoculated into duplicate bioreactors, which were fed exclusively D- or L-lactate. After steady-state was reached, the fed lactate stereoisomers were switched to assess community resilience. Regardless of the fed stereoisomer, the fermentation product spectra were consistent and dominated by acetate, propionate, and CO2. However, microbial communities and biomass yields diverged sharply, with a high relative abundance of Anaerotignum in D-lactate enrichments and Acidipropionibacterium and Propionibacterium in L-lactate enrichments. Notably, the biomass yield for D-lactate feeding was less than half that for L-lactate feeding, suggesting that the two isomers are metabolized through distinct biochemical pathways despite similar product spectra. Metagenomic and metaproteomic analyses confirmed this divergence at the pathway level. Our findings reveal how the stereoisomer identity of microbes shapes their niche specialization in the gut, with implications for understanding the ecology and clinical impact of lactate metabolism.

bioengineering↗

bioRxiv2025

Carbohydrates and the oxidative branch of the pentose phosphate pathway modify Bacteroides thetaiotaomicron phage resistance by phase variable S-layers

The human gut microbiota consists of hundreds of bacterial species, some of which persist in the presence of lytic phage that infect them. Bacteroides employ numerous phase-variable strategies to survive in the presence of phage, including capsular polysaccharides (CPS) and S-layer lipoproteins. We previously reported that a Bacteroides thetaiotaomicron strain lacking CPS exhibits almost complete resistance to multiple phages when forced to express the S-layer protein BT1927. However, this strain was only resistant after certain growth conditions, suggesting nutritional variables alter infection and resistance. We grew this strain on various simple sugars and polysaccharides finding that some substrates (fructose, glucose) promote strong resistance to a single phage (ARB25) while others like N-acetylgalactosamine (GalNAC) and mucin O-glycans increase susceptibility. Mixing fructose and GalNAc indicates the effects of GalNAc are dominant. Despite increasing ARB25 susceptibility, GalNAc did not reduce BT1927 transcript or protein levels. Instead, GalNAc reduced the amount of BT1927 displayed on the cell surface and increased outer membrane vesiculation. Mutants in any of the 3 steps of the oxidative branch of the pentose phosphate pathway--grown in fructose--behaved similarly to wild-type cells grown in GalNAc, illuminating this pathway in regulation of sugar-mediated phage-resistance. Despite promoting strong resistance, cells grown in glucose/fructose sometimes displayed sub-populations that appeared to completely lack surface BT1927, suggesting another checkpoint exists to control whether this phage defense is deployed. Finally, we show the mucin sugar GalNAc increases susceptibility to several other phage, which has implications for B. thetaiotaiomicron persistence in niches like the mucus layer. ImportanceThe persistence of viruses that infect bacteria (bacteriophages or phages) in the human gut microbiome and their effects on bacterial physiology and host health are active areas of investigation. Our study investigates how various sugars and polysaccharides alter phage susceptibility and resistance in the model gut symbiont Bacteroides thetaiotaomicron to lytic phages that are capable of infecting it. Our finding that the mucin sugar, N-acetylgalactosamine, and mucin O-glycans that contain this sugar reduce B. thetaiotaomicron resistance to multiple phages has implications for how this symbiont persists in different gut microhabitats, such as the mucus layer, and which defense mechanisms it can deploy to survive in these niches.

microbiology↗

bioRxiv2025

Characterization and description of Clostridium filamentum ETTB, a novel gut bacterium with TLR5 modulating properties

The Clostridium genus is highly heterogeneous, encompassing numerous species and strains, many of which remain to be isolated and characterized to better understand their relationship to host physiology. This study aimed to isolate and characterize novel bacterial species within the Clostridium genus and explore their potential links to host health. Under microaerophilic conditions, we isolated and characterized three bacterial isolates belonging to a new anaerobic Clostridium species, designating Clostridium sp. DSM 115107 (Clostridium filamentum ETTB3) as the type strain. C. filamentum ETTB isolates are rod- to filament-shaped, Gram-positive bacteria and exhibit poor growth when cultured on rich media such as LYBHI. Genome sequencing and phylogenetic analysis revealed that C. filamentum ETTB belongs to the Clostridium genus and clusters closely with Clostridium saudiense JCC. Interestingly, C. filamentum ETTB has a significantly smaller genome compared to C. saudiense JCC containing a reduced repertoire of genes involved in carbohydrate degradation and amino acid synthesis and a larger number of genes related to cell motility, including an additional copy of the fliC gene. Unlike C. saudiense, C. filamentum ETTB adopted a filamentous morphology when in contact with Caco-2 cells and stimulate the TLR5 pathway in Caco-2 cells. Metagenomics analysis revealed that C. filamentum ETTB is present in both industrialized and non-industrialized populations, although the relative abundance varying considerably between and within individuals. Our study identifies a novel bacterial strain adapted for the human gut that has the potential to influence host immune response by activating TLR5 pathway.

microbiology↗

bioRxiv2024

Medication Use is Associated with Distinct Microbial Features in Anxiety and Depression

This study investigated the relationship between gut microbiota and neuropsychiatric disorders (NPDs), specifically anxiety disorder (ANXD) and/or major depressive disorder (MDD), as defined by DSM-IV or V criteria. The study also examined the influence of medication use, particularly antidepressants and/or anxiolytics, classified through the Anatomical Therapeutic Chemical (ATC) Classification System, on the gut microbiota. Both 16S rRNA gene amplicon sequencing and shallow shotgun sequencing were performed on DNA extracted from 666 fecal samples from the Tulsa-1000 and NeuroMAP CoBRE cohorts. The results highlight the significant influence of medication use; antidepressant use is associated with significant differences in gut microbiota beta diversity and has a larger effect size than NPD diagnosis. Next, specific microbes were associated with ANXD and MDD, highlighting their potential for non-pharmacological intervention. Finally, the study demonstrated the capability of Random Forest classifiers to predict diagnoses of NPD and medication use from microbial profiles, suggesting a promising direction for the use of gut microbiota as biomarkers for NPD. The findings suggest that future research on the gut microbiotas role in NPD and its interactions with pharmacological treatments are needed.

microbiology↗

bioRxiv2022

An integrated systems-biology platform for power-to-gas technology

Methanogenesis allows methanogenic archaea (methanogens) to generate cellular energy for their growth while producing methane. Hydrogenotrophic methanogens thrive on carbon dioxide and molecular hydrogen as sole carbon and energy sources. Thermophilic and hydrogenotrophic Methanothermobacter spp. have been recognized as robust biocatalysts for a circular carbon economy and are now applied in power-to-gas technology. Here, we generated the first manually curated genome-scale metabolic reconstruction for three Methanothermobacter spp.. We investigated differences in the growth performance of three wild-type strains and one genetically engineered strain in two independent chemostat bioreactor experiments. In the first experiment, with molecular hydrogen and carbon dioxide, we found the highest methane production rate for Methanothermobacter thermautotrophicus {Delta}H, while Methanothermobacter marburgensis Marburg reached the highest biomass growth rate. Systems biology investigations, including implementing a pan-model that contains combined reactions from all three microbes, allowed us to perform an interspecies comparison. This comparison enabled us to identify crucial differences in formate anabolism. In the second experiment, with sodium formate, we found stable growth with an M. thermautotrophicus {Delta}H plasmid-carrying strain with similar performance parameters compared to wild-type Methanothermobacter thermautotrophicus Z-245. Our findings reveal that formate anabolism influences the diversion of carbon to biomass and methane with implications for biotechnological applications of Methanothermobacter spp. in power-to-gas technology and for chemical production. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/522236v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1d468aeorg.highwire.dtl.DTLVardef@24a595org.highwire.dtl.DTLVardef@1f2dd60org.highwire.dtl.DTLVardef@1a3d8fc_HPS_FORMAT_FIGEXP M_FIG C_FIG Broader contextRenewable energy sources (e.g., wind and solar) provide carbon-free electric power. However, their intermittency and offset between peak production and demand generate the need to store this electric power. Furthermore, these technologies alone do not satisfy the demand for carbon-based commodities. Power-to-gas technology provides a means to store intermittent renewable electric power with concomitant carbon dioxide recycling into a chemical energy carrier, such as methane, on a centralized and decentralized scale. This is particularly important to establish equitable energy strategies for all countries, as is highlighted by the United Nations Sustainable Development Goals. With this work, we provide an integrated systems-biology platform for Methanothermobacter spp. to optimize biological power-to-gas technology and formulate strategies to produce other value-added products besides methane.

microbiology↗

bioRxiv2020

Strain-level analysis of Bifidobacterium spp. from gut microbiomes of adults of differing lactase persistence genotypes

One of the strongest associations between human genetics and the gut microbiome is a greater relative abundance of Bifidobacterium in adults with lactase gene (LCT) SNPs associated with lactase-non persistence (GG genotypes), versus lactase persistence (AA/AG genotypes). To gain a finer grained phylogenetic resolution of this association, we interrogated 1,680 16S rRNA libraries and 245 metagenomes from gut microbiomes of adults with varying lactase persistence genotypes. We further employed a novel genome-capture based enrichment of Bifidobacterium DNA from a subset of these metagenomes, including monozygotic (MZ) twin pairs, each sampled 2 or 3 times. B. adolescentis and B. longum were the most abundant Bifidobacterium species regardless of host LCT-genotype. LCT- genotypes could not be discriminated based on relative abundances of Bifidobacterium species or Bifidobacterium community structure. Metagenomic analysis of Bifidobacterium-enriched DNA revealed intra-individual temporal stability of B. longum, B. adolescentis, and B. bifidum strains against the background of a changeable microbiome. We also observed greater strain sharing within MZ twin pairs compared to unrelated individuals, and within GG compared to AA/AG individuals, but no effect of host LCTgenotype on Bifidobacterium strain composition. Our results support a "rising tide lift all boats" model for the dominant Bifidobacteria in the adult gut: their higher abundance in lactase-non persistent compared to lactase-persistent individuals results from an expansion at the genus level. Bifidobacterium species are known to be transmitted from mother to child and stable within individuals in infancy and childhood: our results extend this stability into adulthood. IMPORTANCEWhen human populations domesticated animals to drink their milk they adapted genetically with the ability to digest milk into adulthood (lactase persistence). The gut microbiomes of lactase non-persistent people (LNP) differ from those of lactase-persistent people (LP) by containing more bacteria belonging to the Bifidobacteria. These beneficial gut bacteria, which fall into many species, are known to degrade milk in the baby gut. Here, we asked if adult LP and LNP microbiomes differ in the species of Bifidobacteria present. We studied the gut microbiomes of LP and LNP adults, including twins, sampled at several times. In particular, we used a technique to selectively pull out the DNA belonging to the Bifidobacteria: analysis of these DNA segments allowed us to compare Bifidobacteria at the strain level. Our results show that the LNP enhance the abundance of Bifidobacteria regardless of species. We also noted that a persons specific strains are recoverable several years later, and twins tend to share the same ones. Given that Bifidobacteria are inherited from mother to child, strain stability over time in adulthood suggests long term, multi-generational inheritance.

microbiology↗

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↗