Biology subjects

Lawley, T. D.

Publications and source records attributed to Lawley, T. D..

17 recordsLinked to original sources

bioRxiv2025

Bifidobacterium longum subsp. nexus nov., a novel subspecies isolated from infant stool

Bifidobacterium longum is a foundational, genetically diverse member of the infant gut microbiome, yet resolving its subspecies in metagenomic data remains challenging. Here, we performed a deep phylogenetic characterization of the B. longum species utilizing 4,577 fecal metagenomes from the LLNEXT mother-infant cohort alongside a global dataset of 1,220 genomes and metagenome-assembled genomes (MAGs). We identified a novel, geographically widespread lineage: Bifidobacterium longum subsp. nexti. Using a polyphasic taxonomic analysis, including average nucleotide identity and digital DNA-DNA hybridization, confirms subspecies-level divergence. Distinct from other members of the B. longum species, BL. nexti harbors -amylopullulanase and grows on soluble starch and often pullulan, consistent with -glucan utilization. Within the LLNEXT cohort, BL. nexti is enriched in formula-fed infants and shows evidence consistent with vertical transmission. Globally, while BL. nexti is geographically widespread, it usually persists at low relative abundance across diverse populations. By resolving a major fraction of previously unclassified B. longum diversity, this study provides new insights into the specialized lineages and ecological dynamics driving the assembly of the developing infant microbiome.

microbiology↗

bioRxiv2025

Host microbiome determines host specificity of the human whipworm, Trichuris trichiura

Long-term whipworm-host co-evolution has resulted in tropism for the caecum of specific hosts, an organ with the densest microbial population in the body. Here, we demonstrate that the host specificity of human whipworms (Trichuris trichiura) is host microbiome-driven. We successfully establish a T. trichiura infection in a non-primate host using a humanised-microbiota mouse model. We further show, in vitro, that hatching of T. trichiura was triggered by mucosal scrapings of the caecum of human microbiota-associated mice, but not from wild-type mice, which only induced T. muris hatching. Comparative metagenomic analysis of the murine versus humanised microbiomes directly implicated specific bacterial species in T. trichiura egg hatching. Additionally, we demonstrate that host tissue does not directly determine host specificity, as T. trichiura readily infected mouse caecaloids. Our findings indicate that host-microbiome-whipworm co-evolution has resulted in exquisite bacterial-whipworm egg interactions critical for hatching and development of these parasites in their definitive hosts.

microbiology↗

bioRxiv2025

Human milk oligosaccharide metabolism by Clostridium species suppresses inflammation and pathogen growth

Gut microbiome development is strongly impacted by breastmilk and human milk oligosaccharides (HMOs), with short- and long-term health implications. HMO metabolism is best characterised within bifidobacteria, but the full range of other HMO-utilising species remains unknown. This study examined HMO-utilising bacteria that colonise preterm infants (born <32 weeks gestation), their role in microbiome modulation, and their effects on intestinal barrier function. We found that infant-derived Clostridium perfringens, and three other Clostridium species, metabolise HMOs, producing short chain fatty acids, tryptophan catabolites, and other metabolites known to improve host health. C. perfringens inhibited pathobiont growth and supressed inflammation in preterm-derived intestinal organoids. These findings suggest a previously unrecognised role for C. perfringens, specifically those lacking the perfringolysin O gene, in promoting healthy gut development during infancy.

microbiology↗

bioRxiv2024

Enhanced metagenomics-enabled transmission inference with TRACS

Coexisting strains of the same species within the human microbiota pose a substantial challenge to inferring the host-to-host transmission of both pathogenic and commensal microbes. Here, we present TRACS, a highly accurate algorithm for estimating genetic distances between strains at the level of individual SNPs, which is robust to intra-species diversity within the host. Analysis of well-characterised Faecal Microbiota Transplantation datasets, along with extensive simulations, demonstrates that TRACS substantially outperforms existing strain aware transmission inference methods. We use TRACS to infer transmission networks in patients colonised with multiple strains, including SARS-CoV-2 amplicon sequencing data from UK hospitals, deep population sequencing data of Streptococcus pneumoniae and single-cell genome sequencing data from malaria patients infected with Plasmodium falciparum. Applying TRACS to gut metagenomic samples from a large cohort of 176 mothers and 1,288 infants born in UK hospitals revealed species-specific transmission rates between mothers and their infants. Notably, TRACS identified increased persistence of Bifidobacterium breve in infants, a finding missed by previous analyses due to the presence of multiple strains.

bioinformatics↗

bioRxiv2023

Enterocloster clostridioformis induces host intestinal epithelial responses that protect against Salmonella infection

Promoting resistance to enteric pathogen infection is a core function of the gut microbiota. However, many of the host-commensal interactions that likely mediate this protection remain uncharacterised. By screening gnotobiotic mice monocolonised with a range of mouse-derived commensal bacteria we have identified Enterocloster clostridioformis as a protective species against Salmonella Typhimurium infection. Unlike the colonisation resistance induced by some commensal bacteria, E. clostridioformis selectively induces a previously uncharacterised microbe adaptation response at the level of the caecal intestinal epithelium and the underlying mucosal immune system to mediate host-dependent resistance to infection. Triggering this pathway may therefore constitute a novel strategy to enhance protective responses against enteric infections.

microbiology↗

bioRxiv2022

Genomic and ecologic characteristics of the airway microbial-mucosal complex

SO_SCPLOWUMMARYC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWPARAGRAPHC_SCPLOWLung diseases due to infection and dysbiosis affect hundreds of millions of people world-wide1-4. Microbial communities at the airway mucosal barrier are conserved and highly ordered5, reflecting symbiosis and co-evolution with human host factors6. Freed of selection to digest nutrients for the host, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the results of the first systematic culture and whole-genome sequencing of the principal airway bacterial species, identifying abundant novel organisms within the genera Streptococcus, Pauljensenia, Neisseria and Gemella. Bacterial genomes were enriched for genes encoding antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. RNA-targeting CRISPR elements in some taxa suggest the potential to prevent or treat specific viral infections. Homologues of human RO60 present in Neisseria spp. provide a possible respiratory primer for autoimmunity in systemic lupus erythematosus (SLE) and Sjogren syndrome. We interpret the structure and biogeography of airway microbial communities from clinical surveys in the context of whole-genome content, identifying features of airway dysbiosis that may presage breakdown of homeostasis during acute attacks of asthma and chronic obstructive pulmonary disease (COPD). We match the gene content of isolates to human transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways that can sustain host interactions with the microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosal immunity in lung diseases of global significance.

microbiology↗

bioRxiv2022

Strong pathogen competition in neonatal gut colonisation

Bacterial pathogen species and their strains that colonise the human gut are generally understood to compete against both each other and the commensal species colonising this ecosystem. However, currently we are lacking a population-wide quantification of strain-level colonisation dynamics for many common bacterial pathogens and the relationship of colonisation potential to prevalence in disease is unknown. In addition, it is unclear how ecological factors might be modulating the dynamics. Here, using a combination of latest high-resolution metagenomics and strain-level genomic epidemiology methods leveraging large genomic reference libraries of key pathogens, we performed a characterisation of the competition (co-exclusion and co-presence) and colonisation dynamics for a longitudinal cohort of neonatal gut microbiomes. We found a strong inter- and intra-species competition dynamic in the gut colonisation process, but also a number of synergistic relationships among several species belonging to genus Klebsiella, which includes the prominent human pathogen Klebsiella pneumoniae. Additionally, we find no evidence of preferential colonisation by hospital-adapted pathogen lineages in either vaginal or caesarean section birth groups. Our analysis also enables the first unbiased assessment of the strain-level colonisation potential of extra-intestinal pathogenic Escherichia coli (ExPEC) in comparison with their potential to cause bloodstream infections. We determined that the established common ExPEC clones ST73 and ST95 are overall significantly more pathogenic than the more recent, globally circulating multi-drug resistant clone ST131, where only a single subclone (ST131-C2) exhibited excess pathogenic potential. Our study highlights the importance of systematic surveillance of bacterial gut pathogens, not only from disease but also from carriage state, to better inform therapies and preventive medicine in the future.

microbiology↗

bioRxiv2022

In vitro demonstration of broad host range mobile genetic elements transferring antibiotic resistance from the human microbiome

Mobile genetic elements (MGEs) carrying antibiotic resistance genes (ARGs) disseminate ARGs when they mobilise into new bacterial hosts. To investigate the scale of such horizontal gene transfer (HGT) events between human gut commensals and enteropathogens for the first time, we compared 1354 cultured commensal strains (540 species) to 45,403 enteropathogen strains (12 species) and found 64,188 MGE-mediated ARG transfer events between the two groups using established methods. Among the 5931 MGEs involved, we found 15 broad host range elements predicted to have crossed different bacterial phyla while also occurring in animal and environmental microbiomes. We experimentally demonstrated that predicted broad host range MGEs can mobilise from commensals Dorea longicatena and Hungatella hathewayi to enteropathogens Klebsiella oxytoca, crossing phyla simultaneously. Our work establishes the MGE-mediated ARG dissemination network between human gut commensals and enteropathogens and highlights novel broad host range MGEs as targets for future ARG dissemination management.

genomics↗

bioRxiv2021

Two microbiota subtypes identified in Irritable Bowel Syndrome with distinct responses to the low-FODMAP diet

ObjectiveReducing FODMAPs can be clinically beneficial in IBS but the mechanism is poorly understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. DesignWe used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. ResultsUnsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared to IBSH (p = 0.02). Conclusion50% of IBS cases manifested a pathogenic gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP exclusion in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms. O_TEXTBOXSignificance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIIBS subjects often respond to a low FODMAP diet. C_LIO_LIThe gut microbiota has been implicated in IBS. C_LIO_LIThe microbiota in IBS subjects may change with diet. C_LI What are the new findings?O_LIWe were able to stratify patients with IBS according to their gut microbiota species and metabolic gene signatures. C_LIO_LIWe identified a distinct gut microbiota subtype with an enhanced clinical response to a low FODMAP diet compared to other IBS subjects. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe potential development of a microbiota signature as a biomarker to manage IBS cases with a low FODMAP diet recommendation. C_LIO_LIIf the bacteria represented in the IBSP subtype are shown to play a pathogenic role in IBS, perhaps through the metabolic activity this provides a target for new therapies and an intermediate phenotype by which to assess them. C_LI C_TEXTBOX

microbiology↗

bioRxiv2021

Functional and taxonomic comparison of mouse and human gut microbiotas using extensive culturing and metagenomics

Mouse models are essential for biomedical science and drug discovery, yet it is not known how the bacteria in the mouse microbiota - important determinants of phenotypes of health and disease -affect their relevance to human disease. To interrogate the taxonomic and functional differences between the human and mouse gut microbiotas, we developed the Mouse Microbial Genome Collection (MMGC), a compilation of 276 genomes from cultured isolates and 45,218 metagenome-assembled genomes (MAGs) from 1,960 publicly available mouse metagenomes. The MMGC reveals that while only 2.65% of bacterial species are shared between mouse and human, over 80% of annotatable functions are present in both microbiomes. Using drug metabolism and butyrate synthesis as examples, we illustrate that although the species harbouring these key functions can differ between hosts, the MMGC enables identification of functionally equivalent taxa in the mouse and human microbiotas. The MMGC thereby facilitates the informed use of mice in biomedical research by providing access to the conservation and taxonomic locations of bacterial functions of interest.

microbiology↗

bioRxiv2021

Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease

The mammalian gut microbiota consists of hundreds of anaerobic bacterial species that shape intestinal homeostasis and influence host immune responses. Although the causal roles of specific human gut bacterial species in health and disease are emerging, the role of indigenous gut bacteria in driving immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 laboratory mice designed to identify and validate the causes of disease variability in the widely used dextran sulphate sodium (DSS) mouse model of inflammatory bowel disease. Using microbiome analysis, coupled with machine learning and targeted anaerobic culturing, we identified and isolated the novel gut pathobiont species Duncaniella muricolitica and Alistipes okayasuensis and fulfilled Kochs postulates in mice to show that each pathobiont exerts dominant effects in the DSS model leading to variable treatment responses. We show these pathobiont species are common, but not ubiquitous, in mouse facilities around the world, raising experimental design opportunities for improved mouse models of human intestinal diseases.

microbiology↗

bioRxiv2020

Host adaptation in gut Firmicutes is associated with sporulation loss and altered colonisation patterns

Human-to-human transmission of symbiotic, anaerobic bacteria is a fundamental evolutionary adaptation essential for membership of the human gut microbiota. However, despite its importance, the genomic and biological adaptations underpinning symbiont transmission remain poorly understood. Here, we show that sporulation ability, which promotes transmission of anaerobic bacteria, has been independently lost in many distinct evolutionary lineages of gut bacteria belonging to the Firmicutes phyla. Analysis of 1358 genome-sequenced Firmicutes reveals loss of sporulation is associated with features of host-adaptation such as genome reduction and specialized metabolic capabilities. Consistent with these data, analysis of 28,000 gut metagenomes from people around the world demonstrates that bacteria now incapable of sporulation are more abundant but less prevalent in the human population compared to spore-forming bacteria. Our results suggest host adaptation in gut Firmicutes is an evolutionary trade-off between transmission range and colonisation abundance, leading to distinct transmission cycles. We reveal host transmission as an underappreciated process that shapes the evolution, assembly and functions of gut Firmicutes.

microbiology↗

bioRxiv2020

Massive expansion of human gut bacteriophage diversity

Bacteriophages drive evolutionary change in bacterial communities by creating gene flow networks that fuel ecological adaptions. However, the extent of viral diversity and prevalence in the human gut remains largely unknown. Here, we introduce the Gut Phage Database (GPD), a collection of [~]142,000 non-redundant viral genomes (>10 kb) obtained by mining a dataset of 28,060 globally distributed human gut metagenomes and 2,898 reference genomes of cultured gut bacteria. Host assignment revealed that viral diversity is highest in the Firmicutes phyla and that [~]36% of viral clusters (VCs) are not restricted to a single species, creating gene flow networks across phylogenetically distinct bacterial species. Epidemiological analysis uncovered 280 globally distributed VCs found in at least 5 continents and a highly prevalent novel phage clade with features reminiscent of p-crAssphage. This high-quality, large-scale catalogue of phage genomes will improve future virome studies and enable ecological and evolutionary analysis of human gut bacteriophages.

microbiology↗

bioRxiv2020

Comprehensive genome analyses of Sellimonas intestinalis, a potential biomarker of homeostasis gut recovery

Sellimonas intestinalis is a Gram positive and anaerobic bacterial species previously considered as uncultivable. Although little is known about this Lachnospiraceae family member, its increased abundance has been reported in patients who recovered intestinal homeostasis after dysbiosis events. In this context, the aim of this work was taken advantage of a culturomics protocol that allowed the recovery species extremely oxygen-sensitive from faecal samples, which led to the establishment of an S. intestinalis isolate. Whole genome sequencing and taxonomic allocation confirmation were the base to develop comparative analyses including 11 public genomes closely related. Phylogeographic analysis revealed the existence of three lineages (linage-I including isolates from Chile and France, linage-II from South Korea and Finland, and linage-III from China and one isolate from USA). Pangenome analysis on the established dataset revealed that although S. intestinalis seems to have a highly conserved genome (with 50.1% of its coding potential being part of the coregenome), some recombination signals were evidenced. The identification of cluster of orthologous groups revealed a high number of genes involved in metabolism, including amino acid and carbohydrate transport as well as energy production and conversion, which matches with the metabolic profile previously reported for healthy microbiota. Additionally, virulence factors and antimicrobial resistance genes were found (mainly in linage-III), which could favour their survival during antibiotic-induced dysbiosis. These findings provide the basis of knowledge about this species with potential as a bioindicator of intestinal homeostasis recovery and contribute to advance in the characterization of gut microbiota members with beneficial potential.

microbiology↗

bioRxiv2019

Global genomic population structure of Clostridioides difficile

Clostridioides difficile is the primary infectious cause of antibiotic-associated diarrhea. Local transmissions and international outbreaks of this pathogen have been previously elucidated by bacterial whole-genome sequencing, but comparative genomic analyses at the global scale were hampered by the lack of specific bioinformatic tools. Here we introduce EnteroBase, a publicly accessible database (http://enterobase.warwick.ac.uk) that automatically retrieves and assembles C. difficile short-reads from the public domain, and calls alleles for core-genome multilocus sequence typing (cgMLST). We demonstrate that the identification of highly related genomes is 89% consistent between cgMLST and single-nucleotide polymorphisms. EnteroBase currently contains 13,515 quality-controlled genomes which have been assigned to hierarchical sets of single-linkage clusters by cgMLST distances. Hierarchical clustering can be used to identify populations of C. difficile at all epidemiological levels, from recent transmission chains through to pandemic and endemic strains, and is largely compatible with prior ribotyping. Hierarchical clustering thus enables comparisons to earlier surveillance data and will facilitate communication among researchers, clinicians and public-health officials who are combatting disease caused by C. difficile.

microbiology↗

bioRxiv2019

Pangenome analysis reveals genetic isolation in Campylobacter hyointestinalis subspecies adapted to different mammalian hosts

Campylobacter hyointestinalis is an emerging pathogen currently divided in two subspecies: C. hyointestinalis subsp. lawsonii which is restricted to pigs, and C. hyointestinalis subsp. hyointestinalis which can be found in a much wider range of mammalian hosts. Despite C. hyointestinalis has been reported as an emerging pathogen, its evolutionary and host-associated diversification patterns are still vastly unexplored. For this reason, we whole-genome sequenced 13 C. hyointestinalis subsp. hyointestinalis strains and performed a comprehensive comparative analysis including publicly available genomes of C. hyointestinalis subsp. hyointestinalis and C. hyointestinalis subsp. lawsonii to gain insight into the genomic variation of these differentially-adapted subspecies. Both subspecies are distinct phylogenetic lineages which present a barrier to homologous recombination, suggesting genetic isolation. This is further supported by accessory gene patterns that recapitulate the core genome phylogeny. Additionally, C. hyointestinalis subsp. hyointestinalis presents a bigger and more diverse accessory genome, which probably reflects its capacity to colonize different mammalian hosts unlike C. hyointestinalis subsp. lawsonii that is host-restricted. This greater plasticity in the accessory genome of C. hyointestinalis subsp. hyointestinalis correlates to a higher incidence of genome-wide recombination events, that may be the underlying mechanism driving its diversification. Concordantly, both subspecies present distinct patterns of gene families involved in genome plasticity and DNA repair like CRISPR-associated proteins and restriction-modification systems. Together, our results provide an overview of the genetic mechanisms shaping the genomes of C. hyointestinalis subspecies, contributing to understand the biology of Campylobacter species that are increasingly found as emerging pathogens.

genomics↗

bioRxiv2017

Proteomic identification of Axc, a novel beta-lactamase with carbapenemase activity in a meropenem-resistant clinical isolate of Achromobacterxylosoxidans

The development of antibiotic resistance during treatment is a threat to patients and their environment. Insight in the mechanisms of resistance development is important for appropriate therapy and infection control. Here, we describe how through the application of mass spectrometry-based proteomics, a novel beta-lactamase Axc was identified as an indicator of acquired carbapenem resistance in a clinical isolate of Achromobacter xylosoxidans.\n\nComparative proteomic analysis of consecutively collected susceptible and a resistant isolates from the same patient revealed that high Axc protein levels were only observed in the resistant isolate. Heterologous expression of Axc in Escherichia coli significantly increased the resistance towards carbapenems. Importantly, direct Axc mediated hydrolysis of imipenem was demonstrated using pH shift assays and 1H-NMR, confirming Axc as a legitimate carbapenemase. Whole genome sequencing revealed that the susceptible and resistant isolates were remarkably similar.\n\nTogether these findings provide a molecular context for the fast development of meropenem resistance in A. xylosoxidans during treatment and demonstrate the use of mass spectrometric techniques in identifying novel resistance determinants.

microbiology↗