Publications
155 results found
Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, et al., 2022, Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine<i>N</i>-oxide with implications for heart and kidney disorders
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>The host-microbiota co-metabolite trimethylamine<jats:italic>N</jats:italic>-oxide (TMAO) is linked to increased thrombotic and cardiovascular risks. Here we, sought to i) characterize which host variables contribute to fasting serum TMAO levels in real-life settings ii) identify potential actionable therapeutic means related to circulating TMAO.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>We applied “explainable” machine learning, univariate-, multivariate- and mediation analyses of fasting plasma TMAO concentration and a multitude of bioclinical phenotypes in 1,741 adult Europeans of the MetaCardis study. We expanded and validated our epidemiological findings in mechanistic studies in human renal fibroblasts and a murine model of kidney fibrosis following TMAO exposure.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Next to age, kidney function was the primary variable predicting circulating TMAO in MetaCardis, with microbiota composition and diet playing minor, albeit significant roles. Mediation analysis revealed a causal relationship between TMAO and kidney function decline that strengthened at more severe stages of cardiometabolic disease. We corroborated our findings in preclinical models where TMAO exposure augmented conversion of human renal fibroblasts into myofibroblasts and increased kidney scarring<jats:italic>in vivo</jats:italic>. Mechanistically, TMAO aggravated kidney fibrosis due to ERK1/2 hyperactivation synergistically with TGF-β1 signaling. Consistent with our findings, patients receiving next-generation glucose-lowering drugs with reno-protective properties, had significantly lower circulating TMAO when compared to propensity-score matched control individuals.</jats
Penney N, Yeung K, Garcia Perez I, et al., 2022, Multi-omic phenotyping reveals host-microbe responses to bariatric surgery, glycaemic control and obesity, communications medicine, Vol: 2, Pages: 1-18, ISSN: 2730-664X
Background: Resolution of type 2 diabetes (T2D) is common following bariatric surgery, particularly Roux-en-Y gastric bypass. However, the underlying mechanisms have not been fully elucidated.Methods: To address this we compare the integrated serum, urine and faecal metabolic profiles of participants with obesity +/- T2D (n=80, T2D=42) with participants who underwent Roux-en-Y gastric bypass or sleeve gastrectomy (pre and 3-months post-surgery; n=27), taking diet into account. We co-model these data with shotgun metagenomic profiles of the gut microbiota to provide a comprehensive atlas of host-gut microbe responses to bariatric surgery, weight-loss and glycaemic control at the systems level.Results: Here we show that bariatric surgery reverses several disrupted pathways characteristic of T2D. The differential metabolite set representative of bariatric surgery overlaps with both diabetes (19.3% commonality) and body mass index (18.6% commonality). However, the percentage overlap between diabetes and body mass index is minimal (4.0% commonality), consistent with weight-independent mechanisms of T2D resolution. The gut microbiota is more strongly correlated to body mass index than T2D, although we identify some pathways such as amino acid metabolism that correlate with changes to the gut microbiota and which influence glycaemic control.Conclusion: We identify multi-omic signatures associated with responses to surgery, body mass index, and glycaemic control. Improved understanding of gut microbiota - host co-metabolism may lead to novel therapies for weight-loss or diabetes. However, further experiments are required to provide mechanistic insight into the role of the gut microbiota in host metabolism and establish proof of causality.
Smith-Zaitlik T, Shibu P, McCartney AL, et al., 2022, Extended genomic analyses of the broad-host-range phages vB_KmiM-2Di and vB_KmiM-4Dii reveal slopekviruses have highly conserved genomes., Microbiology (Reading), Vol: 168
High levels of antimicrobial resistance among members of the Klebsiella oxytoca complex (KoC) have led to renewed interest in the use of bacteriophage (phage) therapy to tackle infections caused by these bacteria. In this study we characterized two lytic phages, vB_KmiM-2Di and vB_KmiM-4Dii, that were isolated from sewage water against two GES-5-positive Klebsiella michiganensis strains (PS_Koxy2 and PS_Koxy4, respectively). ViPTree analysis showed both phages belonged to the genus Slopekvirus. rpoB gene-based sequence analysis of 108 presumptive K. oxytoca isolates (n=59 clinical, n=49 veterinary) found K. michiganensis to be more prevalent (46 % clinical and 43 % veterinary, respectively) than K. oxytoca (40 % clinical and 6 % veterinary, respectively). Host range analysis against these 108 isolates found both vB_KmiM-2Di and vB_KmiM-4Dii showed broad lytic activity against KoC species. Several hypothetical homing endonuclease genes were encoded within the genomes of both phages, which may contribute to their broad host range. Differences in the tail fibre protein may explain the non-identical host range of the two phages. Pangenome analysis of 24 slopekviruses found that genomes within this genus are highly conserved, with more than 50 % of all predicted coding sequences representing core genes at ≥95 % identity and ≥70 % coverage. Given their broad host ranges, our results suggest vB_KmiM-2Di and vB_KmiM-4Dii represent attractive potential therapeutics. In addition, current recommendations for phage-based pangenome analyses may require revision.
Noble A, Durant L, Dilke SM, et al., 2022, Altered Mucosal Immune-Microbiota Interactions in Familial Adenomatous Polyposis, CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY, Vol: 13
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- Citations: 2
Stachulski A, Knausenberger TB-A, Shah SN, et al., 2022, A host-gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo, TISSUE BARRIERS, Vol: 11, ISSN: 2168-8370
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- Citations: 1
Noble A, Pring ET, Durant L, et al., 2022, Altered immunity to microbiota, B cell activation and depleted gamma delta/resident memory T cells in colorectal cancer, CANCER IMMUNOLOGY IMMUNOTHERAPY, ISSN: 0340-7004
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- Citations: 2
Roberfroid M, Gibson GR, Hoyles L, et al., 2022, Commentary on : Prebiotic effects: metabolic and health benefits., The British Journal of Nutrition: an international journal of nutritional science, Vol: 127, Pages: 554-555, ISSN: 0007-1145
Menghini R, Hoyles L, Cardellini M, et al., 2022, ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids, MOLECULAR METABOLISM, Vol: 59, ISSN: 2212-8778
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- Citations: 1
Fromentin S, Forslund SK, Chechi K, et al., 2022, Microbiome and metabolome features of the cardiometabolic disease spectrum, Nature Medicine, Vol: 28, Pages: 303-+, ISSN: 1078-8956
Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages—acute coronary syndrome, chronic IHD and IHD with heart failure—and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
Chakrabarti A, Geurts L, Hoyles L, et al., 2022, The microbiota-gut-brain axis: pathways to better brain health. Perspectives on what we know, what we need to investigate and how to put knowledge into practice, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 79, ISSN: 1420-682X
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- Citations: 15
Stachulski AV, Knausenberger TB-A, Shah SN, et al., 2022, A host–gut microbial co-metabolite of aromatic amino acids, <i>p</i>-cresol glucuronide, promotes blood–brain barrier integrity <i>in vivo</i>
<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to <jats:italic>p</jats:italic>-cresol by gut microbes, and then to <jats:italic>p</jats:italic>-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Male C57Bl/6J mice were used to assess blood–brain barrier (BBB) permeability and whole brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Mice exposed to pCG showed reduced BBB permeability and significant changes in whole brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilising effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The amino acid phase II metaboli
Belda E, Voland L, Tremaroli V, et al., 2022, Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism, GUT, Vol: 71, Pages: 2463-2480, ISSN: 0017-5749
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- Citations: 16
Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, et al., 2021, Combinatorial, additive and dose-dependent drug-microbiome associations, NATURE, Vol: 600, Pages: 500-+, ISSN: 0028-0836
Hoyles L, Pontifex MG, Rodriguez-Ramiro I, et al., 2021, Regulation of blood brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide, Microbiome, Vol: 9, Pages: 1-21, ISSN: 2049-2618
BackgroundCommunication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied.ResultsHere, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner.ConclusionOur findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.
Nalpas N, Hoyles L, Anselm V, et al., 2021, An integrated workflow for enhanced taxonomic and functional coverage of the mouse fecal metaproteome., Gut Microbes, Vol: 13, Pages: 1-23, ISSN: 1949-0976
Intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behavior. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of fecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of taxa. Furthermore, there is a lack of consensus regarding preparation of fecal samples, as well as downstream bioinformatic analyses following metaproteomics data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse feces in a typical mass spectrometry-based metaproteomic experiment. We show that subtle changes in sample preparation protocols may influence interpretation of biological findings. Two-step database search strategies led to significant underestimation of false positive protein identifications. Unipept software provided the highest sensitivity and specificity in taxonomic annotation of the identified peptides of unknown origin. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.
Vrijheid M, Basagaña X, Gonzalez JR, et al., 2021, Advancing tools for human early lifecourse exposome research and translation (ATHLETE). Project overview, Environmental Epidemiology, Vol: 5, ISSN: 2474-7882
Early life stages are vulnerable to environmental hazards and present important windows of opportunity for lifelong disease prevention. This makes early life a relevant starting point for exposome studies. The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project aims to develop a toolbox of exposome tools and a Europe-wide exposome cohort that will be used to systematically quantify the effects of a wide range of community- and individual-level environmental risk factors on mental, cardiometabolic, and respiratory health outcomes and associated biological pathways, longitudinally from early pregnancy through to adolescence. Exposome tool and data development include as follows: (1) a findable, accessible, interoperable, reusable (FAIR) data infrastructure for early life exposome cohort data, including 16 prospective birth cohorts in 11 European countries; (2) targeted and nontargeted approaches to measure a wide range of environmental exposures (urban, chemical, physical, behavioral, social); (3) advanced statistical and toxicological strategies to analyze complex multidimensional exposome data; (4) estimation of associations between the exposome and early organ development, health trajectories, and biological (metagenomic, metabolomic, epigenetic, aging, and stress) pathways; (5) intervention strategies to improve early life urban and chemical exposomes, co-produced with local communities; and (6) child health impacts and associated costs related to the exposome. Data, tools, and results will be assembled in an openly accessible toolbox, which will provide great opportunities for researchers, policymakers, and other stakeholders, beyond the duration of the project. ATHLETE's results will help to better understand and prevent health damage from environmental exposures and their mixtures from the earliest parts of the life course onward.
Hsieh S-Y, Tariq MA, Telatin A, et al., 2021, Comparison of PCR versus PCR-Free DNA Library Preparation for Characterising the Human Faecal Virome, VIRUSES-BASEL, Vol: 13
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- Citations: 1
Shibu P, McCuaig F, McCartney AL, et al., 2021, Improved molecular characterization of the Klebsiella oxytoca complex reveals the prevalence of the kleboxymycin biosynthetic gene cluster, Microbial Genomics, Vol: 7, Pages: 1-11, ISSN: 2057-5858
As part of the ongoing studies with clinically relevant Klebsiella spp., we characterized the genomes of three clinical GES-5-positive ST138 strains originally identified as Klebsiella oxytoca. blaOXY gene, average nucleotide identity and phylogenetic analyses showed the strains to be Klebsiella michiganensis. Affiliation of the strains to ST138 led us to demonstrate that the current multi-locus sequence typing scheme for K. oxytoca can be used to distinguish members of this genetically diverse complex of bacteria. The strains encoded the kleboxymycin biosynthetic gene cluster (BGC), previously only found in K. oxytoca strains and one strain of Klebsiella grimontii. The finding of this BGC, associated with antibiotic-associated haemorrhagic colitis, in K. michiganensis led us to carry out a wide-ranging study to determine the prevalence of this BGC in Klebsiella spp. Of 7170 publicly available Klebsiella genome sequences screened, 88 encoded the kleboxymycin BGC. All BGC-positive strains belonged to the K. oxytoca complex, with strains of four (K. oxytoca, K. pasteurii, K. grimontii, K. michiganensis) of the six species of complex found to encode the complete BGC. In addition to being found in K. grimontii strains isolated from preterm infants, the BGC was found in K. oxytoca and K. michiganensis metagenome-assembled genomes recovered from neonates. Detection of the kleboxymycin BGC across the K. oxytoca complex may be of clinical relevance and this cluster should be included in databases characterizing virulence factors, in addition to those characterizing BGCs.
Brial F, Chilloux J, Nielsen T, et al., 2021, Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health., Gut, Vol: 70, Pages: 2105-2114, ISSN: 0017-5749
OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health. DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes. RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion. CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.
Hoyles L, Mayneris-Perxachs J, Cardellini M, et al., 2021, Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome, Microbiome, Vol: 9, Pages: 1-18, ISSN: 2049-2618
Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The
Dilke SM, Durant LR, Stentz R, et al., 2021, DIRECT MANIPULATION OF THE INTESTINAL MICROBIOME TO INFLUENCE POSTOPERATIVE OUTCOMES, Publisher: OXFORD UNIV PRESS, ISSN: 0007-1323
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- Citations: 1
Hoyles L, Pontifex MG, Rodriguez-Ramiro I, et al., 2021, Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine <i>N</i>-oxide, Publisher: Cold Spring Harbor Laboratory
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Communication between the gut microbiota and the brain is primarily mediated <jats:italic>via</jats:italic> soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Here we use an integrated <jats:italic>in vitro</jats:italic>/<jats:italic>in vivo</jats:italic> approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine <jats:italic>N</jats:italic>-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.</jats:p></jats:sec>
Nalpas N, Hoyles L, Anselm V, et al., 2020, An integrated workflow for enhanced taxonomic and functional coverage of the mouse faecal metaproteome, Publisher: Cold Spring Harbor Laboratory
The intestinal microbiota plays a key role in shaping host homeostasis by regulating metabolism, immune responses and behaviour. Its dysregulation has been associated with metabolic, immune and neuropsychiatric disorders and is accompanied by changes in bacterial metabolic regulation. Although proteomics is well suited for analysis of individual microbes, metaproteomics of faecal samples is challenging due to the physical structure of the sample, presence of contaminating host proteins and coexistence of hundreds of species. Furthermore, there is a lack of consensus regarding preparation of faecal samples, as well as downstream bioinformatic analyses following metaproteomic data acquisition. Here we assess sample preparation and data analysis strategies applied to mouse faeces in a typical LC-MS/MS metaproteomic experiment. We show that low speed centrifugation (LSC) of faecal samples leads to high protein identification rates and a balanced taxonomic representation. During database search, protein sequence databases derived from matched mouse faecal metagenomes provided up to four times more MS/MS identifications compared to other database construction strategies, while a two-step database search strategy led to accumulation of false positive protein identifications. Comparison of matching metaproteome and metagenome data revealed a positive correlation between protein and gene abundances, as well as significant overlap and correlation in taxonomic representation. Notably, nearly all functional categories of detected protein groups were differentially abundant in the metaproteome compared to what would be expected from the metagenome, highlighting the need to perform metaproteomics when studying complex microbiome samples.
Mayneris-Perxachs J, Puig J, Burcelin R, et al., 2020, The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients, CLINICAL NUTRITION, Vol: 39, Pages: 3408-3418, ISSN: 0261-5614
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- Citations: 7
Tariq MA, Newberry F, Haagmans R, et al., 2020, Genome characterization of a novel Wastewater bacteroides fragilis bacteriophage (vB_BfrS_23) and its host GB124, Frontiers in Microbiology, Vol: 11, Pages: 1-12, ISSN: 1664-302X
Bacteroides spp. are part of the human intestinal microbiota but can under some circumstances become clinical pathogens. Phages are a potentially valuable therapeutic treatment option for many pathogens, but phage therapy for pathogenic Bacteroides spp. including Bacteroides fragilis is currently limited to three genome-sequenced phages. Here we describe the isolation from sewage wastewater and genome of a lytic phage, vB_BfrS_23, that infects and kills B. fragilis strain GB124. Transmission electron microscopy identified this phage as a member of the Siphoviridae family. The phage is stable when held at temperatures of 4 and 60°C for 1 h. It has a very narrow host range, only infecting one host from a panel of B. fragilis strains (n = 8). Whole-genome sequence analyses of vB_BfrS_23 determined it is double-stranded DNA phage and is circularly permuted, with a genome of 48,011 bp. The genome encodes 73 putative open reading frames. We also sequenced the host bacterium, B. fragilis GB124 (5.1 Mb), which has two plasmids of 43,923 and 4,138 bp. Although this phage is host specific, its isolation together with the detailed characterization of the host B. fragilis GB124 featured in this study represent a useful starting point from which to facilitate the future development of highly specific therapeutic agents. Furthermore, the phage could be a novel tool in determining water (and water reuse) treatment efficacy, and for identifying human fecal transmission pathways within contaminated environmental waters and foodstuffs.
D'Amato A, Di Cesare Mannelli L, Lucarini E, et al., 2020, Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients, Microbiome, Vol: 8, Pages: 1-19, ISSN: 2049-2618
BackgroundThe gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions.ResultsYoung adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected.ConclusionThese results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to de
Kujawska M, La Rosa SL, Roger LC, et al., 2020, Succession of bifidobacterium longum strains in response to a changing early life nutritional environment reveals dietary substrate adaptations, iScience, Vol: 23, Pages: 1-29, ISSN: 2589-0042
Diet-microbe interactions play a crucial role in modulation of the early life microbiota and infant health. Bifidobacterium dominates the breast-fed infant gut and may persist in individuals during transition from a milk-based to a more diversified diet. Here, we investigated adaptation of Bifidobacterium longum to the changing nutritional environment. Genomic characterization of 75 strains isolated from nine either exclusively breast- or formula-fed (pre-weaning) infants in their first 18 months revealed subspecies- and strain-specific intra-individual genomic diversity with respect to carbohydrate metabolism, which corresponded to different dietary stages. Complementary phenotypic studies indicated strain-specific differences in utilization of human milk oligosaccharides and plant carbohydrates, whereas proteomic profiling identified gene clusters involved in metabolism of selected carbohydrates. Our results indicate a strong link between infant diet and B. longum diversity and provide additional insights into possible competitive advantage mechanisms of this Bifidobacterium species and its persistence in a single host.
Shibu P, McCuaig F, McCartney A, et al., 2020, The kleboxymycin biosynthetic gene cluster is encoded by several species belonging to the Klebsiella oxytoca complex, Publisher: bioRxiv
As part of ongoing studies with clinically relevant Klebsiella spp., we characterized the genomes of three clinical GES-5-positive strains originally identified as Klebsiella oxytoca. Average nucleotide identity and phylogenetic analyses showed the strains to be Klebsiella michiganensis. In addition to encoding GES-5, the strains encoded SHV-66, a β-lactamase not previously identified in K. michiganensis. The strains further encoded a range of virulence factors and the kleboxymycin biosynthetic gene cluster (BGC), previously only found in K. oxytoca strains and one strain of Klebsiella grimontii. This BGC, associated with antibiotic-associated haemorrhagic colitis, has not previously been reported in K. michiganensis, and this finding led us to carry out a wide-ranging study to determine the prevalence of this BGC in Klebsiella spp. Of 7,170 publicly available Klebsiella genome sequences screened, 88 encoded the kleboxymycin BGC. All BGC-positive strains belonged to the K. oxytoca complex, with strains of four (K. oxytoca, K. pasteurii, K. grimontii, K. michiganensis) of the six species of the complex found to encode the complete BGC. In addition to being found in K. grimontii strains isolated from preterm infants, the BGC was found in K. oxytoca and K. michiganensis metagenome-assembled genomes recovered from neonates. Detection of the kleboxymycin BGC across the K. oxytoca complex may be of clinical relevance and this cluster should be included in databases characterizing virulence factors, in addition to those characterizing BGCs.
Letertre MPM, Munjoma NC, Wolfer K, et al., 2020, A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats, Journal of Proteome Research, Vol: 19, Pages: 3326-3339, ISSN: 1535-3893
Methotrexate (MTX) is a chemotherapeutic agent that cancause a range of toxic side effects including gastrointestinal damage,hepatotoxicity, myelosuppression, and nephrotoxicity and has potentiallycomplex interactions with the gut microbiome. Following untargeted UPLCqtof-MS analysis of urine and fecal samples from male Sprague−Dawley ratsadministered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependentchanges in the endogenous metabolite profiles were detected. Semiquantitativetargeted UPLC-MS detected MTX excreted in urine as well as MTX and twometabolites, 2,4-diamino-N-10-methylpteroic acid (DAMPA) and 7-hydroxyMTX, in the feces. DAMPA is produced by the bacterial enzymecarboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling(16S rRNA gene amplicon sequencing) of fecal samples showed an increase inthe relative abundance of Firmicutes over the Bacteroidetes at low doses ofMTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h,which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to inducecommunity and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thusmay delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinaltoxicity.
Durant L, Stentz R, Noble A, et al., 2020, Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease, Microbiome, Vol: 8, ISSN: 2049-2618
BackgroundBacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all Gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn’s disease (CD) or ulcerative colitis (UC). ResultsIn healthy individuals, Bt OMVs stimulated significant (p<0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p<0.001 and p<0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p<0.01 and p<0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). ConclusionsOverall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients.
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