Imperial College London

Professor Lesley Hoyles

Faculty of MedicineDepartment of Surgery & Cancer

Visiting Professor
 
 
 
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Contact

 

lesley.hoyles11 Website

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

149 results found

Menghini R, Hoyles L, Cardellini M, Casagrande V, Marino A, Gentileschi P, Davato F, Mavilio M, Arisi I, Mauriello A, Montanaro M, Scimeca M, Barton RH, Rappa F, Cappello F, Vinciguerra M, Moreno-Navarrete JM, Ricart W, Porzio O, Fernandez-Real J-M, Burcelin R, Dumas M-E, Federici Met al., 2022, ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids, MOLECULAR METABOLISM, Vol: 59, ISSN: 2212-8778

Journal article

Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall RA, Rowland IR, Wolvers D, Watzl B, Szajewska H, Stahl B, Guarner F, Respondek F, Whelan K, Coxam V, Davicco M-J, Léotoing L, Wittrant Y, Delzenne NM, Cani PD, Neyrinck AM, Meheust Aet 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

Journal article

Fromentin S, Forslund SK, Chechi K, Aron-Wisnewsky J, Chakaroun R, Nielsen T, Tremaroli V, Ji B, Prifti E, Myridakis A, Chilloux J, Andrikopoulos P, Fan Y, Olanipekun MT, Alves R, Adiouch S, Bar N, Talmor-Barkan Y, Belda E, Caesar R, Coelho LP, Falony G, Fellahi S, Galan P, Galleron N, Helft G, Hoyles L, Isnard R, Le Chatelier E, Julienne H, Olsson L, Pedersen HK, Pons N, Quinquis B, Rouault C, Roume H, Salem J-E, Schmidt TSB, Vieira-Silva S, Li P, Zimmermann-Kogadeeva M, Lewinter C, Sondertoft NB, Hansen TH, Gauguier D, Gotze JP, Kober L, Kornowski R, Vestergaard H, Hansen T, Zucker J-D, Hercberg S, Letunic I, Backhed F, Oppert J-M, Nielsen J, Raes J, Bork P, Stumvoll M, Segal E, Clement K, Dumas M-E, Ehrlich SD, Pedersen Oet 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.

Journal article

Chakrabarti A, Geurts L, Hoyles L, Iozzo P, Kraneveld AD, La Fata G, Miani M, Patterson E, Pot B, Shortt C, Vauzour Det 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

Journal article

Belda E, Voland L, Tremaroli V, Falony G, Adriouch S, Assmann KE, Prifiti E, Aron-Wisnewsky J, Debedat J, Le Roy T, Nielsen T, Amouyal C, Andre S, Andreelli F, Blueher M, Chakaroun R, Chilloux J, Coelho LP, Dao MC, Das P, Fellahi S, Forslund S, Galleron N, Hansen TH, Holmes B, Ji B, Pedersen HK, Phuong L, Le Chatelier E, Lewinter C, Manneras-Holm L, Marquet F, Myridakis A, Pelloux V, Pons N, Quinquis B, Rouault C, Roume H, Salem J-E, Sokolovska N, Sondertoft NB, Touch S, Vieira-Silva S, Galan P, Holst J, Gotze JP, Kober L, Vestergaard H, Hansen T, Hercberg S, Oppert J-M, Nielsen J, Letunic I, Dumas M-E, Stumvoll M, Pedersen OB, Bork P, Ehrlich SD, Zucker J-D, Baeckhed F, Raes J, Clement Ket 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, ISSN: 0017-5749

Journal article

Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, Marko L, Aron-Wisnewsky J, Nielsen T, Moitinho-Silva L, Schmidt TSB, Falony G, Vieira-Silva S, Adriouch S, Alves RJ, Assmann K, Bastard J-P, Birkner T, Caesar R, Chilloux J, Coelho LP, Fezeu L, Galleron N, Helft G, Isnard R, Ji B, Kuhn M, Le Chatelier E, Myridakis A, Olsson L, Pons N, Prifti E, Quinquis B, Roume H, Salem J-E, Sokolovska N, Tremaroli V, Valles-Colomer M, Lewinter C, Sondertoft NB, Pedersen HK, Hansen TH, Gotze JP, Kober L, Vestergaard H, Hansen T, Zucker J-D, Hercberg S, Oppert J-M, Letunic I, Nielsen J, Backhed F, Ehrlich SD, Dumas M-E, Raes J, Pedersen O, Clement K, Stumvoll M, Bork Pet al., 2021, Combinatorial, additive and dose-dependent drug-microbiome associations, NATURE, Vol: 600, Pages: 500-+, ISSN: 0028-0836

Journal article

Hoyles L, Pontifex MG, Rodriguez-Ramiro I, Anis-Alavi MA, Jelane KS, Snelling T, Solito E, Fonseca S, Carvalho AL, Carding SR, Muller M, Glen RC, Vauzour D, McArthur Set 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.

Journal article

Nalpas N, Hoyles L, Anselm V, Ganief T, Martinez-Gili L, Grau C, Droste-Borel I, Davidovic L, Altafaj X, Dumas M-E, Macek Bet 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.

Journal article

Vrijheid M, Basagaña X, Gonzalez JR, Jaddoe VWV, Jensen G, Keun HC, McEachan RRC, Porcel J, Siroux V, Swertz MA, Thomsen C, Aasvang GM, Andrušaitytė S, Angeli K, Avraam D, Ballester F, Burton P, Bustamante M, Casas M, Chatzi L, Chevrier C, Cingotti N, Conti D, Crépet A, Dadvand P, Duijts L, van Enckevort E, Esplugues A, Fossati S, Garlantezec R, Gómez Roig MD, Grazuleviciene R, Gützkow KB, Guxens M, Haakma S, Hessel EVS, Hoyles L, Hyde E, Klanova J, van Klaveren JD, Kortenkamp A, Le Brusquet L, Leenen I, Lertxundi A, Lertxundi N, Lionis C, Llop S, Lopez-Espinosa M-J, Lyon-Caen S, Maitre L, Mason D, Mathy S, Mazarico E, Nawrot T, Nieuwenhuijsen M, Ortiz R, Pedersen M, Perelló J, Pérez-Cruz M, Philippat C, Piler P, Pizzi C, Quentin J, Richiardi L, Rodriguez A, Roumeliotaki T, Sabin Capote JM, Santiago L, Santos S, Siskos AP, Strandberg-Larsen K, Stratakis N, Sunyer J, Tenenhaus A, Vafeiadi M, Wilson RC, Wright J, Yang T, Slama Ret 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.

Journal article

Hsieh S-Y, Tariq MA, Telatin A, Ansorge R, Adriaenssens EM, Savva GM, Booth C, Wileman T, Hoyles L, Carding SRet al., 2021, Comparison of PCR versus PCR-Free DNA Library Preparation for Characterising the Human Faecal Virome, VIRUSES-BASEL, Vol: 13

Journal article

Shibu P, McCuaig F, McCartney AL, Kujawska M, Hall LJ, Hoyles Let 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.

Journal article

Brial F, Chilloux J, Nielsen T, Vieira-Silva S, Falony G, Andrikopoulos P, Olanipekun M, Hoyles L, Djouadi F, Neves AL, Rodriguez-Martinez A, Mouawad GI, Pons N, Forslund S, Le-Chatelier E, Le Lay A, Nicholson J, Hansen T, Hyötyläinen T, Clément K, Oresic M, Bork P, Ehrlich SD, Raes J, Pedersen OB, Gauguier D, Dumas M-Eet 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.

Journal article

Hoyles L, Mayneris-Perxachs J, Cardellini M, Latorre J, Davato F, Moreno-Navarette JM, Arnoriaga-Rodriquez M, Serino M, Abbott J, Barton RH, Puig J, Fernandez-Real X, Ricart W, Tomlinson C, Woodbridge M, Gentileschi P, Butcher SA, Holmes E, Nicholson JK, Perez-Brocal V, Moya A, McClain D, Burcelin R, Dumas M-E, Federici M, Fernandez-Real J-Met 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

Journal article

Dilke SM, Durant LR, Stentz R, Wilson A, Tozer PJ, Vaizey CJ, Hoyles L, Carding S, Knight SC, Noble Aet al., 2021, DIRECT MANIPULATION OF THE INTESTINAL MICROBIOME TO INFLUENCE POSTOPERATIVE OUTCOMES, Publisher: OXFORD UNIV PRESS, ISSN: 0007-1323

Conference paper

Hoyles L, Pontifex MG, Rodriguez-Ramiro I, Anis-Alavi MA, Jelane KS, Snelling T, Solito E, Fonseca S, Carvalho AL, Carding SR, Müller M, Glen RC, Vauzour D, McArthur Set 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>

Working paper

Nalpas N, Hoyles L, Anselm V, Ganief T, Martinez-Gili L, Grau C, Droste-Borel I, Davidovic L, Altafaj X, Dumas M-E, Macek Bet 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.

Working paper

Mayneris-Perxachs J, Puig J, Burcelin R, Dumas M-E, Barton RH, Hoyles L, Federici M, Fernandez-Real J-Met 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

Journal article

Tariq MA, Newberry F, Haagmans R, Booth C, Wileman T, Hoyles L, Clokie MRJ, Ebdon J, Carding SRet 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.

Journal article

D'Amato A, Di Cesare Mannelli L, Lucarini E, Man AL, Le Gall G, Branca JJV, Ghelardini C, Amedei A, Bertelli E, Regoli M, Pacini A, Luciani G, Gallina P, Altera A, Narbad A, Gulisano M, Hoyles L, Vauzour D, Nicoletti Cet 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

Journal article

Kujawska M, La Rosa SL, Roger LC, Pope PB, Hoyles L, McCartney AL, Hall LJet 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.

Journal article

Shibu P, McCuaig F, McCartney A, Kujawska M, Hall L, Hoyles Let 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.

Working paper

Letertre MPM, Munjoma NC, Wolfer K, Pechlivanis A, McDonald J, Hardwick RN, Cherrington NJ, Coen M, Nicholson J, Hoyles L, Swann J, Wilson Iet 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.

Journal article

Durant L, Stentz R, Noble A, Reddi D, Brooks J, Gicheva N, O'Connor MJ, Hoyles L, McCartney AL, Man R, Pring ET, Dilke S, Hendy P, Segal JP, Lim DNF, Misra R, Hart AL, Arebi N, Carding SR, Knight SCet 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.

Journal article

Chen Y, Brook TC, Soe CZ, O'Neill I, Alcon-Giner C, Leelastwattanagul O, Phillips S, Caim S, Clarke P, Hall LJ, Hoyles Let al., 2020, Preterm infants harbour diverse Klebsiella populations, including atypical species that encode and produce an array of antimicrobial resistance- and virulence-associated factors, Microbial Genomics, Vol: 6, Pages: 1-20, ISSN: 2057-5858

Klebsiella spp. are frequently enriched in the gut microbiota of preterm neonates, and overgrowth is associated with necrotizing enterocolitis (NEC), nosocomial infections and late-onset sepsis. Little is known about the genomic and phenotypic characteristics of preterm-associated Klebsiella, as previous studies have focused on the recovery of antimicrobial-resistant isolates or culture-independent molecular analyses. The aim of this study was to better characterize preterm-associated Klebsiella populations using phenotypic and genotypic approaches. Faecal samples from a UK cohort of healthy and sick preterm neonates (n=109) were screened on MacConkey agar to isolate lactose-positive Enterobacteriaceae. Whole-genome sequences were generated for Klebsiella spp., and virulence and antimicrobial resistance genes identified. Antibiotic susceptibility profiling and in vitro macrophage and iron assays were undertaken for the Klebsiella strains. Metapangenome analyses with a manually curated genome dataset were undertaken to examine the diversity of Klebsiella oxytoca and related bacteria in a publicly available shotgun metagenome dataset. Approximately one-tenth of faecal samples harboured Klebsiella spp. (Klebsiella pneumoniae, 7.3 %; Klebsiella quasipneumoniae, 0.9 %; Klebsiella grimontii, 2.8 %; Klebsiella michiganensis, 1.8 %). Isolates recovered from NEC- and sepsis-affected infants and those showing no signs of clinical infection (i.e. ‘healthy’) encoded multiple β-lactamases. No difference was observed between isolates recovered from healthy and sick infants with respect to in vitro siderophore production (all encoded enterobactin in their genomes). All K. pneumoniae, K. quasipneumoniae, K. grimontii and K. michiganensis faecal isolates tested were able to reside and persist in macrophages, indicating their immune evasion abilities. Metapangenome analyses of published metagenomic data confirmed our findings regarding the presence of K. michiganensi

Journal article

Cox M, Carney S, Hoyles L, Roy S, Williams R, Breuer J, Chalker V, Moffatt Met al., 2020, Legionella pneumophila typing by direct sequencing of clinical and environmental samples, ATS 2020 International Conference, Publisher: American Thoracic Society, Pages: 1-2, ISSN: 1073-449X

Conference paper

Noble A, Durant L, Reddi D, O'Connor M, Hoyles L, Segal J, Man R, Hendy P, Bouri S, Arebi N, Akbar A, Carding S, Knight Set al., 2020, Deficient resident memory T-cell and CD8 T-cell response to commensals in inflammatory bowel disease, Journal of Crohn's and Colitis, Vol: 14, Pages: 525-537, ISSN: 1873-9946

Background and AimsThe intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD].MethodsResident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed.ResultsSystemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses.ConclusionsA previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

Journal article

Leggett RM, Alcon-Giner C, Heavens D, Caim S, Brook TC, Kujawska M, Martin S, Peel N, Acford-Palmer H, Hoyles L, Clarke P, Hall LJ, Clark MDet al., 2020, Rapid MinION profiling of preterm microbiota and antimicrobial-resistant pathogens, Nature Microbiology, Vol: 5, Pages: 430-442, ISSN: 2058-5276

The MinION sequencing platform offers near real-time analysis of DNA sequence; this makes the tool attractive for deployment in fieldwork or clinical settings. We used the MinION platform coupled to the NanoOK RT software package to perform shotgun metagenomic sequencing and profile mock communities and faecal samples from healthy and ill preterm infants. Using Nanopore data, we reliably classified a 20-species mock community and captured the diversity of the immature gut microbiota over time and in response to interventions such as probiotic supplementation, antibiotic treatment or episodes of suspected sepsis. We also performed rapid real-time runs to assess gut-associated microbial communities in critically ill and healthy infants, facilitated by NanoOK RT software package, which analysed sequences as they were generated. Our pipeline reliably identified pathogenic bacteria (that is, Klebsiella pneumoniae and Enterobacter cloacae) and their corresponding antimicrobial resistance gene profiles within as little as 1 h of sequencing. Results were confirmed using pathogen isolation, whole-genome sequencing and antibiotic susceptibility testing, as well as mock communities and clinical samples with known antimicrobial resistance genes. Our results demonstrate that MinION (including cost-effective Flongle flow cells) with NanoOK RT can process metagenomic samples to a rich dataset in < 5 h, which creates a platform for future studies aimed at developing these tools and approaches in clinical settings with a focus on providing tailored patient antimicrobial treatment options.

Journal article

Kujawska M, La Rosa SL, Pope P, Hoyles L, McCartney A, Hall Let al., 2020, Succession of Bifidobacterium longum strains in response to the changing early-life nutritional environment reveals specific adaptations to distinct dietary substrates, Publisher: Cold Spring Harbor Laboratory

Diet-microbe interactions play a crucial role in infant development and modulation of the early-life microbiota. The genus Bifidobacterium dominates the breast-fed infant gut, with strains of B. longum subsp. longum ( B. longum ) and B. longum subsp. infantis ( B. infantis ) particularly prevalent. Although transition from milk to a more diversified diet later in infancy initiates a shift to a more complex microbiome, specific strains of B. longum may persist in individual hosts for prolonged periods of time. Here, we sought to investigate the adaptation of B. longum to the changing infant diet. Genomic characterisation 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 glycosyl hydrolase families and enzymes, which corresponded to different dietary stages. Complementary phenotypic growth studies indicated strain-specific differences in human milk oligosaccharide and plant carbohydrate utilisation profiles of isolates between and within individual infants, while proteomic profiling identified active polysaccharide utilisation loci involved in metabolism of selected carbohydrates. Our results indicate a strong link between infant diet and B. longum subspecies/strain genomic and carbohydrate utilisation diversity, which aligns with a changing nutritional environment: i.e. moving from breast milk to a solid food diet. These data provide additional insights into possible mechanisms responsible for the competitive advantage of this Bifidobacterium species and its long-term persistence in a single host and may contribute to rational development of new dietary therapies for this important developmental window.

Working paper

Herridge WP, Shibu P, O'Shea J, Brook TC, Hoyles Let al., 2020, Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses, Journal of Medical Microbiology, Vol: 69, Pages: 176-194, ISSN: 0022-2615

Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella -infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.

Journal article

Brial F, Chilloux J, Nielsen T, Vieira-Silva S, Falony G, Hoyles L, Neves A, Rodriguez-Martinez A, Mouawad GI, Pons N, Forslund S, Chatelier EL, Le Lay A, Nicholson J, Hansen T, Clément K, Bork P, Ehrlich D, Raes J, Pedersen O, Gauguier D, Dumas M-E, MetaHIT consortiumet al., 2019, Microbiome determinants and physiological effects of the benzoate-hippurate microbial-host co-metabolic pathway, Publisher: Cold Spring Harbor Laboratory

Objective Gut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate.Design We profiled the urine metabolome by 1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes.Results In-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causality in vivo through chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation.Conclusion Our translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.

Working paper

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