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
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165 results found

Quesada-Vázquez S, Castells-Nobau A, Latorre J, Oliveras-Cañellas N, Puig-Parnau I, Tejera N, Tobajas Y, Baudin J, Hildebrand F, Beraza N, Burcelin R, Martinez-Gili L, Chilloux J, Dumas M-E, Federici M, Hoyles L, Caimari A, Del Bas JM, Escoté X, Fernández-Real J-M, Mayneris-Perxachs Jet al., 2023, Potential therapeutic implications of histidine catabolism by the gut microbiota in NAFLD patients with morbid obesity., Cell Rep Med, Vol: 4

The gut microbiota contributes to the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Histidine is a key energy source for the microbiota, scavenging it from the host. Its role in NAFLD is poorly known. Plasma metabolomics, liver transcriptomics, and fecal metagenomics were performed in three human cohorts coupled with hepatocyte, rodent, and Drosophila models. Machine learning analyses identified plasma histidine as being strongly inversely associated with steatosis and linked to a hepatic transcriptomic signature involved in insulin signaling, inflammation, and trace amine-associated receptor 1. Circulating histidine was inversely associated with Proteobacteria and positively with bacteria lacking the histidine utilization (Hut) system. Histidine supplementation improved NAFLD in different animal models (diet-induced NAFLD in mouse and flies, ob/ob mouse, and ovariectomized rats) and reduced de novo lipogenesis. Fecal microbiota transplantation (FMT) from low-histidine donors and mono-colonization of germ-free flies with Enterobacter cloacae increased triglyceride accumulation and reduced histidine content. The interplay among microbiota, histidine catabolism, and NAFLD opens therapeutic opportunities.

Journal article

English J, Newberry F, Hoyles L, Patrick S, Stewart Let al., 2023, Genomic analyses of Bacteroides fragilis: subdivisions I and II represent distinct species., J Med Microbiol, Vol: 72

Introduction. Bacteroides fragilis is a Gram-negative anaerobe that is a member of the human gastrointestinal microbiota and is frequently found as an extra-intestinal opportunistic pathogen. B. fragilis comprises two distinct groups - divisions I and II - characterized by the presence/absence of genes [cepA and ccrA (cfiA), respectively] that confer resistance to β-lactam antibiotics by either serine or metallo-β-lactamase production. No large-scale analyses of publicly available B. fragilis sequence data have been undertaken, and the resistome of the species remains poorly defined.Hypothesis/Gap Statement. Reclassification of divisions I and II B. fragilis as two distinct species has been proposed but additional evidence is required.Aims. To investigate the genomic diversity of GenBank B. fragilis genomes and establish the prevalence of division I and II strains among publicly available B. fragilis genomes, and to generate further evidence to demonstrate that B. fragilis division I and II strains represent distinct genomospecies.Methodology. High-quality (n=377) genomes listed as B. fragilis in GenBank were included in pangenome and functional analyses. Genome data were also subject to resistome profiling using The Comprehensive Antibiotic Resistance Database.Results. Average nucleotide identity and phylogenetic analyses showed B. fragilis divisions I and II represent distinct species: B. fragilis sensu stricto (n=275 genomes) and B. fragilis A (n=102 genomes; Genome Taxonomy Database designation), respectively. Exploration of the pangenome of B. fragilis sensu stricto and B. fragilis A revealed separation of the two species at the core and accessory gene levels.Conclusion. The findings indicate that B. fragilis A, previously referred to as division II B. fragilis, is an individual species and distinct from B. fragilis sensu stricto. The B. fragilis pangenome analysis supported previous genomic, phylogenetic and resistome screening analyses collectively

Journal article

Eladawy M, Thomas JC, Hoyles L, 2023, Phenotypic and genomic characterization of Pseudomonas aeruginosa isolates recovered from catheter-associated urinary tract infections in an Egyptian hospital., Microb Genom, Vol: 9

Catheter-associated urinary tract infections (CAUTIs) represent one of the major healthcare-associated infections, and Pseudomonas aeruginosa is a common Gram-negative bacterium associated with catheter infections in Egyptian clinical settings. The present study describes the phenotypic and genotypic characteristics of 31 P. aeruginosa isolates recovered from CAUTIs in an Egyptian hospital over a 3 month period. Genomes of isolates were of good quality and were confirmed to be P. aeruginosa by comparison to the type strain (average nucleotide identity, phylogenetic analysis). Clonal diversity among the isolates was determined; eight different sequence types were found (STs 244, 357, 381, 621, 773, 1430, 1667 and 3765), of which ST357 and ST773 are considered to be high-risk clones. Antimicrobial resistance (AMR) testing according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines showed that the isolates were highly resistant to quinolones [ciprofloxacin (12/31, 38.7 %) and levofloxacin (9/31, 29 %) followed by tobramycin (10/31, 32.5 %)] and cephalosporins (7/31, 22.5 %). Genotypic analysis of resistance determinants predicted all isolates to encode a range of AMR genes, including those conferring resistance to aminoglycosides, β-lactamases, fluoroquinolones, fosfomycin, sulfonamides, tetracyclines and chloramphenicol. One isolate was found to carry a 422 938 bp pBT2436-like megaplasmid encoding OXA-520, the first report from Egypt of this emerging family of clinically important mobile genetic elements. All isolates were able to form biofilms and were predicted to encode virulence genes associated with adherence, antimicrobial activity, anti-phagocytosis, phospholipase enzymes, iron uptake, proteases, secretion systems and toxins. The present study shows how phenotypic analysis alongside genomic analysis may help us understand the AMR and virulence profiles of P. aeruginosa contributing to CAUTIs in Egypt.

Journal article

Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, Myridakis A, Forslund S, Nielsen T, Adriouch S, Holmes B, Chilloux J, Vieira-Silva S, Falony G, Salem J-E, Andreelli F, Belda E, Kieswich J, Chechi K, Puig-Castellvi F, Chevalier M, Le Chatelier E, Olanipekun M, Hoyles L, Alves R, Helft G, Isnard R, Køber L, Coelho LP, Rouault C, Gauguier D, Gøtze JP, Prifti E, Froguel P, The MetaCardis C, Zucker J-D, Bäckhed F, Vestergaard H, Hansen T, Oppert J-M, Blüher M, Nielsen J, Raes J, Bork P, Yaqoob M, Stumvoll M, Pedersen O, Ehrlich SD, Clément K, Dumas M-Eet al., 2023, Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied “explainable” machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.

Journal article

Walker AWW, Hoyles L, 2023, Human microbiome myths and misconceptions, NATURE MICROBIOLOGY, Vol: 8, Pages: 1392-1396, ISSN: 2058-5276

Journal article

Molinaro A, Nemet I, Lassen PB, Chakaroun R, Nielsen T, Aron-Wisnewsky J, Bergh P-O, Li L, Henricsson M, Kober L, Isnard R, Helft G, Stumvoll M, Pedersen O, Smith JG, Tang WHW, Clement K, Hazen SL, Backhed Fet al., 2023, Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality, JACC-HEART FAILURE, Vol: 11, Pages: 810-821, ISSN: 2213-1779

Journal article

Alexander J, Posma J, Scott A, Poynter L, Mason S, Herendi L, Roberts L, McDonald J, Cameron S, Darzi A, Goldin R, Takats Z, Marchesi J, Teare J, Kinross Jet al., 2023, Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer, Microbiome, Vol: 11, Pages: 1-14, ISSN: 2049-2618

Background and aimsThe gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes.MethodsA multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months.ResultsThirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10−11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR&

Journal article

McCartney AL, Hoyles L, 2023, The role of Klebsiella populations in preterm infants., Biochem Soc Trans, Vol: 51, Pages: 887-896

The preterm infant microbiota is dominated by Enterobacteriaceae (Escherichia, Klebsiella or Enterobacter spp.), Enterococcus and Staphylococcus spp. Recent work has demonstrated the development of this microbiota is predictable and driven by simple microbe-microbe interactions. Because of their systemic immaturity, including an underdeveloped immune system, preterm infants are susceptible to a range of infections. Numerous retrospective studies have examined the association of the preterm gut microbiota with diseases such as necrotizing enterocolitis (NEC), early-onset sepsis and late-onset sepsis. To date, no single bacterium has been associated with infection in these infants, but a Klebsiella/Enterococcus-dominated faecal microbiota is associated with an increased risk of developing NEC. Staphylococci aid and enterococci inhibit establishment/maintenance of gastrointestinal Klebsiella populations in preterm infants, though the mechanisms underlying these interactions are poorly understood. Klebsiella spp. recovered from healthy and sick preterm infants display similar antimicrobial resistance and virulence profiles, giving no clues as to why some infants develop potentially life-threatening diseases while others do not. The identification of cytotoxin-producing Klebsiella oxytoca sensu lato in the gut microbiota of some preterm infants has led to the suggestion that these bacteria may contribute to NEC in a subset of neonates. This mini review highlights current knowledge on Klebsiella spp. contributing to the preterm gut microbiota and provides insights into areas of research that warrant further attention.

Journal article

Newberry F, Shibu P, Smith-Zaitlik T, Eladawy M, McCartney AL, Hoyles L, Negus Det al., 2023, Lytic bacteriophage vB_KmiS-Kmi2C disrupts biofilms formed by members of the Klebsiella oxytoca complex, and represents a novel virus family and genus, JOURNAL OF APPLIED MICROBIOLOGY, Vol: 134, ISSN: 1364-5072

Journal article

Randall DW, Kieswich J, Hoyles L, McCafferty K, Curtis M, Yaqoob MMet al., 2023, Gut Dysbiosis in Experimental Kidney Disease: A Meta-Analysis of Rodent Repository Data, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 34, Pages: 533-553, ISSN: 1046-6673

Journal article

Stachulski A, Knausenberger TB-A, Shah SN, Hoyles L, McArthur Set al., 2023, A host-gut microbial amino acid co-metabolite, <i>p</i>-cresol glucuronide, promotes blood-brain barrier integrity <i>in vivo</i>, TISSUE BARRIERS, Vol: 11, ISSN: 2168-8370

Journal article

Negus D, Foster G, Hoyles L, 2023, Lelliottia amnigena recovered from the lung of a harbour porpoise, and comparative analyses with Lelliottia spp., Access Microbiol, Vol: 5

Strain M1325/93/1 (herein referred to by our laboratory identifier, GFKo1) of Lelliottia amnigena was isolated from the lung of a harbour porpoise in 1993. The genome sequence and antimicrobial resistance profile (genomic, phenotypic) of the strain were generated, with the genomic data compared with those from closely related bacteria. We demonstrate that the recently described chromosomally encoded AmpC β-lactamase bla LAQ is a core gene of L. amnigena , and suggest that new variants of this class of lactamase are encoded by other members of the genus Lelliottia . Although presence of bla LAQ is ubiquitous across the currently sequenced members of L. amnigena , we highlight that strain GFKo1 is sensitive to ampicillin and cephalosporins. These data suggest that bla LAQ may act as a useful genetic marker for identification of L. amnigena strains, but its presence may not correlate with expected phenotypic resistances. Further studies are required to determine the regulatory mechanisms of bla LAQ in L. amnigena .

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, Vol: 71, Pages: 2463-2480, ISSN: 0017-5749

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice.Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration.Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.Trial registration number NCT02059538.

Journal article

Penney N, Yeung K, Garcia Perez I, Posma J, Kopytek A, Garratt B, Ashrafian H, Frost G, Marchesi J, Purkayastha S, Hoyles L, Darzi A, Holmes Eet 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.

Journal article

Smith-Zaitlik T, Shibu P, McCartney AL, Foster G, Hoyles L, Negus Det 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-SGM, Vol: 168, ISSN: 1350-0872

Journal article

Noble A, Durant L, Dilke SM, Man R, Martin I, Patel R, Hoyles L, Pring ET, Latchford A, Clark SK, Carding SR, Knight SCet al., 2022, Altered Mucosal Immune-Microbiota Interactions in Familial Adenomatous Polyposis, CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY, Vol: 13

Journal article

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

Noble A, Pring ET, Durant L, Man R, Dilke SM, Hoyles L, James SA, Carding SR, Jenkins JT, Knight SCet al., 2022, Altered immunity to microbiota, B cell activation and depleted γδ/resident memory T cells in colorectal cancer, CANCER IMMUNOLOGY IMMUNOTHERAPY, ISSN: 0340-7004

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

Stachulski AV, Knausenberger TB-A, Shah SN, Hoyles L, McArthur Set 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

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: 500-505, ISSN: 0028-0836

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.

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

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