Imperial College London

Professor Lesley Hoyles

Faculty of MedicineDepartment of Surgery & Cancer

Visiting Professor
 
 
 
//

Contact

 

lesley.hoyles11 Website

 
 
//

Location

 

Norfolk PlaceSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

161 results found

Walker AW, Hoyles L, 2023, Human microbiome myths and misconceptions., Nat Microbiol, Vol: 8, Pages: 1392-1396

Over the past two decades, interest in human microbiome research has increased exponentially. Regrettably, this increased activity has brought with it a degree of hype and misinformation, which can undermine progress and public confidence in the research. Here we highlight selected human microbiome myths and misconceptions that lack a solid evidence base. By presenting these examples, we hope to draw increased attention to the implications of inaccurate dogma becoming embedded in the literature, and the importance of acknowledging nuance when describing the complex human microbiome.

Journal article

Molinaro A, Nemet I, Bel Lassen P, Chakaroun R, Nielsen T, Aron-Wisnewsky J, Bergh P-O, Li L, Henricsson M, Køber L, Isnard R, Helft G, Stumvoll M, Pedersen O, Smith JG, Tang WHW, Clément K, Hazen SL, Bäckhed F, MetaCardis Consortiumet al., 2023, Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality., JACC Heart Fail, Vol: 11, Pages: 810-821

BACKGROUND: Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure. OBJECTIVES: The authors aimed to explore whether ImP is associated with heart failure and mortality. METHODS: ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates. RESULTS: ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01). CONCLUSIONS: The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.

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., J Appl Microbiol, Vol: 134

AIMS: This study aimed to characterize the lytic phage vB_KmiS-Kmi2C, isolated from sewage water on a GES-positive strain of Klebsiella michiganensis. METHODS AND RESULTS: Comparative phylogenetic and network-based analyses were used to characterize the genome of phage vB_KmiS-Kmi2C (circular genome of 42 234 bp predicted to encode 55 genes), demonstrating it shared little similarity with other known phages. The phage was lytic on clinical strains of K. oxytoca (n = 2) and K. michiganensis (n = 4), and was found to both prevent biofilm formation and disrupt established biofilms produced by these strains. CONCLUSIONS: We have identified a phage capable of killing clinically relevant members of the K. oxytoca complex (KoC). The phage represents a novel virus family (proposed name Dilsviridae) and genus (proposed name Dilsvirus).

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., J Am Soc Nephrol, Vol: 34, Pages: 533-553

SIGNIFICANCE STATEMENT: Alterations in gut microbiota contribute to the pathophysiology of a diverse range of diseases, leading to suggestions that chronic uremia may cause intestinal dysbiosis that contributes to the pathophysiology of CKD. Various small, single-cohort rodent studies have supported this hypothesis. In this meta-analysis of publicly available repository data from studies of models of kidney disease in rodents, cohort variation far outweighed any effect of experimental kidney disease on the gut microbiota. No reproducible changes in animals with kidney disease were seen across all cohorts, although a few trends observed in most experiments may be attributable to kidney disease. The findings suggest that rodent studies do not provide evidence for the existence of "uremic dysbiosis" and that single-cohort studies are unsuitable for producing generalizable results in microbiome research. BACKGROUND: Rodent studies have popularized the notion that uremia may induce pathological changes in the gut microbiota that contribute to kidney disease progression. Although single-cohort rodent studies have yielded insights into host-microbiota relationships in various disease processes, their relevance is limited by cohort and other effects. We previously reported finding metabolomic evidence that batch-to-batch variations in the microbiome of experimental animals are significant confounders in an experimental study. METHODS: To attempt to identify common microbial signatures that transcend batch variability and that may be attributed to the effect of kidney disease, we downloaded all data describing the molecular characterization of the gut microbiota in rodents with and without experimental kidney disease from two online repositories comprising 127 rodents across ten experimental cohorts. We reanalyzed these data using the DADA2 and Phyloseq packages in R, a statistical computing and graphics system, and analyzed data both in a combined dataset of all s

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

Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, Myridakis A, Forslund SK, 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 MT, Hoyles L, Alves R, Helft G, Isnard R, Køber L, Pedro Coelho L, Rouault C, Gauguier D, Gøtze JP, Prifti E, Zucker J-D, Bäckhed F, Vestergaard H, Hansen T, Oppert J-M, Blüher M, Nielsen J, Raes J, Bork P, Yaqoob MM, Stumvoll M, Pedersen O, Ehrlich SD, Clément K, Dumas M-Eet 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

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 (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.

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

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

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 gamma delta/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

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

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

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

<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

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00706930&limit=30&person=true