Imperial College London

Professor Marc-Emmanuel Dumas

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Systems Medicine
 
 
 
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Contact

 

+44 (0)20 7594 1820m.dumas Website

 
 
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Location

 

E315BBurlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

142 results found

Norris T, Razieh C, Zaccardi F, Yates T, Islam N, Gillies CL, Chudasama Y, Rowlands A, Davies MJ, McCann GP, Banerjee A, Lam CSP, Docherty AB, Openshaw PJM, Baillie JK, Semple MG, Lawson CA, Khunti Ket al., 2022, Impact of cardiometabolic multimorbidity and ethnicity on cardiovascular/renal complications in patients with COVID-19, Heart, Vol: 108, Pages: 1200-1208, ISSN: 1355-6037

Objective Using a large national database of people hospitalised with COVID-19, we investigated the contribution of cardio-metabolic conditions, multi-morbidity and ethnicity on the risk of in-hospital cardiovascular complications and death.Methods A multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 6 February 2020 and 16 March 2021. Logistic models were used to explore associations between baseline patient ethnicity, cardiometabolic conditions and multimorbidity (0, 1, 2, >2 conditions), and in-hospital cardiovascular complications (heart failure, arrhythmia, cardiac ischaemia, cardiac arrest, coagulation complications, stroke), renal injury and death.Results Of 65 624 patients hospitalised with COVID-19, 44 598 (68.0%) reported at least one cardiometabolic condition on admission. Cardiovascular/renal complications or death occurred in 24 609 (38.0%) patients. Baseline cardiometabolic conditions were independently associated with increased odds of in-hospital complications and this risk increased in the presence of cardiometabolic multimorbidity. For example, compared with having no cardiometabolic conditions, 1, 2 or ≥3 conditions was associated with 1.46 (95% CI 1.39 to 1.54), 2.04 (95% CI 1.93 to 2.15) and 3.10 (95% CI 2.92 to 3.29) times higher odds of any cardiovascular/renal complication, respectively. A similar pattern was observed for all-cause death. Compared with the white group, the South Asian (OR 1.19, 95% CI 1.10 to 1.29) and black (OR 1.53 to 95% CI 1.37 to 1.72) ethnic groups had higher risk of any cardiovascular/renal complication.Conclusions In hospitalised patients with COVID-19, cardiovascular complications or death impacts just under half of all patients, with the highest risk in those of South Asian or Black ethnicity and in patients with cardiometabolic multimorbidity.

Journal article

Wu V, Tillner J, Jones E, McKenzie JS, Gurung D, Mroz A, Poynter L, Simon D, Grau C, Altafaj X, Dumas M-E, Gilmore I, Bunch J, Takats Zet al., 2022, High resolution ambient MS imaging of biological samples by desorption electro-flow focussing ionization, Analytical Chemistry, Vol: 94, Pages: 10035-10044, ISSN: 0003-2700

In this study, we examine the suitability of desorption electro-flow focusing ionization (DEFFI) for mass spectrometry imaging (MSI) of biological tissue. We also compare the performance of desorption electrospray ionization (DESI) with and without the flow focusing setup. The main potential advantages of applying the flow focusing mechanism in DESI is its rotationally symmetric electrospray jet, higher intensity, more controllable parameters, and better portability due to the robustness of the sprayer. The parameters for DEFFI have therefore been thoroughly optimized, primarily for spatial resolution but also for intensity. Once the parameters have been optimized, DEFFI produces similar images to the existing DESI. MS images for mouse brain samples, acquired at a nominal pixel size of 50 μm, are comparable for both DESI setups, albeit the new sprayer design yields better sensitivity. Furthermore, the two methods are compared with regard to spectral intensity as well as the area of the desorbed crater on rhodamine-coated slides. Overall, the implementation of a flow focusing mechanism in DESI is shown to be highly suitable for imaging biological tissue and has potential to overcome some of the shortcomings experienced with the current geometrical design of DESI.

Journal article

Habboub N, Manousou P, Forlano R, Mullish BH, Frost G, Challis B, Thursz M, Dumas M-Eet al., 2022, Designing a polymetabolic risk score for non-alcoholic steatohepatitis patients by differentiating their metabolic profiles from healthy controls, JOURNAL OF HEPATOLOGY, Vol: 77, Pages: S179-S179, ISSN: 0168-8278

Journal article

Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G, Danzi MC, Myridakis A, Brandis A, Bello AT, Muller F, Sanchez-Vassopoulos A, De Virgiliis F, Liddell P, Dumas ME, Strid J, Mani S, Dodd D, Di Giovanni Set al., 2022, The gut metabolite indole-3 propionate promotes nerve regeneration and repair, NATURE, Vol: 607, Pages: 585-+, ISSN: 0028-0836

Journal article

Habboub N, Forlano R, Goldin R, Mullish BH, Frost G, Challis B, Thursz MR, Dumas M-E, Manousou Pet al., 2022, EXAMINING THE CORRELATION OF HISTOLOGICAL FEATURES OF NAFLD WITH A POLYMETABOLIC RISK SCORE FOR PREDICTING PATIENTS WITH NAFLD, GASTROENTEROLOGY, Vol: 162, Pages: S1271-S1271, ISSN: 0016-5085

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

Talmor-Barkan Y, Bar N, Shaul AA, Shahaf N, Godneva A, Bussi Y, Lotan-Pompan M, Weinberger A, Shechter A, Chezar-Azerrad C, Arow Z, Hammer Y, Chechi K, Forslund SK, Fromentin S, Dumas M-E, Ehrlich SD, Pedersen O, Kornowski R, Segal Eet al., 2022, Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease, NATURE MEDICINE, Vol: 28, Pages: 295-+, ISSN: 1078-8956

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

Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, Nutalai R, Wang B, Dijokaite A, Khan S, Avinoam O, Bahar M, Skelly D, Adele S, Johnson SA, Amini A, Ritter TG, Mason C, Dold C, Pan D, Assadi S, Bellass A, Omo-Dare N, Koeckerling D, Flaxman A, Jenkin D, Aley PK, Voysey M, Costa Clemens SA, Naveca FG, Nascimento V, Nascimento F, Fernandes da Costa C, Resende PC, Pauvolid-Correa A, Siqueira MM, Baillie V, Serafin N, Kwatra G, Da Silva K, Madhi SA, Nunes MC, Malik T, Openshaw PJM, Baillie JK, Semple MG, Townsend AR, Huang K-YA, Tan TK, Carroll MW, Klenerman P, Barnes E, Dunachie SJ, Constantinides B, Webster H, Crook D, Pollard AJ, Lambe T, OPTIC Consortium, ISARIC4C Consortium, Paterson NG, Williams MA, Hall DR, Fry EE, Mongkolsapaya J, Ren J, Schreiber G, Stuart DI, Screaton GRet al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

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

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 P, 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

de Silva TI, Liu G, Lindsey BB, Dong D, Moore SC, Hsu NS, Shah D, Wellington D, Mentzer AJ, Angyal A, Brown R, Parker MD, Ying Z, Yao X, Turtle L, Dunachie S, COVID-19 Genomics UK COG-UK Consortium, Maini MK, Ogg G, Knight JC, ISARIC4C Investigators, Peng Y, Rowland-Jones SL, Dong Tet al., 2021, The impact of viral mutations on recognition by SARS-CoV-2 specific T cells., iScience, Vol: 24, Pages: 103353-103353, ISSN: 2589-0042

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

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

Wickenhagen A, Sugrue E, Lytras S, Kuchi S, Noerenberg M, Turnbull ML, Loney C, Herder V, Allan J, Jarmson I, Cameron-Ruiz N, Varjak M, Pinto RM, Lee JY, Iselin L, Palmalux N, Stewart DG, Swingler S, Greenwood EJD, Crozier TWM, Gu Q, Davies EL, Clohisey S, Wang B, Maranhao Costa FT, Santana MF, de Lima Ferreira LC, Murphy L, Fawkes A, Meynert A, Grimes G, Filho JLDS, Marti M, Hughes J, Stanton RJ, Wang ECY, Ho A, Davis I, Jarrett RF, Castello A, Robertson DL, Semple MG, Openshaw PJM, Palmarini M, Lehner PJ, Baillie JK, Rihn SJ, Wilson SJet al., 2021, A prenylated dsRNA sensor protects against severe COVID-19, Science, Vol: 374, Pages: 1-18, ISSN: 0036-8075

Journal article

Nuzzo A, Guedj K, Curac S, Hercend C, Bendavid C, Gault N, Tran-Dinh A, Ronot M, Nicoletti A, Bouhnik Y, Castier Y, Corcos O, Peoc'h Ket al., 2021, Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia, Scientific Reports, Vol: 11, Pages: 1-10, ISSN: 2045-2322

Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.

Journal article

Drake TM, Riad AM, Fairfield CJ, Egan C, Knight SR, Pius R, Hardwick HE, Norman L, Shaw CA, McLean KA, Thompson AAR, Ho A, Swann OV, Sullivan M, Soares F, Holden KA, Merson L, Plotkin D, Sigfrid L, de Silva TI, Girvan M, Jackson C, Russell CD, Dunning J, Solomon T, Carson G, Olliaro P, Nguyen-Van-Tam JS, Turtle L, Docherty AB, Openshaw PJ, Baillie JK, Harrison EM, Semple MG, ISARIC4C investigatorset al., 2021, Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study, The Lancet, Vol: 398, Pages: 223-237, ISSN: 0140-6736

BACKGROUND: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. METHODS: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. FINDINGS: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

Bermudez-Martin P, Becker JAJ, Caramello N, Fernandez SP, Costa-Campos R, Canaguier J, Barbosa S, Martinez-Gili L, Myridakis A, Dumas M-E, Bruneau A, Cherbuy C, Langella P, Callebert J, Launay J-M, Chabry J, Barik J, Le Merrer J, Glaichenhaus N, Davidovic Let al., 2021, The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota, Microbiome, Vol: 9, Pages: 1-23, ISSN: 2049-2618

BackgroundAutism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.ConclusionsThe microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

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

Letertre MPM, Myridakis A, Whiley L, Camuzeaux S, Lewis MR, Chappell KE, Thaikkatil A, Dumas M-E, Nicholson JK, Swann JR, Wilson IDet al., 2021, A targeted ultra performance liquid chromatography - Tandem mass spectrometric assay for tyrosine and metabolites in urine and plasma: Application to the effects of antibiotics on mice, JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, Vol: 1164, ISSN: 1570-0232

Journal article

Molinaro A, Lassen PB, Henricsson M, Wu H, Adriouch S, Belda E, Chakaroun R, Nielsen T, Bergh P-O, Rouault C, Andre S, Marquet F, Andreelli F, Salem J-E, Assmann K, Bastard J-P, Forslund S, Le Chatelier E, Falony G, Pons N, Prifti E, Quinquis B, Roume H, Vieira-Silva S, Hansen TH, Pedersen HK, Lewinter C, Sonderskov NB, Kober L, Vestergaard H, Hansen T, Zucker J-D, Galan P, Dumas M-E, Raes J, Oppert J-M, Letunic I, Nielsen J, Bork P, Ehrlich SD, Stumvoll M, Pedersen O, Aron-Wisnewsky J, Clement K, Backhed Fet al., 2020, Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology (vol 11, 5881, 2020), Nature Communications, Vol: 11, ISSN: 2041-1723

Journal article

Giovanni SD, serger E, Chadwick J, Luengo L, Kong G, Zhou L, Crawford G, Danzi M, Myridakis A, Brandis A, Bello A, De Virgiliis F, Dumas M-E, Strid J, Dodd Det al., 2020, The intermittent fasting-dependent gut microbial metabolite indole-3 propionate promotes nerve regeneration and recovery after injury

<jats:title>Abstract</jats:title> <jats:p>The regenerative potential of mammalian peripheral nervous system (PNS) neurons after injury is critically limited by their slow axonal regenerative rate<jats:sup>1</jats:sup>. Since a delayed target re-innervation leads to irreversible loss of function of target organs<jats:sup>2</jats:sup>, accelerated axonal regeneration is required to enhance functional outcomes following injury. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms<jats:sup>3</jats:sup>. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration<jats:sup>4</jats:sup>. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and release of neurotrophins, can be activated by intermittent fasting (IF)<jats:sup>5,6</jats:sup>. IF has in turn been shown to increase synaptic plasticity<jats:sup>7,8</jats:sup> and neurogenesis<jats:sup>9</jats:sup>, partially sharing molecular mechanisms with axonal regeneration. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in the mouse via an unexpected mechanism that relies upon the gram + gut microbiome and an increase of the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by <jats:italic>Clostridium sporogenes</jats:italic> is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-d

Journal article

Molinaro A, Bel Lassen P, Henricsson M, Wu H, Adriouch S, Belda E, Chakaroun R, Nielsen T, Bergh P-O, Rouault C, Andre S, Marquet F, Andreelli F, Salem J-E, Assmann K, Bastard J-P, Forslund S, Le Chatelier E, Falony G, Pons N, Prifti E, Quinquis B, Roume H, Vieira-Silva S, Hansen TH, Pedersen HK, Lewinter C, Sonderskov NB, Kober L, Vestergaard H, Hansen T, Zucker J-D, Galan P, Dumas M-E, Raes J, Oppert J-M, Letunic I, Nielsen J, Bork P, Ehrlich SD, Stumvoll M, Pedersen O, Aron-Wisneswky J, Clement K, Backhed Fet al., 2020, Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology, Nature Communications, Vol: 11, ISSN: 2041-1723

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

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., 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

Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, Forslund SK, Assmann K, Valles-Colomer M, Nguyen TTD, Proost S, Prifti E, Tremaroli V, Pons N, Le Chatelier E, Andreelli F, Bastard J-P, Coelho LP, Galleron N, Hansen TH, Hulot J-S, Lewinter C, Pedersen HK, Quinquis B, Rouault C, Roume H, Salem J-E, Sondertoft NB, Touch S, Dumas M-E, Ehrlich SD, Galan P, Gotze JP, Hansen T, Holst JJ, Kober L, Letunic I, Nielsen J, Oppert J-M, Stumvoll M, Vestergaard H, Zucker J-D, Bork P, Pedersen O, Backhed F, Clement K, Raes Jet al., 2020, Statin therapy is associated with lower prevalence of gut microbiota dysbiosis, NATURE, Vol: 581, Pages: 310-+, ISSN: 0028-0836

Journal article

Bermudez-Martin P, Becker JAJ, Caramello N, Fernandez SP, Costa-Campos R, Canaguier J, Barbosa S, Martinez-Gili L, Myridakis A, Dumas M-E, Bruneau A, Cherbuy C, Langella P, Callebert J, Launay J-M, Chabry J, Barik J, Le Merrer J, Glaichenhaus N, Davidovic Let al., 2020, The microbial metabolite <i>p</i>-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota, Publisher: Cold Spring Harbor Laboratory

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Autism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as fecal, serum and urine levels of microbial metabolites. Yet, a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite <jats:italic>p</jats:italic>-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Mice exposed to <jats:italic>p</jats:italic>-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by <jats:italic>p</jats:italic>-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, <jats:italic>p</jats:italic>-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from <jats:italic>p</jats:italic>-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of <jats:italic>p</jats:italic>-Cresol-treated mice exhibited increased fecal <jats:italic>p-</jats:italic>Cresol levels compared to mice transplanted with the microbiota of control mice and identified possible <jats:italic>p</jats:italic>-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability and fecal <jats:italic>p</jats:italic>-Cresol levels when tran

Working paper

Pean N, Le Lay A, Brial F, Wasserscheid J, Rouch C, Vincent M, Myridakis A, Hedjazi L, Dumas M-E, Grundberg E, Lathrop M, Magnan C, Dewar K, Gauguier Det al., 2020, Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto-Kakizaki rats improves glucose homeostasis through enhanced FXR signalling, Diabetologia, Vol: 63, Pages: 1223-1235, ISSN: 0012-186X

Aims/hypothesisDrug and surgical-based therapies in type 2 diabetes are associated with altered gut microbiota architecture. Here we investigated the role of the gut microbiome in improved glucose homeostasis following bariatric surgery.MethodsWe carried out gut microbiome analyses in gastrectomised (by vertical sleeve gastrectomy [VSG]) rats of the Goto–Kakizaki (GK) non-obese model of spontaneously occurring type 2 diabetes, followed by physiological studies in the GK rat.ResultsVSG in the GK rat led to permanent improvement of glucose tolerance associated with minor changes in the gut microbiome, mostly characterised by significant enrichment of caecal Prevotella copri. Gut microbiota enrichment with P. copri in GK rats through permissive antibiotic treatment, inoculation of gut microbiota isolated from gastrectomised GK rats, and direct inoculation of P. copri, resulted in significant improvement of glucose tolerance, independent of changes in body weight. Plasma bile acids were increased in GK rats following inoculation with P. copri and P. copri-enriched microbiota from VSG-treated rats; the inoculated GK rats then showed increased liver glycogen and upregulated expression of Fxr (also known as Nr1h4), Srebf1c, Chrebp (also known as Mlxipl) and Il10 and downregulated expression of Cyp7a1.ConclusionsOur data underline the impact of intestinal P. copri on improved glucose homeostasis through enhanced bile acid metabolism and farnesoid X receptor (FXR) signalling, which may represent a promising opportunity for novel type 2 diabetes therapeutics.

Journal article

Brial F, Alzaid F, Sonomura K, Kamatani Y, Meneyrol K, Le Lay A, Pean N, Hedjazi L, Sato T-A, Venteclef N, Magnan C, Lathrop M, Dumas M-E, Matsuda F, Zalloua P, Gauguier Det al., 2020, The natural metabolite 4-cresol improves glucose homeostasis and enhances beta-cell function, Cell Reports, Vol: 30, Pages: 2306-2320, ISSN: 2211-1247

Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic β-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and β-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency.

Journal article

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