Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms

Jordi Mayneris-Perxachs, José-Manuel Fernández-Real, Jordi Mayneris-Perxachs, José-Manuel Fernández-Real

Abstract

Thanks to the emergence and recent advances in high-throughput sequencing technologies, it is becoming more evident every day that changes in the microbiome composition are linked to a myriad of health conditions. Despite this, the mechanisms of host-microbiota signalling remain largely unknown. The microbiome has an extensive metabolic activity that leads to the generation of a large number of compounds that are likely to influence host health. Therefore, the microbiome-host cross-talk is in part mediated by microbial-derived metabolites. Unlike metagenomics, which only provides information about microbial genes and thus the microbiome functional potential, metabolic phenotyping is well suited to capture their actual metabolic activity. Here, we provide an overview of these approaches and propose an integration of metagenomics, as a microbiome compositional readout, with faecal and plasma/urine metabolomics, as a functional readout, to unravel novel mechanisms linking the microbiome to host health and disease.

Keywords: metabolic phenotyping; metabolomics; metagenomics; microbial metabolites; microbiome; microbiome composition; microbiome functionality.

© 2019 Federation of European Biochemical Societies.

References

    1. The Human Microbiome Project Consortium (2012) A framework for human microbiome research. Nature 486, 215-221.
    1. The Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486, 207-204.
    1. Evans JM, Morris LS & Marchesi JR (2013) The gut microbiome: the role of a virtual organ in the endocrinology of the host. J Endocrinol 218, R37-R47.
    1. Rojo D, Méndez-García C, Raczkowska BA, Bargiela R, Moya A, Ferrer M & Barbas C (2017) Exploring the human microbiome from multiple perspectives: factors altering its composition and function. FEMS Microbiol Rev 41, 453-478.
    1. Arnold JW, Roach J & Azcarate-Peril MA (2016) Emerging technologies for gut microbiome research. Trends Microbiol 24, 887-901.
    1. Nguyen N-P, Warnow T, Pop M & White B (2016) A perspective on 16S rRNA operational taxonomic unit clustering using sequence similarity. NPJ Biofilms Microbiomes 2, 16004.
    1. Breitwieser FP, Lu J & Salzberg SL (2017) A review of methods and databases for metagenomic classification and assembly. Brief Bioinform 20, 1125-1136.
    1. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I & Tuohy K (2018) Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr 57, 1-24.
    1. Moco S & Ross AB (2015) Can we use metabolomics to understand changes to gut microbiota populations and function? A nutritional perspective. In Metabonomics and Gut Microbiota in Nutrition and Disease (Kochhar S & Martin F-P eds), pp. 83-108. Springer, London.
    1. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W & Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336, 1262-1267.
    1. Martinez KB, Leone V & Chang EB (2017) Microbial metabolites in health and disease: navigating the unknown in search of function. J Biol Chem 292, 8553-8559.
    1. Brial F, Le Lay A, Dumas M-E & Gauguier D (2018) Implication of gut microbiota metabolites in cardiovascular and metabolic diseases. Cell Mol Life Sci 75, 3977-3990.
    1. Canfora EE, Meex RCR, Venema K & Blaak EE (2019) Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 15, 261-273.
    1. Sonnenburg JL & Bäckhed F (2016) Diet-microbiota interactions as moderators of human metabolism. Nature 535, 56-64.
    1. Zhang Z-Y, Monleon D, Verhamme P & Staessen JA (2018) Branched-chain amino acids as critical switches in health and disease. Hypertension 72, 1012-1022.
    1. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BAH, Forslund K, Hildebrand F, Prifti E, Falony G et al. (2016) Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376-381.
    1. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, Martin P, Philippe C, Walker F, Bado A et al. (2013) Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787-1794.
    1. Velasquez M, Centron P, Barrows I, Dwivedi R & Raj D (2018) Gut microbiota and cardiovascular uremic toxicities. Toxins (Basel) 10, 287.
    1. Poesen R, Claes K, Evenepoel P, de Loor H, Augustijns P, Kuypers D & Meijers B (2016) Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J Am Soc Nephrol 27, 3479-3487.
    1. Hung S, Kuo K, Wu C & Tarng D (2017) Indoxyl sulfate: a novel cardiovascular risk factor in chronic kidney disease. J Am Heart Assoc 6, e005022.
    1. Han H, Zhu J, Zhu Z, Ni J, Du R, Dai Y, Chen Y, Wu Z, Lu L & Zhang R (2015) p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J Am Heart Assoc 4, e001852.
    1. Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE & Flint HJ (2013) Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res 57, 523-535.
    1. Holmes E, Loo RL, Stamler J, Bictash M, Yap IKS, Chan Q, Ebbels T, De Iorio M, Brown IJ, Veselkov KA et al. (2008) Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 453, 396-400.
    1. Elliott P, Posma JM, Chan Q, Garcia-Perez I, Wijeyesekera A, Bictash M, D Ebbels TM, Ueshima H, Zhao L, van Horn L et al. (2015) Urinary metabolic signatures of human adiposity. Sci Transl Med 7, 285ra62.
    1. Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD et al. (2007) A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol Genomics 29, 99-108.
    1. Kuzma JN, Schmidt KA & Kratz M (2017) Prevention of metabolic diseases. Curr Opin Clin Nutr Metab Care 20, 286-293.
    1. Bansal T, Alaniz RC, Wood TK & Jayaraman A (2010) The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci USA 107, 228-233.
    1. Aregbesola A, de Mello VDF, Lindström J, Voutilainen S, Virtanen JK, Keinänen-Kiukaanniemi S, Tuomainen T-P, Tuomilehto J & Uusitupa M (2018) Serum adiponectin/Ferritin ratio in relation to the risk of type 2 diabetes and insulin sensitivity. Diabetes Res Clin Pract 141, 264-274.
    1. Laurans L, Venteclef N, Haddad Y, Chajadine M, Alzaid F, Metghalchi S, Sovran B, Denis RGP, Dairou J, Cardellini M et al. (2018) Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med 24, 1113-1120.
    1. Dou L, Sallée M, Cerini C, Poitevin S, Gondouin B, Jourde-Chiche N, Fallague K, Brunet P, Calaf R, Dussol B et al. (2015) The cardiovascular effect of the uremic solute indole-3 acetic acid. J Am Soc Nephrol 26, 876-887.
    1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, Feldstein AE, Britt EB, Fu X, Chung Y-M et al. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63.
    1. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L et al. (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19, 576-585.
    1. Chávez-Talavera O, Tailleux A, Lefebvre P & Staels B (2017) Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152, 1679-1694.e3.
    1. Mayneris-Perxachs J & Swann JR (2019) Metabolic phenotyping of malnutrition during the first 1000 days of life. Eur J Nutr 58, 909-930.
    1. Vernocchi P, Del Chierico F & Putignani L (2016) Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health. Front Microbiol 7, 1144.
    1. Lamichhane S, Sen P, Dickens AM, Orešič M & Bertram HC (2018) Gut metabolome meets microbiome: a methodological perspective to understand the relationship between host and microbe. Methods 149, 3-12.
    1. Zhang A, Sun H, Wang P, Han Y & Wang X (2012) Modern analytical techniques in metabolomics analysis. Analyst 137, 293-300.
    1. Rahimi N, Razi F, Nasli-Esfahani E, Qorbani M, Shirzad N & Larijani B (2017) Amino acid profiling in the gestational diabetes mellitus. J Diabetes Metab Disord 16, 13.
    1. Sarafian MH, Lewis MR, Pechlivanis A, Ralphs S, McPhail MJW, Patel VC, Dumas M-E, Holmes E & Nicholson JK (2015) Bile acid profiling and quantification in biofluids using ultra-performance liquid chromatography tandem mass spectrometry. Anal Chem 87, 9662-9670.
    1. Moya A & Ferrer M (2016) Functional redundancy-induced stability of gut microbiota subjected to disturbance. Trends Microbiol 24, 402-413.
    1. Comte J, Fauteux L & del Giorgio PA (2013) Links between metabolic plasticity and functional redundancy in freshwater bacterioplankton communities. Front Microbiol 4, 112.
    1. Burke C, Steinberg P, Rusch D, Kjelleberg S & Thomas T (2011) Bacterial community assembly based on functional genes rather than species. Proc Natl Acad Sci USA 108, 14288-14293.
    1. Ferrer M, Ruiz A, Lanza F, Haange S-B, Oberbach A, Till H, Bargiela R, Campoy C, Segura MT, Richter M et al. (2013) Microbiota from the distal guts of lean and obese adolescents exhibit partial functional redundancy besides clear differences in community structure. Environ Microbiol 15, 211-226.
    1. Rojo D, Gosalbes MJ, Ferrari R, Pérez-Cobas AE, Hernández E, Oltra R, Buesa J, Latorre A, Barbas C, Ferrer M et al. (2015) Clostridium difficile heterogeneously impacts intestinal community architecture but drives stable metabolome responses. ISME J 9, 2206-2220.
    1. Rojo D, Hevia A, Bargiela R, López P, Cuervo A, González S, Suárez A, Sánchez B, Martínez-Martínez M, Milani C et al. (2015) Ranking the impact of human health disorders on gut metabolism: systemic lupus erythematosus and obesity as study cases. Sci Rep 5, 8310.
    1. Wu GD, Compher C, Chen EZ, Smith SA, Shah RD, Bittinger K, Chehoud C, Albenberg LG, Nessel L, Gilroy E et al. (2016) Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 65, 63-72.
    1. Sze MA & Schloss PD (2016) Looking for a signal in the noise: revisiting obesity and the microbiome. MBio 7, e01018-16.
    1. Turnbaugh PJ & Gordon JI (2008) An invitation to the marriage of metagenomics and metabolomics. Cell 134, 708-713.
    1. Shao L, Ling Z, Chen D, Liu Y, Yang F & Li L (2018) Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study. Front Microbiol 9, 3166.
    1. Aron-Wisnewsky J, Prifti E, Belda E, Ichou F, Kayser BD, Dao MC, Verger EO, Hedjazi L, Bouillot J-L, Chevallier J-M et al. (2019) Major microbiota dysbiosis in severe obesity: fate after bariatric surgery. Gut 68, 70-82.
    1. Kurilshikov A, van den Munckhof ICL, Chen L, Bonder MJ, Schraa K, Rutten JHW, Riksen NP, de Graaf J, Oosting M, Sanna S et al. (2019) Gut microbial associations to plasma metabolites linked to cardiovascular phenotypes and risk. Circ Res 124, 1808-1820.
    1. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HMB, Coakley M, Lakshminarayanan B, O’Sullivan O et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178-184.
    1. Raman M, Ahmed I, Gillevet PM, Probert CS, Ratcliffe NM, Smith S, Greenwood R, Sikaroodi M, Lam V, Crotty P et al. (2013) Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 11, 868-875.e3.
    1. Karu N, Deng L, Slae M, Guo AC, Sajed T, Huynh H, Wine E & Wishart DS (2018) A review on human fecal metabolomics: methods, applications and the human fecal metabolome database. Anal Chim Acta 1030, 1-24.
    1. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC & Siuzdak G (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 106, 3698-3703.
    1. Bouatra S, Aziat F, Mandal R, Guo AC, Wilson MR, Knox C, Bjorndahl TC, Krishnamurthy R, Saleem F, Liu P et al. (2013) The human urine metabolome. PLoS ONE 8, e73076.
    1. Beger RD, Dunn W, Schmidt MA, Gross SS, Kirwan JA, Cascante M, Brennan L, Wishart DS, Oresic M, Hankemeier T et al. (2016) Metabolomics enables precision medicine: “A White Paper, Community Perspective”. Metabolomics 12, 149.
    1. Kieffer DA, Piccolo BD, Vaziri ND, Liu S, Lau WL, Khazaeli M, Nazertehrani S, Moore ME, Marco ML, Martin RJ et al. (2016) Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am J Physiol Renal Physiol 310, F857-F871.
    1. Benítez-Páez A, Kjølbaek L, Gómez Del Pulgar EM, Brahe LK, Astrup A, Matysik S, Schött H-F, Krautbauer S, Liebisch G, Boberska J et al. (2019) A multi-omics approach to unraveling the microbiome-mediated effects of arabinoxylan oligosaccharides in overweight humans. mSystems 4, e00209-19.
    1. Dao MC, Sokolovska N, Brazeilles R, Affeldt S, Pelloux V, Prifti E, Chilloux J, Verger EO, Kayser BD, Aron-Wisnewsky J et al. (2019) A data integration multi-omics approach to study calorie restriction-induced changes in insulin sensitivity. Front Physiol 9, 1958.
    1. Cui X, Ye L, Li J, Jin L, Wang W, Li S, Bao M, Wu S, Li L, Geng B et al. (2018) Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci Rep 8, 635.
    1. Ulaszewska MM, Weinert CH, Trimigno A, Portmann R, Andres Lacueva C, Badertscher R, Brennan L, Brunius C, Bub A, Capozzi F et al. (2019) Nutrimetabolomics: an integrative action for metabolomic analyses in human nutritional studies. Mol Nutr Food Res 63, e1800384.
    1. Lindon JC, Nicholson JK, Holmes E, Keun HC, Craig A, Pearce JTM, Bruce SJ, Hardy N, Sansone SA, Antti H et al. (2005) Summary recommendations for standardization and reporting of metabolic analyses. Nat Biotechnol 23, 833-838.
    1. Jenkins H, Hardy N, Beckmann M, Draper J, Smith AR, Taylor J, Fiehn O, Goodacre R, Bino RJ, Hall R et al. (2004) A proposed framework for the description of plant metabolomics experiments and their results. Nat Biotechnol 22, 1601-1606.
    1. Bino RJ, Hall RD, Fiehn O, Kopka J, Saito K, Draper J, Nikolau BJ, Mendes P, Roessner-Tunali U, Beale MH et al. (2004) Potential of metabolomics as a functional genomics tool. Trends Plant Sci 9, 418-425.
    1. Sumner LW, Amberg A, Barrett D, Beale MH, Beger R, Daykin CA, Fan TWM, Fiehn O, Goodacre R, Griffin JL et al. (2007) Proposed minimum reporting standards for chemical analysis: Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics 3, 211-221.
    1. Salek RM, Neumann S, Schober D, Hummel J, Billiau K, Kopka J, Correa E, Reijmers T, Rosato A, Tenori L et al. (2015) COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access. Metabolomics 11, 1587-1597.
    1. Vinaixa M, Schymanski EL, Neumann S, Navarro M, Salek RM & Yanes O (2016) Mass spectral databases for LC/MS- and GC/MS-based metabolomics: State of the field and future prospects. Trends Analyt Chem 78, 23-35.
    1. Misra BB, Langefeld CD, Olivier M & Cox LA (2019) Integrated omics: tools, advances and future approaches. J Mol Endocrinol R21-R45.
    1. Pinu FR, Beale DJ, Paten AM, Kouremenos K, Swarup S, Schirra HJ & Wishart D (2019) Systems biology and multi-omics integration: viewpoints from the metabolomics research community. Metabolites 9, 76.
    1. Chong J & Xia J (2017) Computational approaches for integrative analysis of the metabolome and microbiome. Metabolites 7, 62.

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