Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome

Microbiome - Tập 4 - Trang 1-12 - 2016
Ludovic Giloteaux1, Julia K. Goodrich1,2, William A. Walters1,2, Susan M. Levine3, Ruth E. Ley1,2, Maureen R. Hanson1
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, USA
2Department of Microbiology, Cornell University, Ithaca, USA
3Private Practice, New York, USA

Tóm tắt

Gastrointestinal disturbances are among symptoms commonly reported by individuals diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, whether ME/CFS is associated with an altered microbiome has remained uncertain. Here, we profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39). We also examined a set of inflammatory markers in blood: C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14). We observed elevated levels of some blood markers for microbial translocation in ME/CFS patients; levels of LPS, LBP, and sCD14 were elevated in ME/CFS subjects. Levels of LBP correlated with LPS and sCD14 and LPS levels correlated with sCD14. Through deep sequencing of bacterial rRNA markers, we identified differences between the gut microbiomes of healthy individuals and patients with ME/CFS. We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum. In the patient cohort, we find less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory. Using a machine learning approach trained on the data obtained from 16S rRNA and inflammatory markers, individuals were classified correctly as ME/CFS with a cross-validation accuracy of 82.93 %. Our results indicate dysbiosis of the gut microbiota in this disease and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in ME/CFS.

Tài liệu tham khảo

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–9.

Riedl A, Schmidtmann M, Stengel A, Goebel M, Wisser AS, Klapp BF, et al. Somatic comorbidities of irritable bowel syndrome: a systematic analysis. J Psychosom Res. 2008;64(6):573–82.

Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122(4):1140–56.

Wojczynski MK, North KE, Pedersen NL, Sullivan PF. Irritable bowel syndrome: a co-twin control analysis. Am J Gastroenterol. 2007;102(10):2220–9.

Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. 2000;160(2):221–7.

Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis. 1991;13 Suppl 1:S8–11.

Jones JF, Nisenbaum R, Reeves WC. Medication use by persons with chronic fatigue syndrome: results of a randomized telephone survey in Wichita, Kansas. Health Qual Life Outcomes. 2003;1:74.

Borody TJ, Nowak A, Finlayson S. The GI microbiome and its role in chronic fatigue syndrome: a summary of bacteriotherapy. ACNEM J. 2012;31(3):3–8.

Sullivan A, Nord CE, Evengard B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J. 2009;8:4.

Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009;1(1):6.

Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, Lewis DP, McGregor N, et al. Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009;23(4):621–8.

Fremont M, Coomans D, Massart S, De Meirleir K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 2013;22:50–6.

Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007;104(34):13780–5.

Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.

Komaroff AL, Buchwald DS. Chronic fatigue syndrome: an update. Annu Rev Med. 1998;49:1–13.

Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, et al. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016;21(2):261–9.

Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015;1(1).

Vyboh K, Jenabian MA, Mehraj V, Routy JP. HIV and the gut microbiota, partners in crime: breaking the vicious cycle to unearth new therapeutic targets. J Immunol Res. 2015;2015:614127.

Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007;99(1–3):237–40.

Schumann RR. Function of lipopolysaccharide (LPS)-binding protein (LBP) and CD14, the receptor for LPS/LBP complexes: a short review. Res Immunol. 1992;143(1):11–5.

Pelsers MMAL, Hermens WT, Glatz JFC. Fatty acid-binding proteins as plasma markers of tissue injury. Clinica Chimica Acta. 2005;352(1–2):15–35.

Medicine II. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, D.C: The National Academies Press; 2015.

Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57(2):601–9.

Openshaw PJ. Crossing barriers: infections of the lung and the gut. Mucosal Immunol. 2009;2(2):100–2.

Wellmann W, Fink PC, Benner F, Schmidt FW. Endotoxaemia in active Crohn’s disease. Treatment with whole gut irrigation and 5-aminosalicylic acid. Gut. 1986;27(7):814–20.

Wyatt J, Vogelsang H, Hubl W, Waldhoer T, Lochs H. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet. 1993;341(8858):1437–9.

Anas AA, Hovius JW, van 't Veer C, van der Poll T, de Vos AF. Role of CD14 in a mouse model of acute lung inflammation induced by different lipopolysaccharide chemotypes. PLoS One. 2010;5(4):e10183.

Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, Asadullah K, et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J Immunol. 2007;178(9):5973–81.

Wan Y, Freeswick PD, Khemlani LS, Kispert PH, Wang SC, Su GL, et al. Role of lipopolysaccharide (LPS), interleukin-1, interleukin-6, tumor necrosis factor, and dexamethasone in regulation of LPS-binding protein expression in normal hepatocytes and hepatocytes from LPS-treated rats. Infect Immun. 1995;63(7):2435–42.

Butt HL, Dunstan R, N.R. M, T. R. Bacterial colonosis in patients with persistent fatigue. In Proceedings of the AHMF international clinical and scientific conference Sydney, Australia: AHMF; 2001.

Brodie EL, Desantis TZ, Joyner DC, Baek SM, Larsen JT, Andersen GL, et al. Application of a high-density oligonucleotide microarray approach to study bacterial population dynamics during uranium reduction and reoxidation. Appl Environ Microbiol. 2006;72(9):6288–98.

Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT, Schmidt TM, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis. 2008;197(3):435–8.

Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139(6):1844–54. e1.

McMurtry VE, Gupta RW, Tran L, Blanchard EE, Penn D, Taylor CM, et al. Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. Microbiome. 2015;3:11.

Fujimoto T, Imaeda H, Takahashi K, Kasumi E, Bamba S, Fujiyama Y, et al. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn’s disease. J Gastroenterol Hepatol. 2013;28(4):613–9.

Hippe B, Remely M, Bartosiewicz N, Riedel M, Nichterl C, Schatz L, et al. Abundance and diversity of GI microbiota rather than IgG4 levels correlate with abdominal inconvenience and gut permeability in consumers claiming food intolerances. Endocr Metab Immune Disord Drug Targets. 2014;14(1):67–75.

Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731–6.

Martinez-Medina M, Aldeguer X, Gonzalez-Huix F, Acero D, Garcia-Gil LJ. Abnormal microbiota composition in the ileocolonic mucosa of Crohn’s disease patients as revealed by polymerase chain reaction-denaturing gradient gel electrophoresis. Inflamm Bowel Dis. 2006;12(12):1136–45.

Sartor RB. Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation. Mucosal Immunol. 2011;4(2):127–32.

Sartor RB. Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology. 2010;139(6):1816–9.

Davies CA, Rocks SA, O'Shaughnessy MC, Perrett D, Winyard PG. Analysis of nitrite and nitrate in the study of inflammation. Methods Mol Biol. 2003;225:305–20.

Thiennimitr P, Winter SE, Winter MG, Xavier MN, Tolstikov V, Huseby DL, et al. Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc Natl Acad Sci U S A. 2011;108(42):17480–5.

Winter SE, Lopez CA, Baumler AJ. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 2013;14(4):319–27.

Winter SE, Winter MG, Xavier MN, Thiennimitr P, Poon V, Keestra AM, et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science. 2013;339(6120):708–11.

Quevrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut. 2016;65(3):415–25.

Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63(8):1275–83.

Pozuelo M, Panda S, Santiago A, Mendez S, Accarino A, Santos J, et al. Reduction of butyrate- and methane-producing microorganisms in patients with irritable bowel syndrome. Sci Rep. 2015;5:12693.

Varela E, Manichanh C, Gallart M, Torrejon A, Borruel N, Casellas F, et al. Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Aliment Pharmacol Ther. 2013;38(2):151–61.

Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009;15(8):1183–9.

Saemann MD, Bohmig GA, Osterreicher CH, Burtscher H, Parolini O, Diakos C, et al. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J. 2000;14(15):2380–2.

Segain JP, Raingeard de la Bletiere D, Bourreille A, Leray V, Gervois N, Rosales C, et al. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease. Gut. 2000;47(3):397–403.

Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–76.

Kassinen A, Krogius-Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133(1):24–33.

Tana C, Umesaki Y, Imaoka A, Handa T, Kanazawa M, Fukudo S. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Motil. 2010;22(5):512–9. e114-5.

Malinen E, Rinttila T, Kajander K, Matto J, Kassinen A, Krogius L, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100(2):373–82.

Matto J, Maunuksela L, Kajander K, Palva A, Korpela R, Kassinen A, et al. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome—a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol. 2005;43(2):213–22.

Maukonen J, Satokari R, Matto J, Soderlund H, Mattila-Sandholm T, Saarela M. Prevalence and temporal stability of selected clostridial groups in irritable bowel syndrome in relation to predominant faecal bacteria. J Med Microbiol. 2006;55(Pt 5):625–33.

Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002;122(1):44–54.

Wu X, Ma C, Han L, Nawaz M, Gao F, Zhang X, et al. Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr Microbiol. 2010;61(1):69–78.

Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O'Neil DA, et al. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut. 2005;54(2):242–9.

Groeger D, O'Mahony L, Murphy EF, Bourke JF, Dinan TG, Kiely B, et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013;4(4):325–39.

Knights D, Costello EK, Knight R. Supervised classification of human microbiota. FEMS Microbiol Rev. 2011;35(2):343–59.

Papa E, Docktor M, Smillie C, Weber S, Preheim SP, Gevers D, et al. Non-invasive mapping of the gastrointestinal microbiota identifies children with inflammatory bowel disease. PLoS One. 2012;7(6):e39242.

Walters WA, Xu Z, Knight R. Meta-analyses of human gut microbes associated with obesity and IBD. FEBS Lett. 2014;588(22):4223–33.

Bell DS. The doctor’s guide to chronic fatigue syndrome. Reading, Mass: Addison-Wesley; 1995.

Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika. 1965;52(3–4):591–611.

Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4516–22.

Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789–99.

Chao A. Non-parametric estimation of the number of classes in a population. Scandinavian Journal of Statistics. 1984;11:265–70.

Shannon CE. A mathematical theory of communication. Bell SystTech J. 1948;27:379–423.

Faith DP. Conservation evaluation and phylogenetic diversity. Biol Conserv. 1992;61:1–10.

Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):R60.

Liaw A, Wiener M. Classification and regression by randomForest. R News. 2002;2:18–22.

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