The role of the intestinal microbiota in type 1 diabetes mellitus

Nature Reviews Endocrinology

Volumn 12, Issue 3, 2016, Pages 154-167

  Knip, Mikael ^a   Siljander, Heli ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; BUTYRIC ACID; RNA 16S;

AUTOIMMUNE DISEASE; AUTOIMMUNITY; BACTERIUM CULTURE; BACTEROIDETES; DIET SUPPLEMENTATION; DISEASE COURSE; DNA SEQUENCE; ENVIRONMENTAL CHANGE; FECES MICROFLORA; HUMAN; IMMUNE SYSTEM; IMPAIRED GLUCOSE TOLERANCE; INSULIN DEPENDENT DIABETES MELLITUS; INTESTINE FLORA; LIFESTYLE MODIFICATION; METAGENOMICS; MICROBIAL DIVERSITY; MICROBIOME; MOLECULAR BIOLOGY; NEXT GENERATION SEQUENCING; NONHUMAN; OBSERVATIONAL STUDY; PRIORITY JOURNAL; REVIEW; SEX DIFFERENCE; ANIMAL; MICROBIOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; SEXUAL DEVELOPMENT;

ANIMALS; DIABETES MELLITUS, TYPE 1; GASTROINTESTINAL MICROBIOME; HUMANS; SEX CHARACTERISTICS;

EID: 84958116286     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2015.218     Document Type: Review

References (145)

1. Knip, M., et al. Environmental triggers and determinants of β cell autoimmunity and type 1 diabetes. Diabetes 54, S125-S136 (2005
2. Atkinson, M. A., Eisenbarth, G. S., & Michels, A. W. Type 1 diabetes. Lancet 383, 69-82 (2014
3. Knip, M. Pathogenesis of type 1 diabetes: implications for incidence trends. Horm. Res. Paediatr. 76 (Suppl. 1), 57-64 (2011
4. Harjutsalo, V., Sund, R., Knip, M., & Groop, P. H. Incidence of type 1 diabetes in Finland. JAMA 310, 427-428 (2013
5. Okada, H., Kuhn, C., Feillet, H., & Bach, J. F. The ?hygiene hypothesis? for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1-9 (2010
6. Kondrashova, A., Seiskari, T., Ilonen, J., Knip, M., & Hyöty, H. The ?hygiene hypothesis? and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS 121, 478-493 (2013
7. von Hertzen, L., et al. Helsinki alert of biodiversity and health. Ann. Med. 47, 218-225 (2015
8. Quercia, S., et al. From lifetime to evolution: timescales of human gut microbiota adaptation. Front. Microbiol. 5, 587 (2014
9. Hooper, L. V., Littman, D. R., & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268-1273 (2012
10. Qin, J., et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65 (2010
11. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K., & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220-230 (2012
12. Renz, H., Brandtzaeg, P., & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9-23 (2012
13. Sommer, F., & Bäckhed, F. The gut microbiota-masters of host development and physiology. Nat. Rev. Microbiol. 11, 227-238 (2013
14. Garn, H., Neves, J. F., Blumberg, R. S., & Renz, H. Effect of barrier microbes on organ based inflammation. J. Allergy Clin. Immunol. 131, 1465-1478 (2013
15. West, C. E., Jenmalm, M. C., & Prescott, S. L. The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin. Exp. Allergy 45, 43-53 (2015
16. Dunne, J. L., et al. The intestinal microbiome in type 1 diabetes. Clin. Exp. Immunol. 177, 30-37 (2014
17. West. C. E., et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J. Allergy Clin. Immunol. 135, 3-13 (2015
18. Costello, E. K., et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694-1697 (2009
19. Booijink, C. C., et al. High temporal and inter individual variation detected in the human ileal microbiota. Environ. Microbiol. 12, 3213-3227 (2010
20. El Aidy, S., van der Bogert, B., & Kleerebezem, M. The small intestine microbiota, nutritional modulation and relevance for health. Curr. Opin. Biotechnol. 32, 14-20 (2015
21. Franzosa, E. A., et al. Relating the metatranscriptome and metagenome of the human gut. Proc. Natl Acad. Sci. USA 111, E2329-E2338 (2014
22. Goodrich, J. K., et al. Conducting a microbiome study. Cell 158, 250-262 (2014
23. Fraher, M. H., O?Toole, P. W., & Quigley, E. M. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat. Rev. Gastroenterol. Hepatol. 9, 312-322 (2012
24. Jumpstart Consortium Human Microbiome Project Data Generation Working Group. Evaluation of 16S rDNA based community profiling for human microbiome research. PLoS ONE 7, e39315 (2012
25. Morgan, X. C., & Huttenhower, C. Meta?omic analytic techniques for studying the intestinal microbiome. Gastroenterology 146, 1437-1448 (2014
26. Doll, H. M., et al. Utilizing novel diversity estimators to quantify multiple dimensions of microbial biodiversity across domains. BMC Microbiol. 13, 259 (2013
27. Rajilic Stojanovic, M., et al. Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ. Microbiol. 11, 1736-1751 (2009
28. Lee, C. K., et al. Groundtruthing next gen sequencing for microbial ecology biases and errors in community structure estimates from PCR amplicon pyrosequencing. PLoS ONE 7, e44224 (2012
29. Langille, M. G., et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31, 814-821 (2013
30. Franzosa, E. A., et al. Sequencing and beyond: integrating molecular ?omics? for microbial community profiling. Nat. Rev. Microbiol. 13, 360-372 (2015
31. Caporaso, J. G., et al. QIIME allows analysis of high throughput community sequencing data. Nat. Methods 7, 335-336 (2010
32. Schloss, P. D., et al. Introducing mothur: open source, platform independent, community supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537-7541 (2009
33. DeSantis, T. Z., et al. Greengenes, a chimera checked 16S rRNA gene database and workbench compatible with ARB. Appl. Environ. Microbiol. 72, 5069-5072 (2006
34. Pruesse, E., et al. SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res. 35, 7188-7196 (2007
35. Sul, W. J., et al. Bacterial community comparisons by taxonomy supervised analysis independent of sequence alignment and clustering. Proc. Natl Acad. Sci. USA 108, 14637-14642 (2011
36. Lozupone, C. A., et al. Meta analyses of studies of the human microbiota. Genome Res. 23, 1704-1714 (2013
37. Yatsunenko, T., et al. Human gut microbiome viewed across age and geography. Nature 486, 222-227 (2012
38. Song, S. J., et al. Cohabiting family members share microbiota with one another and with their dogs. eLIFE 2, e00458 (2013
39. Koren, O., et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470-480 (2012
40. Aagaard, K., et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014
41. Matamoro, S., Gras Leguen, C., Le Vacon, F., Potel, G., & de La Cochetiere, M. F. Development of intestinal microbiota in infants and its impact on health. Trends Microbiol. 21, 167-173 (2013
42. Mackie, R. I., Sghir, A., & Gaskins, H. R. Developmental microbial ecology of the neonatal gastrointestinal tract. Am. J. Clin. Nutr. 69, S1035-S1045 (1999
43. Khafipour, E., & Ghia, J. E. Mode of delivery and inflammatory disorders. J. Immunol. Clin. Res. 1, 1004 (2013
44. Dominguez Bello, M. G., Blaser, M. J., Ley, R. E., & Knight, R. Development of the human gastrointestinal microbiota and insights from high throughput sequencing. Gastroenterology 140, 1713-1719 (2011
45. Dominguez Bello, M. G., et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971-11975 (2010
46. Biasucci, G., Benenati, B., Morelli, L., Bessi, E., & Boehm, G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J. Nutr. 138, 1796S-1800S (2008
47. Jakobsson, H. E., et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonization and reduced Th1 responses in infants delivered by caesarean section. Gut 63, 559-566 (2014
48. Penders, J., et al.Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood. J. Allergy Clin. Immunol. 132, 601-607 (2013
49. Neu, J., & Rushing, J. Caesarean versus vaginal delivery: long term infant outcomes and the hygiene hypothesis. Clin. Perinatol. 38, 321-331 (2011
50. Grönlund, M. M., Grzeskowiak, L., Isolauri, E., & Salminen, S. Influence of mother?s intestinal microbiota on gut colonization in the infant. Gut Microbes 2, 227-233 (2011
51. Ege, M. J., et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701-709 (2011
52. Sjögren, Y. M., Jenmalm, M. C., Böttcher, M. F., Björkstén, B., & Sverremark Ekström, E. Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin. Exp. Allergy 39, 518-526 (2009
53. Hanski, I., et al. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc. Natl Acad. Sci. USA 109, 8334-8339 (2012
54. Hollister, E. B., Gao, C., & Versalovic, J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology 146, 1449-1458 (2014
55. Borre, Y. E., Moloney, R. D., Clarke, G., Dinan, T. G., & Cryan, J. F. The impact of microbiota on brain and behavior: mechanisms and therapeutic potential. Adv. Exp. Med. Biol. 817, 373-403 (2014
56. Jeffery, I. B., et al. An irritable bowel syndrome subtype defined by species specific alterations in faecal microbiota. Gut 61, 997-1006 (2012
57. Stark, P. L., & Lee, A. The microbial ecology of the large bowel of breast fed and formula fed infants during the first year. J. Med. Microbiol. 15, 189-203 (1982
58. Jost, T., Lacroix, C., Braegger, C. P., Rochat, F., & Chassard, C. Vertical mother-neonate transfer of maternal gut bacteria via breastfeeding. Environ. Microbiol. 3, 203-220 (2013
59. Arumugam, M., et al. Enterotypes of the human gut microbiome. Nature 473, 174-180 (2011
60. Kramer, M. S. Breastfeeding and allergy: the evidence. Ann. Nutr. Metab. 59 (Suppl. 1), 20-26 (2011
61. Elenberg, Y., & Shaoul, R. The role of infant nutrition in the prevention of future disease. Front. Pediatr. 2, 73 (2014
62. Robinson, S., & Fall, C. Infant nutrition and later health: a review of current evidence. Nutrients 4, 859-874 (2012
63. Ballard, O., & Morrow, A. L. Human milk composition: nutrients and bioactive factors. Pediatr. Clin. North Am. 60, 49-74 (2013
64. Donnet Hughes, A., et al. Potential role of the intestinal microbiota of the mother in neonatal immune education. Proc. Nutr. Soc. 69, 407-415 (2010
65. Zivkovic, A. M., German, J. B., Lebrilla, C. B., & Mills, D. A. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc. Natl Acad. Sci. USA 108, 4653-4658 (2011
66. Garrido, D., Barile, D., & Mills, D. A. A molecular basis for bifidobacterial enrichment in the infant gastrointestinal tract. Adv. Nutr. 3, 415S-421S (2012
67. De Filippo, C., et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691-14696 (2010
68. Lee, S., Sung, J., Lee, J., & Ko, G. Comparison of the gut microbiotas of healthy adult twins living in South Korea and the United States. Appl. Environ. Microbiol. 77, 7433-7437 (2011
69. Maurice, C. F., Haiser, H. J., & Turnbaugh, P. J. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39-50 (2013
70. Vanhoutte, T., Huys, G., Brandt, E., & Swings, J. Temporal stability analysis of the microbiota in human feces by denaturing gradient gel electrophoresis using universal and group specific 16S rRNA gene primers. FEMS Microbiol. Ecol. 48, 437-446 (2004
71. Tannock, G. W., et al. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20. Appl. Environ. Microbiol. 66, 2578-2588 (2000
72. Zhao, J., Murray, S., & Lipuma, J. J. Modeling the impact of antibiotic exposure on human microbiota. Sci. Rep. 4, 4345 (2014
73. Kemppainen, K. M., et al. Early childhood gut microbiomes show strong geographical differences among subjects at high risk for type 1 diabetes. Diabetes Care 38, 329-332 (2015
74. The TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 249-348 (2007
75. Wu, G. D., et al. Linking long term dietary patterns with gut microbial enterotypes. Science 334, 105-108 (2011
76. Ottman, N., Smidt, H., de Vos, W. M., & Belzer, C. The function of our microbiota: who is out there and what do they do? Front. Cell. Infect. Microbiol. 2, 104 (2012
77. Vaarala, O. Is the origin of type 1 diabetes in the gut. Immunol. Cell Biol. 90, 271-278 (2012
78. Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777-780 (2001
79. Gale, E. A. M., & Gillespie, K. M. Diabetes and gender. Diabetologia 44, 3-15 (2001
80. Mueller, S., et al. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross sectional study. Appl. Environ. Microbiol. 72, 1027-1033 (2006
81. Markle, J. G. M., et al. Sex differences in the gut microbiome drive hormone dependent regulation of autoimmunity. Science 339, 1084-1088 (2013
82. Yurkovetskiy, L., et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400-412 (2013
83. Serrezze, D. V., & Chen, Y. G. Of mice and men: use of animal models to identify possible interventions for the prevention of autoimmune diabetes in humans. Trends Immunol. 26, 603-607 (2005
84. Gonzalez, A., et al. Genetic control of diabetes progression. Immunity 7, 873-883 (1997
85. Wong, F. S., et al. Identification of an MHC class I restricted autoantigen in type 1 diabetes by screening an organ specific cDNA library. Nat. Med. 5, 1026-1031 (1999
86. Tisch, R., et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non obese diabetic mice. Nature 366, 72-75 (1993
87. Garchon, H. J., Bedossa, P., Eloy, L., & Bach, J. F. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non obese diabetic mice. Nature 353, 260-262 (1991
88. Reddy, S., Bibby, N. J., & Elliott, R. B. Ontogeny of islet cell antibodies, insulin autoantibodies and insulitis in the non obese diabetic mouse. Diabetologia 31, 322-328 (1988
89. Shimada, A., Charlton, B., Taylor Edwards, C., & Fathman, C. G. β cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. Diabetes 45, 1063-1067 (1996
90. Greiner, T. U., et al. The gut microbiota modulates glycemic control and the serum metabolite profile in non obese diabetic mice. PLoS ONE 9, e110359 (2014
91. Wen, L., et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109-1113 (2008
92. Peng, J., et al. Long term effect of gut microbiota transfer on diabetes development. J. Autoimmun. 53, 85-94 (2014
93. King, C., & Sarvetnick, N. The incidence of type 1 diabetes in NOD mice is modulated by restricted flora not germ free conditions. PLoS ONE 6, e17049 (2011
94. Kriegel, M. A., et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 108, 11548-11553 (2011
95. Hansen, C. H., et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55, 2285-2294 (2012
96. Alam, C., et al. Inflammatory tendencies and overproduction of IL 17 in the colon of young NOD mice are counteracted with diet change. Diabetes 59, 2237-2246 (2010
97. Emani, R., et al. Peritoneal cavity is a route for gut derived microbial signals to promote autoimmunity in non obese diabetic mice. Scand. J. Immunol. 81, 102-109 (2015
98. Hansen, C. H., et al. A maternal gluten free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes 63, 2821-2832 (2014
99. Marietta, E. V., et al. Low incidence of spontaneous type 1 diabetes in non obese diabetic mice raised on gluten free diets is associated with changes in the intestinal microbiome. PLoS ONE 8, e78687 (2013
100. Toivonen, R. K., et al. Fermentable fibres condition colon microbiota and promote diabetogenesis in NOD mice. Diabetologia 57, 2183-2192 (2014
101. Wolf, K. J., et al. Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice. J. Histochem. Cytochem. 62, 237-250 (2014
102. Roep, B. O., & Atkinson, M. Animal models have little to teach us about type 1 diabetes: 1. In support of this proposal. Diabetologia 47, 1650-1656 (2004
103. Kimpimäki, T., et al. The first signs of β cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study. J. Clin. Endocrinol. Metab. 86, 4782-4788 (2001
104. Parikka, V., et al. Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia 55, 1926-1936 (2012
105. Krischer, J. P., et al. The 6 year incidence of diabetes associated autoantibodies in genetically at risk children: the TEDDY study. Diabetologia 58, 980-987 (2015
106. Kostic, A. D., et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260-273 (2015
107. Giongo, A., et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82-91 (2011
108. Kupila, A., et al. Feasibility of genetic and immunological prediction of type 1 diabetes in a population based birth cohort. Diabetologia 44, 290-297 (2001
109. Brown, C. T., et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE 6, e25792 (2011
110. Knip, M., et al. Dietary intervention in infancy and later signs of beta cell autoimmunity. N. Engl. J. Med. 363, 1900-1908 (2010
111. Vaarala, O., et al. Removal of bovine insulin from cow?s milk formula and early initiation of beta cell autoimmunity. Arch. Pediatr. Adolesc. Med. 166, 608-614 (2012
112. de Goffau, M. C., et al. Fecal microbiota composition differs between children with β cell autoimmunity and those without. Diabetes 62, 1238-1244 (2013
113. Hummel, S., Pflüger, M., Hummel, M., Bonifacio, E., & Ziegler, A. G. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34, 1301-1305 (2011).
114. Endesfelder, D., et al. Compromised gut microbiota networks in children with anti islet cell autoimmunity. Diabetes 63, 2006-2014 (2014
115. Davis Richardson, A., et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front. Microbiol. 5, 678 (2014
116. Leonard, M. T., et al. The methylome of the gut microbiome: disparate Dam methylation patterns in intestinal Bacteroides dorei. Front. Microbiol. 5, 361 (2014
117. Kallionpää, H., et al. The standard of hygiene and immune adaptation in newborn infants. Clin. Immunol. 155, 136-147 (2014
118. Alkanani, A. K., et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes 64, 3510-3520 (2015
119. Murri, M., et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case control study. BMC Med. 11, 46 (2013
120. Mejía León, M. E., Petrosino, J. F., Ajami, N. J., Domínguez Bello, M. G., & de la Barca, A. M. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci. Rep. 4, 3814 (2014
121. Hague, A., Butt, A. J., & Paraskeva, C. The role of butyrate in human colonic epithelial cells: an energy source or inducer of differentiation and apoptosis? Proc. Nutr. Soc. 55, 937-943 (1996
122. Peng, L., Li, Z. R., Green, R. S., Holzman, I. R., & Lin, J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP activated protein kinase in Caco 2 cell monolayers. J. Nutr. 139, 1619-1625 (2009
123. Vaarala, O., Atkinson, M. A., & Neu, J. The ?perfect storm? for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 57, 2555-2562 (2008
124. Hansen, C. H., et al. Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice. J. Immunol. 193, 1213-1222 (2014
125. de Goffau, M. C., et al. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia 57, 1569-1577 (2014
126. Patil, K. R., et al. Taxonomic metagenome sequence assignment with structured output models. Nat. Methods 8, 191-192 (2011
127. Huson, D. H., Auch, A. F., Qi, J., & Schuster, S. C. MEGAN analysis of metagenomic data. Genome Res. 17, 377-386 (2007
128. Segata, N., et al. Metagenomic microbial community profiling using unique clade specific marker genes. Nat. Methods 9, 811-814 (2012
129. Martin, J., et al. Optimizing read mapping to reference genomes to determine composition and species prevalence in microbial communities. PLoS ONE 7, e36427 (2012
130. Luo, C., et al. Strain profiling and genotyping of microbial communities from metagenomic sequence data. Nat. Biotechnol. 33, 1045-1052 (2015
131. Li, R., et al. De novo assembly of human genomes with massively parallel short read sequencing. Genome Res. 20, 265-272 (2010
132. Zerbino, D. R., & Birney, E. Velvet: algorithms for de novo short read assembly using de Bruijn graphs. Genome Res. 18, 821-829 (2008
133. Namiki, T., Hachiya, T., Tanaka, H., & Sakakibara, Y. MetaVelvet: an extension of Velvet assembler to de novo metagenome assembly from short sequence reads. Nucleic Acids Res. 40, e155 (2012
134. Kultima, J. R., et al. MOCAT: a metagenomics assembly angene prediction toolkit. PLoS ONE 7, e47656 (2012
135. Karlsson, F. H., et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99-103 (2013
136. Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M., & Hirakawa, M. KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res. 38, D355-D360 (2010
137. Tatusov, R. L., et al. The COG database: an updated version includes eukaryotes. BMC Bioinformatics 4, 41 (2003
138. Punta, M., et al. The Pfam protein families database. Nucleic Acids Res. 40, D290-D301 (2012
139. Cantarel, B. L., et al. The Carbohydrate Active EnZymes database (CAZy): an expert resource for Glycogenomics. Nucleic Acids Res. 37, D233-238 (2009
140. Arumugam, M., Harrington, E. D., Foerstner, K. U., Raes, J., & Bork, P. Smash Community: a metagenomic annotation and analysis tool. Bioinformatics 26, 2977-2978 (2010
141. Abubucker, S., et al. Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput. Biol. 8, e1002358 (2012
142. Sanli, K., Karlsson, F. H., Nookaew, I., & Nielsen, J. FANTOM: functional and taxonomic analysis of metagenomes. BMC Bioinformatics 14, 38 (2013
143. Seshadri, R., Kravitz, S. A., Smarr, L., Gilna, P., & Frazier, M. CAMERA: a community resource for metagenomics. PLoS Biol. 5, e75 (2007
144. Markowitz, V. M., et al. IMG/M: a data management and analysis system for metagenomes. Nucleic Acids Res. 36, D534-D538 (2008
145. Meyer, F., et al. The metagenomics RAST server-A public resource for the automatic phylogenetic and functional analysis of metagenomes. BMC Bioinformatics 9, 386 (2008