1887

Abstract

There is a growing appreciation that microbiota composition can significantly affect host health and play a role in disease onset and progression. This study assessed the impact of streptozotocin (STZ)-induced type-1-diabetes (T1D) on intestinal microbiota composition and diversity in Sprague–Dawley rats, compared with healthy controls over time. T1D was induced by injection of a single dose (60 mg STZ kg) of STZ, administered via the intraperitoneal cavity. Total DNA was isolated from faecal pellets at weeks 0 (pre-STZ injection), 1, 2 and 4 and from caecal content at week 5 from both healthy and T1D groups. High-throughput 16S rRNA sequencing was employed to investigate intestinal microbiota composition. The data revealed that although intestinal microbiota composition between the groups was similar at week 0, a dramatic impact of T1D development on the microbiota was apparent post-STZ injection and for up to 5 weeks. Most notably, T1D onset was associated with a shift in the  :  ratio (<0.05), while at the genus level, increased proportions of lactic acid producing bacteria such as and were associated with the later stages of T1D progression (<0.05). Coincidently, T1D increased caecal lactate levels (<0.05). Microbial diversity was also reduced following T1D (<0.05). Principle co-ordinate analyses demonstrated temporal clustering in T1D and control groups with distinct separation between groups. The results provide a comprehensive account of how T1D is associated with an altered intestinal microbiota composition and reduced microbial diversity over time.

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2015-01-01
2024-03-28
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References

  1. Adolphe A. B., Glasofer E. D., Troetel W. M., Ziegenfuss J., Stambaugh J. E., Weiss A. J., Manthei R. W. 1975; Fate of streptozotocin (NSC-85998)in patients with advanced cancer. Cancer Chemother Rep 59:547–556[PubMed]
    [Google Scholar]
  2. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. 1997; Gapped blast and psi-blast: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402 [View Article][PubMed]
    [Google Scholar]
  3. Atkinson M. A., Chervonsky A. 2012; Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease. Diabetologia 55:2868–2877 [View Article][PubMed]
    [Google Scholar]
  4. Barcelo A., Claustre J., Moro F., Chayvialle J. A., Cuber J. C., Plaisancié P. 2000; Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46:218–224 [View Article][PubMed]
    [Google Scholar]
  5. Bellavia M., Tomasello G., Romeo M., Damiani P., Lo Monte A. I., Lozio L., Campanella C., Marino Gammazza A., Rappa F.& other authors ( 2013; Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis. Med Microbiol Immunol 202:393–406 [View Article][PubMed]
    [Google Scholar]
  6. Boerner B. P., Sarvetnick N. E. 2011; Type 1 diabetes: role of intestinal microbiome in humans and mice. Ann N Y Acad Sci 1243:103–118 [View Article][PubMed]
    [Google Scholar]
  7. Brown C. T., Davis-Richardson A. G., Giongo A., Gano K. A., Crabb D. B., Mukherjee N., Casella G., Drew J. C., Ilonen J.& other authors ( 2011; Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE 6:e25792 [View Article][PubMed]
    [Google Scholar]
  8. Brugman S., Klatter F. A., Visser J. T., Wildeboer-Veloo A. C., Harmsen H. J., Rozing J., Bos N. A. 2006; Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?. Diabetologia 49:2105–2108 [View Article][PubMed]
    [Google Scholar]
  9. Burger-van Paassen N., Vincent A., Puiman P. J., van der Sluis M., Bouma J., Boehm G., van Goudoever J. B., van Seuningen I., Renes I. B. 2009; The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J 420:211–219 [View Article][PubMed]
    [Google Scholar]
  10. Calcinaro F., Dionisi S., Marinaro M., Candeloro P., Bonato V., Marzotti S., Corneli R. B., Ferretti E., Gulino A.& other authors ( 2005; Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48:1565–1575 [View Article][PubMed]
    [Google Scholar]
  11. Caporaso J. G., Kuczynski J., Stombaugh J., Bittinger K., Bushman F. D., Costello E. K., Fierer N., Peña A. G., Goodrich J. K.& other authors ( 2010; qiime allows analysis of high-throughput community sequencing data. Nat Methods 7:335–336 [View Article][PubMed]
    [Google Scholar]
  12. Cardwell C. R., Stene L. C., Joner G., Cinek O., Svensson J., Goldacre M. J., Parslow R. C., Pozzilli P., Brigis G.& other authors ( 2008; Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 51:726–735 [View Article][PubMed]
    [Google Scholar]
  13. Carratù R., Secondulfo M., de Magistris L., Iafusco D., Urio A., Carbone M. G., Pontoni G., Cartenì M., Prisco F. 1999; Altered intestinal permeability to mannitol in diabetes mellitus type I. J Pediatr Gastroenterol Nutr 28:264–269 [View Article][PubMed]
    [Google Scholar]
  14. Chen V. B., Davis I. W., Richardson D. C. 2009; king (Kinemage, Next Generation): a versatile interactive molecular and scientific visualization program. Protein Sci 18:2403–2409 [View Article][PubMed]
    [Google Scholar]
  15. de Goffau M. C., Luopajärvi K., Knip M., Ilonen J., Ruohtula T., Härkönen T., Orivuori L., Hakala S., Welling G. W.& other authors ( 2013; Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 62:1238–1244 [View Article][PubMed]
    [Google Scholar]
  16. Dominguez-Bello M. G., Costello E. K., Contreras M., Magris M., Hidalgo G., Fierer N., Knight R. 2010; Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107:11971–11975 [View Article][PubMed]
    [Google Scholar]
  17. Duffy L. C. 2000; Interactions mediating bacterial translocation in the immature intestine. J Nutr 130:Suppl432S–436S[PubMed]
    [Google Scholar]
  18. Ehehalt S., Dietz K., Willasch A. M., Neu A.Baden-Württemberg Diabetes Incidence Registry (DIARY) Group 2010; Epidemiological perspectives on type 1 diabetes in childhood and adolescence in Germany: 20 years of the Baden-Württemberg Diabetes Incidence Registry (DIARY). Diabetes Care 33:338–340 [View Article][PubMed]
    [Google Scholar]
  19. Finnie I. A., Dwarakanath A. D., Taylor B. A., Rhodes J. M. 1995; Colonic mucin synthesis is increased by sodium butyrate. Gut 36:93–99 [View Article][PubMed]
    [Google Scholar]
  20. Gibson G. R., Willems A., Reading S., Collins M. D. 1996; Fermentation of non-digestible oligosaccharides by human colonic bacteria. Proc Nutr Soc 55:899–912 [View Article][PubMed]
    [Google Scholar]
  21. Giongo A., Gano K. A., Crabb D. B., Mukherjee N., Novelo L. L., Casella G., Drew J. C., Ilonen J., Knip M.& other authors ( 2011; Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 5:82–91 [View Article][PubMed]
    [Google Scholar]
  22. Greenblum S., Turnbaugh P. J., Borenstein E. 2012; Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A 109:594–599 [View Article][PubMed]
    [Google Scholar]
  23. Haas B. J., Gevers D., Earl A. M., Feldgarden M., Ward D. V., Giannoukos G., Ciulla D., Tabbaa D., Highlander S. K.& other authors ( 2011; Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res 21:494–504 [View Article][PubMed]
    [Google Scholar]
  24. Hamer H. M., Jonkers D., Venema K., Vanhoutvin S., Troost F. J., Brummer R. J. 2008; Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27:104–119 [View Article][PubMed]
    [Google Scholar]
  25. Huson D. H., Auch A. F., Qi J., Schuster S. C. 2007; megan analysis of metagenomic data. Genome Res 17:377–386 [View Article][PubMed]
    [Google Scholar]
  26. Karunanayake E. H., Hearse D. J., Mellows G. 1976; Streptozotocin: its excretion and metabolism in the rat. Diabetologia 12:483–488 [View Article][PubMed]
    [Google Scholar]
  27. King C., Sarvetnick N. 2011; The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS ONE 6:e17049 [View Article][PubMed]
    [Google Scholar]
  28. Kleessen B., Blaut M. 2005; Modulation of gut mucosal biofilms. Br J Nutr 93:Suppl. 1S35–S40 [View Article][PubMed]
    [Google Scholar]
  29. Kleessen B., Hartmann L., Blaut M. 2003; Fructans in the diet cause alterations of intestinal mucosal architecture, released mucins and mucosa-associated bifidobacteria in gnotobiotic rats. Br J Nutr 89:597–606 [View Article][PubMed]
    [Google Scholar]
  30. Klimesova K., Kverka M., Zakostelska Z., Hudcovic T., Hrncir T., Stepankova R., Rossmann P., Ridl J., Kostovcik M.& other authors ( 2013; Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm Bowel Dis 19:1266–1277 [View Article][PubMed]
    [Google Scholar]
  31. Knip M., Virtanen S. M., Becker D., Dupré J., Krischer J. P., Åkerblom H. K.TRIGR Study Group 2011; Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). Am J Clin Nutr 94:Suppl.1814S–1820S [View Article][PubMed]
    [Google Scholar]
  32. Kruskal W. H., Wallis W. A. 1952; Use of ranks in one-criterion variance analysis. J Am Stat Assoc 47:583–621 [View Article]
    [Google Scholar]
  33. Kuitunen M., Saukkonen T., Ilonen J., Akerblom H. K., Savilahti E. 2002; Intestinal permeability to mannitol and lactulose in children with type 1 diabetes with the HLA-DQB1*02 allele. Autoimmunity 35:365–368 [View Article][PubMed]
    [Google Scholar]
  34. Lenzen S. 2008; The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226 [View Article][PubMed]
    [Google Scholar]
  35. Ley R. E., Bäckhed F., Turnbaugh P., Lozupone C. A., Knight R. D., Gordon J. I. 2005; Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102:11070–11075 [View Article][PubMed]
    [Google Scholar]
  36. Ley R. E., Turnbaugh P. J., Klein S., Gordon J. I. 2006; Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023 [View Article][PubMed]
    [Google Scholar]
  37. Liévin V., Peiffer I., Hudault S., Rochat F., Brassart D., Neeser J. R., Servin A. L. 2000; Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut 47:646–652 [View Article][PubMed]
    [Google Scholar]
  38. Liou A. P., Paziuk M., Luevano J. M. Jr, Machineni S., Turnbaugh P. J., Kaplan L. M. 2013; Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 5:178ra41 [View Article][PubMed]
    [Google Scholar]
  39. Louis P., Flint H. J. 2009; Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett 294:1–8 [View Article][PubMed]
    [Google Scholar]
  40. Manichanh C., Rigottier-Gois L., Bonnaud E., Gloux K., Pelletier E., Frangeul L., Nalin R., Jarrin C., Chardon P.& other authors ( 2006; Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55:205–211 [View Article][PubMed]
    [Google Scholar]
  41. Murphy E. F., Cotter P. D., Healy S., Marques T. M., O’Sullivan O., Fouhy F., Clarke S. F., O’Toole P. W., Quigley E. M.& other authors ( 2010; Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 59:1635–1642 [View Article][PubMed]
    [Google Scholar]
  42. Murri M., Leiva I., Gomez-Zumaquero J. M., Tinahones F. J., Cardona F., Soriguer F., Queipo-Ortuño M. I. 2013; Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med 11:46 [View Article][PubMed]
    [Google Scholar]
  43. Noble J. A., Erlich H. A. 2012; Genetics of type 1 diabetes. Cold Spring Harb Perspect Med 2:a007732 [View Article][PubMed]
    [Google Scholar]
  44. Notkins A. L., Lernmark A. 2001; Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 108:1247–1252 [View Article][PubMed]
    [Google Scholar]
  45. O’Toole P. W., Claesson M. J. 2010; Gut microbiota: changes throughout the lifespan from infancy to elderly. Int Dairy J 20:281–291 [View Article]
    [Google Scholar]
  46. Patterson C. C., Dahlquist G., Soltész G., Green A.EURODIAB ACE Study Group. Europe and Diabetes 2001; Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia 44:Suppl. 3B9–B16 [View Article][PubMed]
    [Google Scholar]
  47. Peng L., He Z., Chen W., Holzman I. R., Lin J. 2007; Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res 61:37–41 [View Article][PubMed]
    [Google Scholar]
  48. Peng L., Li Z. R., Green R. S., Holzman I. R., Lin J. 2009; 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 [View Article][PubMed]
    [Google Scholar]
  49. Price M. N., Dehal P. S., Arkin A. P. 2010; FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS ONE 5:e9490 [View Article][PubMed]
    [Google Scholar]
  50. Pruesse E., Quast C., Knittel K., Fuchs B. M., Ludwig W., Peplies J., Glöckner F. O. 2007; silva: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res 35:7188–7196 [View Article][PubMed]
    [Google Scholar]
  51. Pryde S. E., Duncan S. H., Hold G. L., Stewart C. S., Flint H. J. 2002; The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett 217:133–139 [View Article][PubMed]
    [Google Scholar]
  52. Rea M. C., Dobson A., O’Sullivan O., Crispie F., Fouhy F., Cotter P. D., Shanahan F., Kiely B., Hill C., Ross R. P. 2011; Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci U S A 108:Suppl. 14639–4644 [View Article][PubMed]
    [Google Scholar]
  53. Roesch L. F., Lorca G. L., Casella G., Giongo A., Naranjo A., Pionzio A. M., Li N., Mai V., Wasserfall C. H.& other authors ( 2009; Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model. ISME J 3:536–548 [View Article][PubMed]
    [Google Scholar]
  54. Romond M. B., Colavizza M., Mullié C., Kalach N., Kremp O., Mielcarek C., Izard D. 2008; Does the intestinal bifidobacterial colonisation affect bacterial translocation?. Anaerobe 14:43–48 [View Article][PubMed]
    [Google Scholar]
  55. Sapone A., de Magistris L., Pietzak M., Clemente M. G., Tripathi A., Cucca F., Lampis R., Kryszak D., Cartenì M.& other authors ( 2006; Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55:1443–1449 [View Article][PubMed]
    [Google Scholar]
  56. Sartor R. B. 2008; Microbial influences in inflammatory bowel diseases. Gastroenterology 134:577–594 [View Article][PubMed]
    [Google Scholar]
  57. Sartor R. B., Mazmanian S. K. 2012; Intestinal microbes in inflammatory bowel diseases. Am J Gastroenterol Suppl 1:15–21 [View Article]
    [Google Scholar]
  58. Schein P., Kahn R., Gorden P., Wells S., Devita V. T. 1973; Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch Intern Med 132:555–561 [View Article][PubMed]
    [Google Scholar]
  59. Shimotoyodome A., Meguro S., Hase T., Tokimitsu I., Sakata T. 2000; Short chain fatty acids but not lactate or succinate stimulate mucus release in the rat colon. Comp Biochem Physiol A Mol Integr Physiol 125:525–531 [View Article][PubMed]
    [Google Scholar]
  60. Stecher B., Hardt W. D. 2008; The role of microbiota in infectious disease. Trends Microbiol 16:107–114 [View Article][PubMed]
    [Google Scholar]
  61. Turnbaugh P. J., Ley R. E., Mahowald M. A., Magrini V., Mardis E. R., Gordon J. I. 2006; An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031 [View Article][PubMed]
    [Google Scholar]
  62. Turnbaugh P. J., Hamady M., Yatsunenko T., Cantarel B. L., Duncan A., Ley R. E., Sogin M. L., Jones W. J., Roe B. A.& other authors ( 2009; A core gut microbiome in obese and lean twins. Nature 457:480–484 [View Article][PubMed]
    [Google Scholar]
  63. Urich T., Lanzén A., Qi J., Huson D. H., Schleper C., Schuster S. C. 2008; Simultaneous assessment of soil microbial community structure and function through analysis of the meta-transcriptome. PLoS ONE 3:e2527 [View Article][PubMed]
    [Google Scholar]
  64. Vaarala O., Atkinson M. A., Neu J. 2008; The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 57:2555–2562 [View Article][PubMed]
    [Google Scholar]
  65. Vavra J. J., Deboer C., Dietz A., Hanka L. J., Sokolski W. T. 1959-1960; Streptozotocin, a new antibacterial antibiotic. Antibiot Annu 7:230–235[PubMed]
    [Google Scholar]
  66. Wall R., Marques T. M., O’Sullivan O., Ross R. P., Shanahan F., Quigley E. M., Dinan T. G., Kiely B., Fitzgerald G. F.& other authors ( 2012; Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. Am J Clin Nutr 95:1278–1287 [View Article][PubMed]
    [Google Scholar]
  67. Wang Z. T., Yao Y. M., Xiao G. X., Sheng Z. Y. 2004; Risk factors of development of gut-derived bacterial translocation in thermally injured rats. World J Gastroenterol 10:1619–1624[PubMed]
    [Google Scholar]
  68. Wu K. K., Huan Y. 2008; Streptozotocin-induced diabetic models in mice and rats. In Current Protocols in Pharmacology5471–54714 Edited by Enna S. J., Williams M., Kenakin T., McGonigle P., Ruggeri B. New York: Wiley; [View Article]
    [Google Scholar]
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