Regulatory properties of the intestinal microbiome effecting the development and treatment of diabetes

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 19, Issue 2, 2012, Pages 73-80

  Romano Keeler, Joann ^a   Weitkamp, Jöern Hendrik ^a   Moore, Daniel J ^a  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

diabetes; immunity; metabolism; microbiome; T regulatory cells; Th17

Indexed keywords

BACTERIAL RNA; HLA DQ ANTIGEN; INTERLEUKIN 17; MYELOID DIFFERENTIATION FACTOR 88; RETINOID RELATED ORPHAN RECEPTOR GAMMA; RNA 16S; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTOME;

AUTOIMMUNITY; BACILLUS CEREUS; BACTERIAL GENE; BACTEROIDES FRAGILIS; CD4+ T LYMPHOCYTE; CLOSTRIDIUM; FIRMICUTES; GENE AMPLIFICATION; GENOMICS; HIGH THROUGHPUT SCREENING; HUMAN; IMMUNOREGULATION; INSULIN DEPENDENT DIABETES MELLITUS; INTESTINE FLORA; LACTOBACILLUS JOHNSONII; LYMPHOCYTE ACTIVATION; MICROBIAL COMMUNITY; MICROBIOME; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORGANOGENESIS; PANCREAS; PATHOGENESIS; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; TH17 CELL;

ADAPTIVE IMMUNITY; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; FEMALE; HUMANS; INTESTINES; MALE; METAGENOME; T-LYMPHOCYTES, REGULATORY;

EID: 84858291541     PISSN: 1752296X     EISSN: 17522978     Source Type: Journal    
DOI: 10.1097/MED.0b013e3283514d43     Document Type: Review

References (38)

1. Stene LC, Ronningen KS, Undlien DE, Joner G. Does the relative risk for type 1 diabetes conferred by HLA-DQ, INS, and PTPN22 polymorphisms vary with maternal age, birth weight, or cesarean section? Pediatr Diabetes 2011; 12:91-94.
2. D'Angeli MA, Merzon E, Valbuena LF, et al. Environmental factors associated with childhood-onset type 1 diabetes mellitus: an exploration of the hygiene and overload hypotheses. Arch Pediatr Adolesc Med 2010; 164:732-738.
3. Bonifacio E, Warncke K, Winkler C, et al. Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. Diabetes 2011; 60:3300-3306.
4. Knip M, Virtanen SM, Seppa K, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 2010; 363:1900-1908. This study further supports a role of dietary interventions in modulating autoimmunity. Future specification of the microbiome in this study may be an important stop in understanding microbiome-T1D interactions.
5. Turnbaugh PJ, Ley RE, Hamady M, et al. The human microbiome project. Nature 2007; 449:804-810. (Pubitemid 47598620)
6. Prosser JI. Replicate or lie. Environ Microbiol 2010; 12:1806-1810.
7. Schellenberg J, Links MG, Hill JE, et al. Pyrosequencing of the chaperonin-60 universal target as a tool for determining microbial community composition. Appl Environ Microbiol 2009; 75:2889-2898.
8. Gosalbes MJ, Durban A, Pignatelli M, et al. Metatranscriptomic approach to analyze the functional human gut microbiota. PLoS One 2011; 6:e17447. This study examines the human microbiome from a functional level by applying a metatranscriptomic approach whereby mRNA is extracted from fecal samples to categorize microbial gene expression within the GI tract. This represents an important extension from genome analysis to functional approaches.
9. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature 2011; 473:174-180. This study represents a new approach to classifying the human microbiome in terms of species and functions. Whether 'enterotype' will eventually be recognized as the HLA of the microbiome remains to be seen. However, integrative classification strategies offer a strong opportunity to reveal host-bacteria-disease interactions by accounting for multiple factors involved in these complex interactions.
10. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005; 308:1635-1638. (Pubitemid 40807514)
11. Zoetendal EG, von Wright A, Vilpponen-Salmela T, et al. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl Environ Microbiol 2002; 68:3401-3407. (Pubitemid 34734038)
12. King C, Sarvetnick N. The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS One 2011;6:e17049. See Ref. [12].
13. Alam C, Bittoun E, Bhagwat D, et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in nonobese diabetic (NOD) mice. Diabetologia 2011; 54:1398-1406. These two studies [12■,13■] revisit the notion of acceleration of diabetes in germ-free NOD mice. These studies confirm that not all bacteria are likely to be disease protective and invite further mechanistic dissection of the hygiene hypothesis.
14. Valladares R, Sankar D, Li N, et al. Lactobacillus johnsonii N6.2 mitigates the development of type 1 diabetes in BB-DP rats. PLoS One 2010; 5:e10507.
15. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 2009; 31:677-689.
16. Wu HJ, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 2010; 32:815-827. This study is an important counterpoint to [17■■] below as it shows that segmented filamentous bacteria permit certain autoimmune conditions. How the outcome of SFB-immune interactions determines disease versus protection is an important area for development.
17. Kriegel MA, Sefik E, Hill JA, et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U S A 2011; 108:11548-11553. This study describes a key diabetes-protective bacterial species. Understanding the mechanism of this protection and how residence of these SFB are modulated in the gut is a key area for advancing diabetes prediction and therapy.
18. Lochner M, Berard M, Sawa S, et al. Restricted microbiota and absence of cognate TCR antigen leads to an unbalanced generation of Th17 cells. J Immunol 2011; 186:1531-1537.
19. Wohlfert E, Belkaid Y. Plasticity of T reg at infected sites. Mucosal Immunol 2010; 3:213-215.
20. Ferraro A, Socci C, Stabilini A et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 2011; 60:2903-2913.
21. Round JL,Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 2010; 107:12204-12209. Round et al. present the first identification of a bacterial product that induces Treg development. B. fragilis PSA was found to induce IL-10 producing Treg.
22. +dendritic cells residing in the gut-associated lymphoid tissues. This study suggests that B. fragilis-derived PSA induces Treg directly through TLR2-mediated signaling to suppress Th17 cell responses, and therefore promote colonization by B. fragilis. This represents the first identification of a bacterial protein that modulates host immunity and may lead to pharmacologic approaches to do the same.
23. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331:337-341. This study demonstrated that colonization of germ-free mice with a cocktail of Clostridium species promotes Treg induction and activity in the colon but not the small intestine. Clostridium-mediated Treg accumulation was observed at extraintestinal sites as well and resulted in resistance to experimental autoimmunity.
24. Livingston M, Loach D, Wilson M, et al. Gut commensal Lactobacillus reuteri 100-23 stimulates an immunoregulatory response. Immunol Cell Biol 2010; 88:99-102.
25. Hall JA, Bouladoux N, Sun CM, et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 2008; 29:637-649.
26. Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 2008; 455:1109-1113.
27. Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011; 334:255-258. This study extends the model of innate immunity-commensal interactions by providing the first evidence of a host defense molecule that limits bacterial-gut interactions.
28. Visser JT, Lammers K, Hoogendijk A, et al. Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone biobreeding rat. Diabetologia 2010; 53:2621-2628.
29. Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 2011; 5:82-91. This study provides the first description of the microbiome in persons genetically at risk for T1D that progress to autoantibody positivity. The small sample size awaits confirmation and extension.
30. McNulty NP, Yatsunenko T, Hsiao A et al. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med 2011; 3:106ra106. This study shows that ingestion of probiotic yogurt did not significantly change the arrangement of the host gut microbiota, but did alter metabolic pathways predominantly those related to carbohydrate processing.
31. Brown CT, Davis-Richardson AG, Giongo A, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 2011; 6:e25792. This study used a metagenomic approach to identify that patients with type 1 diabetes have a lower proportion of butyrate producing, and therefore mucin promoting bacteria, which may increase gut permeability.
32. Huang X, Moore DJ, Ketchum RJ, et al. Resolving the conundrum of islet transplantation by linking metabolic dysregulation, inflammation, and immune regulation. Endocr Rev 2008; 29:603-630.
33. Jumpertz R, Le DS, Turnbaugh PJ, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr 2011; 94:58-65. This study demonstrates how modest alterations in caloric consumption induce rapid changes in the gut microbiota and subsequent nutrient absorption and energy harvest in obese and lean individuals.
34. Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in human adults with type 2 diabetes differs from nondiabetic adults. PLoS One 2010; 5:e9085. This is one of the first descriptions of the gut microbiome in individuals with type 2 diabetes.
35. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444:1022-1023. (Pubitemid 46018512)
36. Schwiertz A, Taras D, Schafer K, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010; 18:190-195.
37. Murphy EF, Cotter PD, Healy S, et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 2010; 59:1635-1642.
38. Sonnenburg ED, Zheng H, Joglekar P, et al. Specificity of polysaccharide use in intestinal bacteroides species determines diet-induced microbiota alterations. Cell 2010; 141:1241-1252. This study illustrates the role of polysaccharide utilization loci (PUL) within microbial genomes as a mechanism by which bacterial communities respond to dietary modifications through the specificity of PUL expression. This study represents a key step to understanding the rules of symbiosis that we may ultimately manipulate for clinical gains.