Abstract
The gut microbiota structure, dynamics, and function result from interactions with environmental and host factors, which jointly influence the communication between the gut and peripheral tissues, thereby contributing to health programming and disease risk. Incidence of both type-1 and type-2 diabetes has increased during the past decades, suggesting that there have been changes in the interactions between predisposing genetic and environmental factors. Animal studies show that gut microbiota and its genome (microbiome) influence alterations in energy balance (increased energy harvest) and immunity (inflammation and autoimmunity), leading to metabolic dysfunction (e.g., insulin resistance and deficiency). Thus, although they have different origins, both disorders are linked by the association of the gut microbiota with the immune–metabolic axis. Human studies have also revealed shifts in microbiome signatures in diseased subjects as compared with controls, and a few of them precede the development of these disorders. These studies contribute to pinpointing specific microbiome components and functions (e.g., butyrate-producing bacteria) that can protect against both disorders. These could exert protective roles by strengthening gut barrier function and regulating inflammation, as alterations in these are a pathophysiological feature of both disorders, constituting common targets for future preventive approaches.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Olivares M, Neef A, Castillejo G, et al. The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing celiac disease. Gut 2014 (doi:10.1136/gutjnl-2014–306931).
Salonen A, Lahti L, Salojarvi J, et al. Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. ISME J 2014 (doi:10.1038/ismej.2014.63).
Maslowski KM, Mackay CR . Diet, gut microbiota and immune responses. Nat Immunol 2011;12:5–9.
Sela DA, Mills DA . The marriage of nutrigenomics with the microbiome: the case of infant-associated bifidobacteria and milk. Am J Clin Nutr 2014;99:697S–703S.
Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455:1109–13.
Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010;328:228–31.
Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS, Wen L . Long term effect of gut microbiota transfer on diabetes development. J Autoimmun 2014;53:85–94.
Musso G, Gambino R, Cassader M . Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care 2010;33:2277–84.
Sanz Y, Moya-Pérez A . Microbiota, inflammation and obesity. In: Lyte Mark, Cryan John F, eds. Microbial Endocrinology: The Microbiota–Gut–Brain Axis in Health and Disease. New York: Springer, 2014:291–317.
Caesar R, Reigstad CS, Bäckhed HK, et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 2012;61:1701–7.
Serino M, Luche E, Gres S, et al. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 2012;61:543–53.
Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI . Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007;104:979–84.
Moore AM, Munck C, Sommer MO, Dantas G . Functional metagenomic investigations of the human intestinal microbiota. Front Microbiol 2011;2:188.
Rey FE, Faith JJ, Bain J, et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J Biol Chem 2010;285:22082–90.
Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103.
Fernandes CA, Fievez L, Neyrinck AM, Delzenne NM, Bureau F, Vanbever R . Sirtuin inhibition attenuates the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun 2012;420:857–61.
Caricilli AM, Picardi PK, de Abreu LL, et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 2011;9:e1001212.
Kim KA, Gu W, Lee IA, Joh EH, Kim DH . High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012;7:e47713.
Devkota S, Wang Y, Musch MW, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 2012;487:104–8.
Amar J, Serino M, Lange C, et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 2011;54:3055–61.
Cano PG, Santacruz A, Trejo FM, Sanz Y . Bifidobacterium CECT 7765 improves metabolic and immunological alterations associated with obesity in high-fat diet-fed mice. Obesity 2013;21:2310–2122.
Sanz Y, Rastmanesh R, Agostoni C . Understanding the role of gut microbes and probiotics in obesity: how far are we? Pharmacol Res 2013;69:144–55.
Verdam FJ, Fuentes S, de Jonge C, et al. Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity 2013;21:E607–15.
Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541–6.
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.
Santacruz A, Marcos A, Warnberg J, et al. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity 2009;17:1906–15.
Cotillard A, Kennedy SP, Kong LC, et al. Dietary intervention impact on gut microbial gene richness. Nature 2013;500:585–8.
Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
Gauffin Cano P, Santacruz A, Moya Á, Sanz Y . Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 2012;7:e41079.
Kootte RS, Vrieze A, Holleman F, et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes, Obes Metab 2012;14:112–20.
Kalliomäki M, Collado MC, Salminen S, Isolauri E . Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008;87:534–8.
Bergström A, Skov TH, Bahl MI, et al. Establishment of intestinal microbiota during early life: a longitudinal, explorative study of a large cohort of Danish infants. Appl Environ Microbiol 2014;80:2889–900.
Santacruz A, Collado MC, García-Valdés L, et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr 2010;104:83–92.
Karlsson CL, Molin G, Cilio CM, Ahrné S . The pioneer gut microbiota in human neonates vaginally born at term—a pilot study. Pediatr Res 2011;70:282–6.
Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010;5:e9085.
Wu X, Ma C, Han L, et al. Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr Microbiol 2010;61:69–78.
Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012;490:55–60.
Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103.
Zhang X, Shen D, Fang Z, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 2013;8:e71108.39.
Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V . Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 2011;34:392–7.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37:Suppl 1:S81–90.
Vaarala O, Atkinson MA, Neu J . The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 2008;57:2555–62.
Roep BO, Tree TI . Immune modulation in humans: implications for type 1 diabetes mellitus. Nat Rev Endocrinol 2014;10:229–42.
Secondulfo M, Iafusco D, Carratu R, et al. Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig Liver Dis 2004;36:35–45.
Sapone A, de Magistris L, Pietzak M, et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 2006;55:1443–9.
Bosi E, Molteni L, Radaelli MG, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 2006;49:2824–7.
Brugman S, Klatter FA, Visser JT, et al. 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 2006;49:2105–8.
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.
Calcinaro F, Dionisi S, Marinaro M, et al. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 2005;48:1565–75.
Marietta EV, Gomez AM, Yeoman C, 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 2013;8:e78687.
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.
Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 2011;5:82–91.
Murri M, Leiva I, Gomez-Zumaquero JM, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case–control study. BMC Med 2013;11:46.
Soyucen E, Gulcan A, Aktuglu-Zeybek AC, Onal H, Kiykim E, Aydin A . Differences in the gut microbiota of healthy children and those with type 1 diabetes. Pediatr Int 2014;56:336–43.
Cardwell CR, Stene LC, Joner G, et al. Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 2008;51:726–35.
Pereira PF, Alfenas Rde C, Araújo RM . Does breastfeeding influence the risk of developing diabetes mellitus in children? A review of current evidence. J Pediatr (Rio J) 2014;90:7–15.
Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010;107:11971–5.
Decker E, Engelmann G, Findeisen A, et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 2010;125:e1433–40.
Rewers M, Liu E, Simmons J, Redondo MJ, Hoffenberg EJ . Celiac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin North Am 2004;33:197–214, xi.
Palma GD, Capilla A, Nova E, et al. Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS One 2012;7:e30791.
Krause I, Anaya JM, Fraser A, et al. Anti-infectious antibodies and autoimmune-associated autoantibodies in patients with type I diabetes mellitus and their close family members. Ann NY Acad Sci 2009;1173:633–9.
Laitinen OH, Honkanen H, Pakkanen O, et al. Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes. Diabetes 2014;63:446–55.
Honeyman MC, Coulson BS, Stone NL, et al. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000;49:1319–24.
Lönnrot M, Korpela K, Knip M, et al. Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. Diabetes 2000;49:1314–8.
Levy-Marchal C, Patterson CC, Green A, EURODIAB ACE Study Group. Europe and Diabetes. Geographical variation of presentation at diagnosis of type I diabetes in children: the EURODIAB study. European and Dibetes. Diabetologia 2001;44:Suppl 3:B75–80.
Author information
Authors and Affiliations
Corresponding author
PowerPoint slides
Rights and permissions
About this article
Cite this article
Sanz, Y., Olivares, M., Moya-Pérez, Á. et al. Understanding the role of gut microbiome in metabolic disease risk. Pediatr Res 77, 236–244 (2015). https://doi.org/10.1038/pr.2014.170
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2014.170
This article is cited by
-
MicroBVS: Dirichlet-tree multinomial regression models with Bayesian variable selection - an R package
BMC Bioinformatics (2020)
-
Gut microbiota: a perspective of precision medicine in endocrine disorders
Journal of Diabetes & Metabolic Disorders (2020)
-
A poly-herbal blend (Herbagut®) on adults presenting with gastrointestinal complaints: a randomised, double-blind, placebo-controlled study
BMC Complementary and Alternative Medicine (2018)
-
Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet
Scientific Reports (2017)
-
Evaluation of differential effects of metformin treatment in obese children according to pubertal stage and genetic variations: study protocol for a randomized controlled trial
Trials (2016)


