Gomes et al. Nutrition Journal 2014, 13:60 http://www.nutritionj.com/content/13/1/60 REVIEW Open Access Gut microbiota, probiotics and diabetes Aline Corado Gomes1, Allain Amador Bueno2, Rávila Graziany Machado de Souza1 and João Felipe Mota1* Abstract Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes. Keywords: Probiotics, Diabetes mellitus, Gut microbiota, Inflammation, Insulin resistance Introduction cardiovascular diseases and dyslipidaemia [3,4]. It has According to the World Health Organization [1], the also been suggested that altered intestinal microbiota global prevalence of diabetes is approximately 10%, leads to increased intestinal permeability and mucosal reaching up to 33% of the population in some regions. immune response, contributing to the development of Diabetes is a condition of multifactorial origin, including diabetes. Increased intestinal permeability is a result of genetic and environmental factors, and accounts for 3.5% reduced expression of tight junction proteins, eventually of the mortality cases due to non-communicable chronic favouring the translocation of bacterial lipopolysaccharide diseases. Scientific evidence suggests increased inflamma- (LPS), which may result in metabolic endotoxemia and tory stress is related to molecular mechanisms leading to insulin resistance [5,6]. insulin resistance, and the intestinal microbiota interacts Modulation of intestinal microbiota by probiotics may with environmental factors and susceptible genetic factors, facilitate the management of a number of clinical condi- contributing to the development of diabetes [2]. tions [7]. Probiotics may be involved in the maintenance The human gastrointestinal tract contains in average 1014 of a healthier gut microbiota, and have also been identified microorganisms/ml of luminal content, and features as effective adjuvants in insulin resistance therapies [8-10]. over 5000 bacterial species. Among bacterial species, Hence, this systematic review appraises the current litera- approximately 90% of them belong to the Bacteroi- ture covering gut microbiota, probiotics and diabetes. detes phyla, composed mainly of Gram– bacteria, and Our aim is to clarify the currently described effects of the Firmicutes phyla, composed mainly of Gram + bacteria. probiotics in the prevention and management of type 1 It has been suggested that the intestinal microbiota (T1D) and type 2 (T2D) diabetes mellitus. composition is associated with conditions such as aller- gies, intestinal inflammatory diseases, cancer, diabetes, Methods * Correspondence: [email protected] A systematic literature review has been performed over 1 Laboratório de Investigação em Nutrição Clínica e Esportiva (Labince). the electronic databases Medline PubMed and SciELO Faculdade de Nutrição, Universidade Federal de Goiás, Rua 227 Qd. 68s/nº - Setor Leste Universitário, Goiânia, Goiás, Brazil (The Scientific Electronic Library Online). The reference Full list of author information is available at the end of the article list of identified articles has also been reviewed. For this © 2014 Gomes et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gomes et al. Nutrition Journal 2014, 13:60 Page 2 of 13 http://www.nutritionj.com/content/13/1/60 search, the following descriptors were considered: "dia- phytochemicals [20] can modify the bacterial metabolic betes," "oxidative stress", "probiotics", "inflammation", activity [21]. High fat diets modify the intestinal micro- "insulin" and "microbiota". The logical connectives "and", biota, leading to increased intestinal permeability and "or" and "and not" were systematically used to combine susceptibility to microbial antigens, which ultimately descriptors and terms used to trace the publications. correlates with the occurrence of metabolic endotoxemia As a result of this appraisal conducted in December and insulin resistance [22]. 2013, 287 publications were identified. Subsequently, The molecular mechanisms involved in high fat diets the articles that met the following inclusion criteria and modulation of the intestinal microbiota are not fully were selected: (a) experimental studies that investigated elucidated, but as this typical diet increases fatty acid assessment of insulin sensitivity, glucose tolerance test, oxidation in the liver and adipose tissue, the evidence intestinal permeability and or markers of oxidative stress available suggests the reactive oxygen species (ROS) and inflammation; (b) literature review articles; (c) articles generated reduce mucus production in the intestinal preferably published after 2002. epithelium. Thus, the weakened intestinal barrier integ- After reconsideration based on the inclusion criteria, rity allows the translocation of intestinal bacteria [23]. 166 articles were excluded for one of the two following Furthermore, production of malondialdehyde as result reasons: the effects of probiotics were related to other of polyunsaturated fatty acid oxidation induces damage pathologies other than diabetes; or, probiotics were not to the epithelial cell membranes, increasing intestinal the main objective of the study. Therefore, 121 articles tight junction permeability [24,25]. met all the inclusion criteria and were reviewed. Diabetic individuals have lower counts of Bifidobacterium and Faecalibacterium prausnitzii, both of them Gram + [26] Intestinal microbiota and type 2 diabetes with anti-inflammatory properties [26,27]. Despite the Muscle and adipose tissue resistance to insulin actions perturbations already observed in the intestinal microbiota observed in T2D is triggered mainly by a complex com- of type 2 diabetic subjects, it is still necessary to elucidate bination of genetic predisposition, body composition, whether the variations in the microbiota, intestinal barrier nutritional and environmental factors. Insulin receptor, and metabolic endotoxemia are causes or consequences of glucose transporter and post-receptor perturbations are diabetes. Interestingly, Mehta et al. [28] showed that acute observed in T2D. Eventually, peripheral tissues exposed to inflammation induced by intravenous administration chronic compensatory hyperinsulinemia become resistant of LPS promotes metabolic endotoxemia and systemic to insulin [11]. Studies have shown the intestinal micro- insulin resistance, following modulation of specific biota is associated with the development of metabolic adipose inflammatory and insulin signaling pathways. diseases, as obese and diabetic subjects present pertur- The relationship between LPS and the development of bations in the proportions of Firmicutes, Bacteroidetes T2D has been observed in some clinical trials [29-33]. and Proteobacterias [4,12]. Concurrent with metabolic endotoxemia, translocation Mammals present sterile gastrointestinal tract at birth, of live bacteria from the intestinal barrier into the blood and their microbiota is gradually accumulated after birth appears to be related to the development of T2D [34,35]. through the physical contact with the breast and the One of the features common to metabolic diseases environment [13]. Infants’ intestinal microbiota is mainly such as obesity and T2D is a mild chronic inflammatory formed by Bifidobacteria and Enterobacteria, and it changes state, which could possibly be – among other factors – the progressively into a more complex pattern, observed in result of TLR activation by LPS, present in the cell wall adults [14]. These microorganisms and their metabolites of Gram– bacteria. The TLRs comprise a large family interact with the intestinal epithelial cells differently in of cell membrane proteins present in different types of the small and large intestines. Such microbiological and cells, recognizing microbe-associated molecular patterns biochemical variations are attributed to the distinct (MAMPs) during