The role of inTesTinal microbioTa in energeTic meTabolism : new perspecTives in combaTing obesiTy

The knowledge that the composition of intestinal microbiota is different in lean and obese humans indicates that the microbiota plays an important role in the pathophysiology of obesity. Studies show that diet composition promotes the modification of intestinal bacterial species, favoring the increase of energy extraction from the diet, insulin resistance and obesity. Unbalanced diets, with overload fat and low fiber content, lead to increased Firmicutes and Proteobacteria phyla favoring dysbiosis, endotoxemia and inflammation. The use of probiotics, prebiotics and symbiotics, in order to modulate the composition of intestinal microbiome, may be a promising therapy for the reduction of the metabolic complications of obesity; however, further studies should be conducted to establish which probiotic species are suitable to help in the treatment of obesity.

The increasing prevalence of obesity has led the World Health Organization (WHO) to consider it as the world's largest epidemic of the century, being referred to as the most important nutritional disorder in developed and developing countries 1 .Prevalence of obesity and related diseases, such as metabolic syndrome, non-alcoholic fatty liver disease, diabetes, cardiovascular diseases, and cancer, has increased dramatically worldwide 2,3 .Recent insights have generated an entirely new perspective, suggesting that the microbiota may be involved in the development of these disorders 4 .Clarke et al. demonstrated through fecal transplantation experiments that obesity and metabolic syndrome may be associated with alterations of the intestinal microbiota composition 5 .Components of the intestinal microbiota can facilitate the extraction of calories from substances ingested in the diet, which provides nutrients for the growth of microbes or can be stored as fat 6 .Studies in germ free animals demonstrated that the composition of the intestinal microbiota has a profound influence on the onset and progression of human diseases, including obesity, and on the regulation of energy harvest and fat storage [6][7][8] .The so called "obesogenic microbiota" promotes more efficient energy extraction from the diet and predisposes to the development of obesity.

INTESTINAL MICROBIOTA AND ITS RELATION TO OBESITY
The human gut is the natural habitat of an extraordinary bacterial community 9,10 .The main functions of the intestinal microbiota include metabolic activities that result in energy and absorbable nutrient storage, important trophic effects on the intestinal epithelium, immune function and protection of the host against pathogenic microorganisms 10,11 .
Studies with germ-free animals revealed the role of the microbiota as a major environmental factor that affects the collection and storage of energy derived from ingested nutrients 8,12 .Backhed et al. showed that implantation of the intestinal microbiota of conventionally raised mice into germ-free mice resulted in a 60% increase of body fat in transplanted animals 8 .Ridaura et al. 12 transplanted fecal microbiota from obese and lean mice into germ-free mice Microbiota and obesity and observed an increase in body weight and fat mass, as well as in metabolic phenotypes associated with obesity, in those which were transplanted with microbiota from obese mice.An interesting observation from this study was that the mice which were transplanted with the microbiota from obese animals developed less body fat in comparison to the animals that received microbiota from the lean mice.The presence of specific bacteria of lean animals in obese animals was also observed.These results revealed transferable and modifiable effects of microbiota and the interactions between diet and microbiota 12 .Turnbaugh et al. demonstrated that the microbiota of obese mice was more efficient in energy utilization from food and that there was an increase in adiposity after transplantation of the microbiota from obese to germ-free animals 7 .
A study to evaluate the influence of diet on the composition of the intestinal microbiota found that the shift to a high-fat diet caused a decrease in Bacteroidetes phylum and an increase in Firmicutes and Proteobacteria phyla.This strengthens the hypothesis that the diet is a determining factor for the composition of the intestinal microbiota 13 .Carilicci et al. found that the Firmicutes phylum may be related to insulin resistance and obesity 14 .Increased ratio of Firmicutes in the microbiota seems to influence the onset of diabetes and obesity in two ways: first, by increasing the capacity to extract energy from food (some species of Firmicutes break polysaccharide molecules) and/or increasing its absorption; second, by favoring the increase of intestinal permeability and the passage of LPS (lipopolysaccharides) into the bloodstream and leading to the inflammatory state of obesity 6,7,14,15 .
After comparing bacterial 16S rRNA gene sequences from intestinal microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, Ley et al. observed that the composition of the intestinal microbial community can promote increased fat deposition 16 .These authors concluded that the intentional manipulation of community structure may be useful for the regulation of energy balance in obese individuals 16 .

PREBIOTICS AND PROBIOTICS IN THE MODULATION OF OBESOGENIC MICROBIOTA
Accumulating evidence of the strong relationship between intestinal microbiota and obesity led to the hypothesis that the manipulation of the microbiota may contribute to obesity prevention strategies.Studies on this issue in animals and human beings have been conducted in order to evaluate the action of prebiotics and/or probiotics on obesity and overweight treatment [17][18][19] .
A study conducted by Million et al. was designed to investigate which species of bacteria -Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, animalis Bifidobacterium and Lactobacilliwere associated with obesity or normal weight 20 .This study showed that obesity is associated with decreased presence of M. smithii and increased presence of L. reuteri in microbiota composition.In addition, higher levels of B. animalis, L. paracasei, L. plantarum, were associated with normal weight 20.To highlight the modulation effect of the intestinal microbiota in the host metabolism, a double-blind intervention was performed: 30 placebo-controlled obese women were treated with prebiotics (inulin-type fructans) for 3 months (16 g/day).The treatment increased the number of Bifidobacterium and Faecalibacterium prausnitzii; both bacteria were negatively correlated with serum levels of lipopolysaccharides.Prebiotics also decreased the proportion of Bacteroides intestinalis, B. vulgatus and Propionibacterium, an effect associated with a slight decrease in fat mass 21 .
According to Vrieze et al., the manipulation of the gut microbiota may be considered as a therapeutic agent, since dysbiosis is associated with obesity and insulin resistance in humans 22 .The administration of prebiotics, probiotics or symbiotics can improve gut barrier integrity, rebalance microbiota composition and reduce the inflammation state, thus ameliorating metabolic balance and promoting weight loss.

DYSBIOSIS HIGH FAT DIET AND INFLAMMATORY CONDITION
Eating behavior can be considered as one of the factors that most influence quality of life.Eastern people have always believed that all diseases begin in the gut and there is a fundamental relationship between the intestines and health.Excessive consumption of processed foods, beverages, sugar, and fat, as well as undesirable interactions between nutrients, contribute to change intestinal microbiota leading to dysbiosis 23,24 .
Ingestion of a high fat diet promotes low-grade inflammation, which contributes to the development of obesity-associated diseases 24 .Clinical studies showed associations between obesity, intestinal microbiota composition, and endotoxemia [24][25][26][27] .Unbalanced diets, with overload fat and low fiber content, lead to increased levels of LPS, favoring endotoxemia.Nutrient load is a key variable that can influence the structure of the intestinal bacterial community.Individuals with a low bacterial diversity are characterized by more adiposity, insulin resistance, and dyslipidemia, and a pronounced inflammatory phenotype when compared to individual with a higher bacterial richness 26 .
The impact of dietary fat in the intestinal microbiota and the development of a low grade inflammation have been studied by Cani et al. 28 .They observed that administration of a high fat diet caused changes in the composition of the microbiota, which contributed to a significant increase in intestinal permeability, reduced the expression of genes encoding proteins of the tight junctions, and increased plasma concentrations of LPS, contributing to the development of endotoxemia 28 .Furthermore, an increase in the levels of blood glucose, fasting insulin, body weight, and fat mass, which was related to increased levels of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL] 6, IL-1b, macrophage inflammatory protein-1) in plasma, adipose tissue, liver and muscle 28 .These results suggest that modulation of the microbiota for the reduction of plasma levels of LPS can be a therapeutic strategy to control processes associated with inflammatory diseases.

CONCLUSION
Obesity is a systemic disease and new approaches are needed for its treatment.Evidence related to the role of intestinal microbiota in obesity shows that this is an important issue to address in obese patients, together with approaches that include diet, physical activity, psychological treatment, medications, and sometimes surgery.