REVISIÓN

Intestinal microbiota; relevance to obesity and modulation by prebiotics and probiotics

Microbiota intestinal; relevancia para la obesidad y la modulación de los prebióticos y probióticos

Sandra Tavares da Silva¹, Carolina Araújo dos Santos¹ and Josefina Bressan²

¹MSc student in Nutritional Science. Federal University at Viçosa. Brazil.
²Professor at the Department of Nutrition and Health. Federal University of Viçosa. Brazil.

ABSTRACT

Introduction: The intestinal microbiota has several beneficial functions related to host health. Studies suggest that it may be related to the presence of metabolic diseases, including obesity.
Objective: A bibliographic survey was carried out upon the relationship between the intestinal microbiota and obesity and the possible impacts of the use of prebiotics and probiotics, aiming to understand this complex and promising interaction.
Methods: A search was conducted in the Lilacs, PubMed, SciElo and ScienceDirect databases, using the keywords "gut microbiota" and "obesity".
Results and discussion: We identified 613 original studies. After careful selection, 61 original articles were included in this review. The others indicated that there are differences in the microbial composition between obese and non-obese patients and the possible mechanisms involved. Alteration is caused in the energy homeostasis, in the use of dietary intake and storage of lipids due to the composition of the intestinal microbiota. Among the studies that evaluated the microbiota modulation, seven used probiotics; 24 used prebiotics, and five studies were performed using food. After dietary manipulation, the growth of bifidobacteria was obtained in 10 studies, in association with weight reduction, adipogenic effects of diet, intestinal permeability and inflammatory markers.
Conclusion: Knowledge on the impact of the microbiota on metabolic pathways allows to conceive new factors associated with obesity and modulation by prebiotics and probiotics. In this sense, the main effect observed was the increase in bifidobacteria, usually accompanied by weight loss and enhancement of parameters related to obesity.

Key words: Intestinal microbiota. Obesity. Prebiotics. Probiotics.

Introducción: La microbiota intestinal tiene varias funciones beneficiosas relacionadas con la salud del hombre y estudios sugieren una posible relación con la presencia de enfermedades metabólicas como la obesidad.
Objetivos: Se realizó una revisión sobre la relación entre la microbiota intestinal y la obesidad, así como los posibles impactos del uso de pre y probióticos, a fin de conocer como ocurre esta compleja interacción.
Métodos: Se realizó una búsqueda electrónica de la literatura en las bases de datos Lilacs, PubMed, Science Direct y Scielo utilizandose las palabras clave "microbiota intestinal" y "obesidad".
Resultados y discusión: Se identificaron 613 estudios. Después de aplicar los criterios de inclusión y exclusión, 61 artículos originales fueron incluidos. La composición de la microbiota intestinal promueve alteración en la homeostasis energética, en la utilización de la dieta ingerida y en el almacenamiento de los lípidos. De los estudios que evaluaron la modulación de la microbiota, siete utilizaron probióticos y 24 prebióticos, de estos cinco estudios con alimentos. El aumento de bifidobacterias tras la manipulación dietética se observó en 10 estudios, asociándose a la reducción de peso, a los efectos adipogénicos de la dieta, a la permeabilidad intestinal y a los marcadores inflamatorios.
Conclusiones: La aclaración del impacto de la microbiota en las vías metabólicas permite encontrar nuevos factores asociados a la obesidad y la modulación por prey probióticos. En este sentido, el principal efecto observado fue un aumento de bifidobacterias, que usualmente está acompañado por la pérdida de peso y los parámetros relacionados con la obesidad.

Palabras clave: Microbiota intestinal. Obesidad. Prebióticos. Probióticos.

Abbreviations
AMP: Adenosine Monophosphate.
AMPK: AMP-Activated Protein Kinase. ]]> ANGPTL 4: Angiopoietin-Like 4.
BMI: Body Mass Index.
CD 28: Cluster of Differentiation 28.
EG: EmuGold^®.
FIAF: Fasting-Induced Adipose Factor.
FOS: Fructooligosaccharides.
GLP-1: Glucagon-Like Peptide-1.
GOS: Galactooligosaccharides.
IL-6: Interleukin-6.
Lilacs: Latin American and Caribbean Literature. ]]> LPL: Lipoprotein Lipase.
LPS: Lipopolysaccharides.
MeSH: Medical Subject Headings.
n-3 PUFA: Omega-3 Polyunsaturated Fatty Acids.
PV: PreVitae^®.
SCFA: Short Chain Fatty Acids.
Scielo: Scientific Eletronic Library Online.
SRCD: Mixture of aqueous extract of Salacia reticulate and Cyclodextrin.
TG: Triglycerides.
TLR4: Toll-Like Receptor-4. ]]> TNF-α: Tumor Necrosis Factor α.
VLDL: Very Low Density Lipoprotein.

Introduction

Symbiosis between a host and the intestinal microbiota is essential for triggering local and systemic responses favorable to the health of the host. The intestinal microbiota is composed of about 100 trillion bacteria and encompasses more than 1,000 species.^12,34 It plays an important role in protection against pathogenic microorganisms, development and homeostasis of immune cells, digestion of polysaccharides that is indigestible by human enzymes and fat metabolism, among other functions.^1,2,5

Food is the substrate for the growth of microbiota and directly affects its composition. Bazzocchi et al.⁶ claim that increased consumption of refined sugars, saturated fat and sodium, to the detriment of fiber, minerals, vitamins and antioxidant compounds has led to significant changes in the intestinal ecosystem over the years, which may result in increased chronic diseases, such as obesity.⁷

Studies suggest that the intestinal microbiota plays an important role in energy homeostasis, and that the microbiota of individuals with predisposition to obesity is favorable to the occurrence of metabolic diseases.^8,9 It is considered the existence of an "obesogenic microbiota" that can extract energy from the diet more efficiently10 and relate to subclinical chronic inflammation due to dysbiosis and increased intestinal permeability.^11,12 Thus, knowledge on the intestinal microecology, as well as their signaling pathways and regulation, can help identify new therapeutic and intervention targets.⁹ In this context, microbiota manipulation by prebiotics and probiotics becomes a possible modifier of the microbial profile and can favor the health of hosts, by triggering beneficial systemic responses.¹³

Therefore, this article aims to analyze scientific literature on the relevance of the intestinal microbiota to obesity and the possible mechanisms involved, highlighting possible ways of modulating it in order to prevent and/or treat obesity.

Methods

This study is a literature review of scientific articles containing: (i) basic research on the relationship between intestinal microbiota and obesity, (ii) clinical studies about the intestinal microbiota and the modulation by prebiotics, (iii) clinical studies about the intestinal microbiota and the modulation by probiotics. This literature review was conducted in major health databases: Medline, Lilacs, PubMed and SciELO and ScienceDirect. The following keywords were used in the search: terms "gut microbiota" and "obesity" paired with "prebiotics" and "probiotics" and the same expressions in Portuguese and Spanish. MeSH (Medical Subject Headings) was consulted for guidance in the selection of the descriptors used in the review process. The titles and abstracts of all studies identified by the search on electronic platforms were screened. The full texts of potentially relevant studies were read to note the inclusion criteria. Full papers were obtained from journals available on the website of the CAPES Foundation (Ministry of Health, Brazil). We excluded those studies that did not make reference to the relationship between intestinal microbiota and obesity or modulation by prebiotics and probiotics. The period considered for inclusion of articles was from 2000 to 2012.

Identification of studies

Figure 1 shows the flowchart for the selection of the articles used in this study.

The initial search provided 1,041 articles. After exclusion of the review studies, and duplicated results, 613 articles were separated for the study. The first selection was carried through the reading of the titles, followed by analysis of the abstracts and, finally, the assessment of the full texts and selection. After this refinement, 61 articles that deal with intestinal microbiota and its relationship with obesity were selected. Twentynine experimental studies and five experimental trials were analyzed. The remaining articles addressed differences in microbial composition between obese and non-obese patients as well as the mechanisms involved.

The search for articles was conducted independently by two researchers, who selected together the works to be included in the study. The papers selected were organized into two themes: relevance of microbiota to obesity and modulation by prebiotics and probiotics.

Results and discussion

Intestinal microbiota and its relation with obesity

The identification of differences in the intestinal microbiota of obese and thin people¹⁴ suggests the involvement of microbiota in energy homeostasis and storage of lipids.¹¹ Changes in microbial composition were observed in diabetic¹⁵ animal models and in those with metabolic syndrome,¹⁶ which reinforces its possible association with metabolic disorders.

The increased expression of genes related to codification of enzymes which are responsible for the degradation of indigestible polysaccharides would lead obese animals to greater generation of fermentation products, with fewer calories remaining in the feces, compared to thin animals.¹⁰ In this case, the intestinal microbiota would affect both sides of energy balance by acting in absorption and regulating host genes related to obesity.¹⁸

In another study on transfer of microbiota to germfree animals, the acquisition of microbiota led to a rapid weight gain associated with the stimulation of hepatic glycogenesis and triglyceride synthesis. After installation of the microbiota, stimulation of detoxification pathways was observed with altered expression of cytochrome P450 enzymes, strengthening microbial activity in the process of xenobiotic metabolization.¹⁹

Human intestinal microbiota is composed predominantly of two phyla: Firmicutes and Bacteroidetes.²⁰ Both in humans and in animal models, obesity was correlated to changes in these groups^8,21-23 and obese individuals would present predominance of Firmicutes and a smaller proportion of Bacteroidetes when compared to non-obese.¹⁵

The comparison of sequences of 16S rRNA of intestinal bacteria of obese (ob/ob) and lean (ob/+ and +/+) mice showed a 50% reduction in the Bacteroidetes and proportional increase in the Firmicutes.⁸ In obese pigs, the proportion of Bacteroidetes was negatively correlated with body weight when compared to lean pigs, even when both groups were fed with the same diet and underwent the same environmental conditions.²⁴

In studies with humans, comparisons of the microbiota were made among 20 obese individuals to 20 healthy ones with normal weight (controls) and to 9 patients with anorexia nervosa. The comparison confirmed the reduction of Bacterioidetes in obese people, as observed in animal models; and there was no difference for Firmicutes among the groups. It was observed, however, a significant increase in Lactobacillus in obese. Since this species is widely used in food industry, people should be warned about its possible association with obesity. In the same study, the anorexic patients showed significantly higher concentration of Methanobrevibacter smithii suggesting a possible adaptive response to nutrient deprivation. Besides removing excess H₂ from the intestinal lumen, which compromises the fermentation process, M. smithii reduces H₂ with CO₂ for methane production leading to better use of a hypocaloric diet.²²

Zhang et al.¹⁴ observed an increase of the group Archaea in obese individuals, a group that in animal models was associated with higher extraction of polysaccharides from the diet, by the removal of H₂ formed by fermentation and increased production of short chain fatty acids (SCFA).²⁵

Differences between the microbial profile of obese and non-obese were also observed in pregnant women^26,27 and children.^28,29 In a prospective study, it was observed that the composition and development of the microbiota in children is influenced by weight, Body Mass Index (BMI), and the weight gain during pregnancy. In the groups Bacteroides, Clostridium and Staphylococcus, a clear change was observed in the predisposition to greater energy storage and development of inflammatory processes.²⁶

Organisms predisposed to obesity are believed to have an intestinal microbial community that promotes more efficient extraction and/or storage of energy from the diet consumed when compared to the microbiota of non-obese⁸ and that the diet would be able to modulate the microbial ecology.²¹ It is proposed that some mechanisms are interconnected (fig. 2): fermentation of dietary polysaccharides that cannot be digested by human enzymes, subsequent intestinal absorption of monosaccharides and SCFA, transport to the liver and production of triglycerides by de novo synthesis, with lipid deposition in the adipocytes and transport to other tissues, such as muscles.^9,30

Besides increased utilization of the nutrients ingested, recent studies suggest the occurrence of a relationship between the composition of the microbiota and subclinical chronic inflammation associated with obesity.¹⁷ Bacterial lipopolysaccharides (LPS) are believed to trigger this process. LPS are products that degrade the cell wall of gram-negative bacteria that, in large quantities, are transported to the intestinal capillaries by a mechanism that depends on the TLR4 receptor (Toll-Like Receptor-4) of the intestinal mucosa. The binding of LPS to the TLR4 receptor initiates a cascade of inflammatory events with the secretion of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor a (TNF-α). Transported to other tissues by chylomicrons synthesized from a high fat diet, LPL stimulate the production of inflammatory cytokines and promote a condition called "metabolic endotoxemia.¹¹

Chronic administration of high-fat diet for four weeks significantly increased LPS plasma concentration. When endotoxemia was induced by subcutaneous infusion of LPS, fasting glycemia, insulinemia and the body weight, liver and adipose tissue presented similar increase, as observed in the animals that ingested high-fat diet. Increased inflammatory markers and hepatic triglycerides were also observed. These findings demonstrate that endotoxemia alters inflammatory condition and is related to weight gain and diabetes. It suggests that LPS decrease could be an important strategy in the control of metabolic diseases.¹¹

Another mechanism associated with obesity is the suppression of Fasting-Induced Adipose Factor (FIAF) by intestinal microbiota. FIAF is an inhibitor of lipoprotein lipase (LPL), an enzyme that hydrolyzes triglycerides and stimulates its storage in adipocytes. Colonization increases LPL activity and lipid storage through FIAF suppression, an essential procedure for the deposition of triglyceride in fat cells mediated by microbiota.^9,30

Germ-free C57BL/6 mice were resistant to obesity when submitted to the consumption of a diet rich in fats and sugars. Protection against obesity is believed to be related to two independent but complementary mechanisms that result in reduced lipid storage: high levels of FIAF and increased activity of AMP-activated protein kinase (adenosine monophosphate) (AMPK), an enzyme that favors lipid oxidation in muscles and liver.³⁰

Microbial profile can be changed by weight loss. Obese individuals, who initially presented predominance of Firmicutes in comparison to Bacteroidetes, altered their microbial profile to an inverse proportion after the intake of low-calorie diets (with restriction in carbohydrates or lipids) for one year, regardless of the diet²¹ used. Reduced Firmicute/Bacteroidete ratio was observed in obese individuals after weight loss, which suggests that the manipulation of specific bacteria could benefit the treatment of obesity. In another study, the replacement of a standard diet by a high-fat diet in mice, led to a reduction of Bacteroidetes and increase of Firmicutes and Proteobacteria, regardless of the presence or absence of obesity, which suggests that a high fat diet, instead of obesity itself, as the main responsible for changes in intestinal microbiota and determines its composition.³¹

Also associated with weight loss, and possibly with changes in the amount and type of diet eaten, bariatric surgery is related to changes in microbial diversity.³² Reduction in the phylum Firmicutes was evident in individuals after Roux en Y gastric bypass procedure, as well as a proportional increase in Gammaproteobacteria.¹⁴

Therefore, studies indicate the potential of intestinal microbiota as a biomarker, mediator and new therapeutic target for metabolic diseases,¹⁰ including obesity.

Microbiota modulation through prebiotics and probiotics

Due to evidence of the relationship between intestinal microbiota and obesity, it is necessary to understand if it is possible to manipulate this microbiota to prevent obesity or contribute to weight reduction. In this sense, studies with animals and humans have been developed using food and compounds with prebiotic and probiotic allegation.

Studies with animal models are presented in table I,^33-57 focusing on the main objective, the test food/compound, and the main findings.

Among the studies that used probiotics, the Lactobacillus species were the most explored and presented different results. While the administration of Lactobacillus ingluvieie and Lactobacillus increased body weight^44,49,56 and inflammatory markers in mice,⁴⁴ doses of Lactobacillus paracasei reduced fat accumulation. This result was explained by the authors as an effect of L. paracasei, which increased gene expression for ANGPTL 4 (Angiopoietin-Like 4), a circulating lipoprotein lipase inhibitor.⁴⁸ In another study, the addition of Lactobacillus plantarum to the high fat diet reduced the average size of adipocytes compared to the control diet.⁴⁹

Supplementation with Lactobacillus ingluviei in the diet of BALB/C mice led to increased DNA expression for Firmicutes and Lactobacillus.⁴⁴ As previously demonstrated, increased proportion of Firmicutes is a common finding in obese mice^12,41,47 and some studies with probiotics have shown effects that favored reduction in this proportion.^41,47

Everard et al.⁴⁷ administered prebiotics to genetically obese animals and observed reduction in the amount of Firmicutes and increase in the amount of Bacterioidetes, as well as reduced lipid reserves. In the study of Panell and Reiner,⁴¹ the amount of Bacterioidetes was negatively correlated with the consumption of energy, fat percentage, and body weight.

Other microorganisms seem to have a significant effect on the "obesogenic microbiota", such as bifidobacteria. Among the legumes studied by Queiróz-Monici et al.,³³ dietary fiber and resistant starch from pea led to a significant increase in the content of bifidobacteria. When analyzing the effects of fermentable (oligofructose) and non-fermentable (cellulose) fibers on the intestinal microbiota of obese mice, Cani et al.³⁶ found more significant results in the groups that received oligofructose. This group, compared to control, showed increased total content of bacteria, Bifidobacterium spp., Lactobacillus spp. and Clostridium coccoides. In the group treated with cellulose, increased total content of bacteria and the Bifidobacterium spp. was observed. In this study, it was also concluded that the use of prebiotics reduced intestinal permeability, and the latter was related to the growth of Bifidobacterium spp.

High fat diets increase intestinal permeability^12,37 and one of the reasons for that may be the reduction of gene expression that encode the proteins of the junctions among colonocytes.³⁷ The results presented by Cani et al.³⁶ point out that the modulation of the microbiota by using prebiotics in mice may favor the intestinal wall by reducing endotoxemia and systemic and liver inflammation, which brings beneficial consequences for metabolic disorders.

The use of prebiotics and probiotics aiming to modulate the hormonal response of the gastrointestinal tract has also been investigated in animals.^41,44,33,33 The administration of a mixture of aqueous extracts during six months reduced food intake and, consequently, weight gain, followed by an increase in serum adiponectin, a hormone with significant anti-inflammatory³³ activity. The lactitol supplementation increased the acute postprandial of peptide YY.³³ The addition of inulin and oligofructose also increased the serum concentrations of this peptide, which is a hormone with anorexigenic action.⁴¹ The hormone leptin is another appetite suppressant that has been positively correlated with weight.^49,31 Cani et al.³⁶ reported that oligofructose caused an increase in the concentrations of GLP-1 (Glucagon-Like Peptide-1), a hormone that acts on gastric emptying.

The addition of prebiotics and probiotics to the diet of animals is also associated with increased tolerance to glucose,^39,47,31 reduction of low-grade inflammation⁴⁷ as well as in rate of total cholesterol,^49,36 which are conditions often related to obesity.

The works on humans are summarized in table II.^4,38-61

Among the studies analyzed, four deal with the modulation of intestinal microecology, three of those describe the expansion in the number of bifidobacteria.^4,38,39 Although these studies do not report significant effects on food intake, except for the study with gums,⁶¹ works using animals associate increased bifidobacteria to reduced food intake¹² and increased concentrations of anorexigenic hormones.^36,41

Shinohara et al.⁴ assessed the effects of apple consumption in healthy volunteers and found increased content of Bifidobacterium and Lactobacillus in feces while Bacterioidetes presented reduction. The authors contend that the increased amount of SCFA, resulting from the increase of certain groups of bacteria by pectin fermentation, inhibited the growth of Bacterioidetes. Moreover, they claim that regular use of apple, one of the most common fruits worldwide, may have beneficial effects on health. According to Calame et al.,⁶¹ Arabic gum may be important for the treatment of obesity or weight maintenance once they increase satiety, thus reducing food intake.

In order to evaluate the impact of a prenatal intervention with probiotics on the development of obesity in children in a period of 10 years, units containing Lactobacillus rhamnosus or placebo were administered to pregnant women. Through the anthropometric measurements the concluded that early modulation of the microbiota could modify the standard of weight gain in children during the first six months of life.⁶⁰ However, the breast-feeding condition of the children involved in the study was not clear and may cause some confusion since breast-feeding itself provides numerous benefits, including prevention of obesity in childhood and adult life.⁶²

Ten of the animal studies that analyzed microbiota modulation reported increased amount of bifidobacteria,^{4,33,34,35,36,38,40,41,52,58} which was followed by reduced weight gain,^33,34 reduced adipogenic effects of a high fatdiet,³⁵ reduced intestinal permeability^36,41 and decreased inflammatory markers.^34,52 The modulation of these microorganisms is supposed to contribute to the prevention and even reduction of the impacts of excessive weight. In the clinical trials analyzed, increased Bifidobacterium was observed after three weeks of coffee intake (three cups a day); two weeks of apple intake (two units a day);^34,52 and three weeks of consumption of 5 g or 10 g of chocolate containing galactooligosaccharides.⁵⁸ Other effects were reported in the work of Shinohara et al.,⁴ including increased production of SCFA. The relatively short period of the clinical trials may have been insufficient to make the benefits that accompany the increased bifidobacteria, which were found in the experimental studies, could be clinically visible in humans.

Advances achieved in knowledge about the role of each species may contribute to the "obesogenic microbiota". Neyrink et al.³⁵ analyzed the effects of chitinglucan on dysbiosis in mice with obesity induced by high fat diet and found a negative correlation between the bacterium Clostridium XIV (e.g. Roseburia spp) and weight gain and lipid accumulation. Million et al.¹³ examined feces of lean and obese individuals and identified the depletion of Methanobrevibacter smithii and Bacterioidetes and the presence of Lactobacillus reuteri, under obesity condition.

Progress in genomics techniques will soon allow the determination of which microorganisms among the species are the main responsible for increased conversion of food into energy in the large intestine. It will also reveal the most effective probiotics in the modulation of "obesogenic microbiota".

Conclusion

The participation of the intestinal microbiota in weight gain and the elucidation of its impact on metabolic pathways lead to factors associated with obesity and indicate new possible intervention targets. Regarding modulation by prebiotics and probiotics, differences in methods and results were observed. However, increased bifidobacteria were the main modulator effect observed, usually accompanied by weight loss and obesity-related parameters, supposing the minimization of the impact of excess weight on health. The short period of intervention of some studies may have been the cause of little apparent effects, which are promising, though.

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Correspondence:
Josefina Bressan.
Department of Nutrition and Health. ]]> Federal University of Viçosa.
Avenida PH Rolfs, s/n, Centro.
36 570-000 Viçosa, MG, Brazil.
E-mail: jbrm@ufv.br

Recibido: 22-II-2013.
Aceptado: 27-VI-2013.