Efeito da modulação da microbiota intestinal sobre a ação da estimulação beta3-adrenérgica e da triiodotironina no tecido adiposo

Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2018.Introdução: A microbiota intestinal pode estar relacionada com a patogênese e progressão da obesidade, por meio da sua influência sobre processos metabólicos do hospedeiro, dentre eles o gasto energético. Este tem como um de seus componentes a termogênese adaptativa no tecido adiposo (TA) termogênico. Os principais estímulos à termogênese adaptativa são a sinalização 3-adrenérgica e o hormônio tireoidiano (HT). Objetivo: Avaliar o efeito da modulação da microbiota intestinal sobre o efeito da sinalização β3-adrenérgica ou pelo HT no TA. Métodos: Camundongos machos C57BL/6 foram alimentados com dieta normolipídica ou hiperlipídica e divididos aleatoriamente em seis grupos contento cinco animais cada: controle, antibióticos (ATB), agonista 3-adrenérgico (CL316,243), triiodotironina (T3), antibióticos + CL316,243 e antibióticos + T3. Os animais foram tratados com ATB na água de beber (vancomicina 0,5 g/L e ciprofloxacina 0,2 g/L por 5 semanas), CL316,243 por via intraperitoneal (1 mg/kg/dia, 5 dias) e T3 por via intraperitoneal (10 g/dia, 3 dias). Foram avaliados ganho de peso corporal, ingestão hídrica, ingestão de energia, eficiência calórica, massa dos depósitos de TA e do fígado, expressão de genes relacionados à termogênese e à ação do HT no TA, concentração sérica de TSH e atividade da desiodinase tipo 2 (DIO2) no tecido adiposo branco (TAB) subcutâneo axilar. Resultados: No cenário de dieta normolipídica, o CL316,243 reduziu a massa do TAB visceral e, na presença de ATB, reduziu a massa do TAB subcutâneo. O T3 reduziu a massa do TAB epididimal e, na presença de ATB, aumentou a massa do TA marrom (TAM). O CL316,243 ou T3 aumentaram a expressão de Ucp1 no TAB e, na presença de ATB, houve acentuação da indução de Ucp1 em resposta ao CL316,243. A modulação da microbiota reduziu a atividade da DIO2 e não modificou a concentração sérica de TSH. No cenário de dieta hiperlipídica, o uso CL316,243 e o T3, isoladamente e com ATB, não modificaram a massa de TAB. O T3 aumentou a massa do TAM. O CL316,243 e T3, isoladamente, aumentaram a expressão de Ucp1 no TAB; o co-tratamento com ATB acentuou a indução de Ucp1 pelo CL316,243 e diminuiu a indução deste transcrito pelo T3. No TAB inguinal, o uso de ATB acentuou a indução de Ppargc1a e Dio2 pelo CL316,243 e pelo T3. No TAB epididimal, o tratamento com ATB diminuiu a indução de Prmd16 pelo T3. A modulação da microbiota resultou em tendência de redução da atividade da DIO2 e não modificou a concentração sérica de TSH. Conclusão: Em condições basais, a microbiota intestinal não apresenta efeito significativo sobre a transcrição do gene que codifica a UCP-1 no TAB e no TAM, porém pode reduzir a ação do HT por diminuir sua ativação intracelular no TAB. Além disso, a resposta do TAB aos estímulos termogênicos clássicos parece ser influenciada de forma distinta pela microbiota intestinal.Background: Gut microbiota composition is associated with the pathogenesis and progression of obesity, possibly due to its major role in regulating components of the host’s metabolic homeostasis, such energy expenditure. The latter comprises adaptive thermogenesis in adipose tissue (AT), which is classically stimulated by β3-adrenergic signaling and thyroid hormone (TH). Objective: To evaluate the effect of gut microbiota modulation on the action of β3-adrenergic signaling and TH on AT. Methods: Male C57BL/6 mice were fed a control or high fat diet and randomly assigned into six groups containing five animals each: control, antibiotics (ATB), β3-adrenergic agonist (CL316,243), triiodothyronine (T3), antibiotics + CL316,243 and antibiotics + T3. The animals were treated with ATB in drinking water (vancomycin 0.5 g/L and ciprofloxacin 0.2 g/L for 5 weeks), CL316,243 intraperitoneally (1 mg/kg/day, 5 days) and T3 intraperitoneally (10 μg/day, 3 days). Body weight gain, water intake, energy intake, caloric efficiency, AT and liver mass, expression of genes related to thermogenesis and to the action of TH in TA, serum TSH concentration and type 2 deiodinase (DIO2) activity in axillary subcutaneous white adipose tissue (WAT) were evaluated. Results: In the control diet scenario, CL316,243 reduced visceral WAT mass and, in the presence of ATB, reduced the mass of subcutaneous WAT. T3 reduced visceral (epididymal) WAT mass and, in the presence of ATB, increased brown AT (BAT) mass. Treatment with CL316,243 or T3 increased Ucp1 expression in WAT and, in the presence of ATB, there was an enhancement of Ucp1 induction in response to CL316,243. Modulation of gut microbiota reduced the activity of DIO2 in WAT and did not modify the serum TSH concentration. In the high fat diet scenario, CL316,243 and T3, alone or with ATB, did not modify the WAT mass, and T3 increased BAT mass. Both treatment with CL316,243 or T3 alone increased Ucp1 expression in WAT; co-treatment with ATB enhanced the induction of Ucp1 by CL316,243 and decreased the induction of this transcript by T3. In inguinal WAT, ATB treatment enhanced the induction of Ppargc1a and Dio2 by CL316,243 and T3. In epididymal WAT, treatment with ATB decreased the induction of Prmd16 by T3. Modulation of gut microbiota resulted in a trend towards reduction of DIO2 activity in WAT and did not modify the serum TSH concentration. Conclusion: Under basal conditions, the gut microbiota has no significant effect on the transcription of the gene encoding UCP-1 in TAB and TAM, but may reduce TH action in WAT by decreasing its intracellular activation. Moreover, WAT response to classical thermogenic stimuli seems to be influenced differently by the gut microbiota

Avaliação da microbiota intestinal e sua relação com parâmetros metabólicos em mulheres com obesidade mórbida

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Nutrição, Florianópolis, 2014Introdução: A microbiota intestinal refere-se aos micro-organismos que reside no trato gastrointestinal, sendo colonizada por bactérias que habitam permanentemente e temporariamente este órgão. Além dos fatores comumente envolvidos nas disfunções metabólicas presentes no indivíduo obeso, a microbiota intestinal pode estar relacionada com a patogênese e a progressão da obesidade. Na obesidade o acúmulo do tecido adiposo acarreta alterações na homeostase glicêmica e no perfil lipídico. Alterações dessas vias metabólicas pela obesidade podem estar relacionadas com a microbiota intestinal. Objetivo: Avaliar as concentrações fecais de Bifidobacterium spp., Lactobacillus spp., pH fecal e parâmetros metabólicos em mulheres com obesidade mórbida e comparar com as mulheres eutróficas, como também associar as concentrações de Bifidobacterium spp. e Lactobacillus spp com os parâmetros metabólicos, em mulheres com obesidade mórbida. Métodos: Estudo transversal realizado em 19 mulheres com obesidade mórbida no pré-operatório da cirurgia bariátrica e em 13 mulheres eutróficas. Foram realizadas coleta de fezes, para determinação dos gêneros Bifidobacterium spp, Lactobacillus spp. e pH fecal, coleta de sangue pra determinação dos parâmetros lipídicos e glicêmicos, coleta de dados clínicos e avaliação do estado nutricional. Para todos os testes estatísticos realizado, foi adotado o nível de significância de pAbstract: Background: The gut microbiota consists in the colony of microorganisms that reside in the gastrointestinal tract, being colonized by bacteria that inhabit permanently and temporarily this organ In addition to the common factors involved in metabolic dysfunctions in obese individual, the gut microbiota may be related to the pathogenesis and progression of obesity. In obesity, the accumulation of adipose tissue leads to changes in glucose homeostasis and lipid profile. Abnormalities in these metabolic pathways triggered by obesity may be related to the gut microbiota. Objectives: Evaluate the concentrations feacal of Bifidobacterium spp., Lactobacillus spp., fecal pH and metabolic parameters in obese women and compared with non-obese women. Associate these concentrations of Bifidobacterium spp. and Lactobacillus spp with metabolic parameters in women with morbid obesity. Methods: Cross-sectional study with 19 women with morbid obesity in preoperative bariatric surgery and 13 normal-weight women. Stool samples were collected to determine Bifidobacterium spp., Lactobacillus spp. and fecal pH, as well as blood samples for determination of lipid and glycemic parameters. Clinical data collection and evaluation of nutritional status were also performed. For all statistical tests performed, a significance level of p <0.05 was adopted. Results: Fecal concentrations of Bifidobacterium spp., Lactobacillus spp. and fecal pH were not significantly different between the study groups. Plasma concentrations of HDL-C, VLDL-C, triacylglycerol, glycated hemoglobin, insulin and HOMA-IR showed a significant difference between the study groups (p <0.05). There was no association between concentrations of Bifidobacterium spp. and Lactobacillus spp. with glycemic and lipid parameters in women with morbid obesity. Conclusion: The concentrations of Bifidobacterium spp. and Lactobacillus spp are similar in the groups studied, there was also no association of these bacteria with metabolic parameters. These results with possible influence of the period of monitoring and nutritional guidelines, prior to surgical indication Nevertheless, this study provides subsidy for the continuity of longitudinal studies to evaluate interventions

Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity : a systematic review and meta-analysis

Objective Endocrine-disrupting chemicals (EDCs) are viewed as a major potential link between the environment and obesity development. We did a systematic review and meta-analysis to examine the association between exposure to EDCs and obesity. Data sources, design and eligibility criteria PubMed, Scopus and Web of Science were searched from inception to 6 June 2018 for studies primarily addressing the association between exposure to EDCs after the age of 2 years and anthropometric measures of obesity or body fat. The Newcastle-Ottawa scale was used to assess the risk of bias. Data extraction and synthesis Two independent reviewers screened and conducted data extraction and synthesis. A third reviewer resolved disagreements. Results A total of 73 studies investigating bisphenol A (32 286 individuals), organochlorine compounds (34 567 individuals), phthalates (21 401 individuals), polybrominated biphenyls (2937 individuals), polycyclic aromatic hydrocarbons (5174 individuals), parabens (4097 individuals), benzoic acid (3671 individuals) and polyfluoroalkyl substances (349 individuals) met our inclusion criteria. Most had a cross-sectional design and low or medium risk of bias. In qualitative analysis, bisphenol A and phthalates were consistently associated with general and abdominal obesity, in children and adults, and some studies suggested this association was age-dependent and gender-dependent. Meta-analysis indicated a significant association between exposure to bisphenol A and overweight (OR 1.254, 95%CI 1.005 to 1.564), obesity (OR 1.503, 95%CI 1.273 to 1.774) and increased waist circumference (OR 1.503, 95%CI 1.267 to 1.783) in adults, and between exposure to 2,5-dichlorophenol and obesity in children (OR 1.8, 95%CI 1.1018 to 3.184). Conclusion Most observational studies supported a positive association between obesity and exposure to EDCs. Although causality cannot be determined from these data, they underscore the need to limit human exposure to EDCs in light of the evidence from animal and cellbased studies indicating the effects of these chemicals on adiposity

LOWER BIFIDOBACTERIA COUNTS IN ADULT PATIENTS WITH CELIAC DISEASE ON A GLUTEN-FREE DIET

Context The ingestion of gluten is responsible for the symptoms of Celiac disease, but other environmental factors can also influence. Strains of the Bifidobacterium genus have been shown to afford protection against the inflammatory response and mucosal damage caused by gliadin peptides in vitro. Objectives This study was designed to compare the concentration of fecal bifidobacteria and pH of patients with celiac disease on gluten-free diet and control subjects in order to identify if the imbalance on fecal microbiota still remain during the treatment of celiac disease and identify the necessity of dietary supplementation with pre- or probiotics. Methods It was analyzed the feces of 42 healthy subjects and 14 celiac patients. The bifidobacteria count in feces was done in selective medium BIM-25. Microscopic analysis of the colonies was performed by Gram stain. The identification of the genus Bifidobacterium was performed by determination of fructose-6-phosphate phosphoketolase. Fecal pH was measured using a pH meter. Results The concentration of bifidobacteria per gram of feces was significantly higher in healthy subjects (controls) (1.5 ± 0.63 x108 CFU/g) when compared to celiac patients (2.5 ± 1.5 x107 CFU/g). The fecal pH was not different between celiac patients (7.19 ± 0.521) and controls (7.18 ± 0.522). Conclusions These results suggest that with lower levels of bifidobacteria, celiac patients have an imbalance in the intestinal microbiota, regardless of pH, even while on a gluten-free diet. This fact could favor the pathological process of the disorder

Análise dos fatores associados ao risco nutricional de pacientes em hemodiálise

Objetivo: Analisar a frequência e os fatores associados ao risco nutricional (RN) de pacientes com doença renal crônica (DRC) submetidos à hemodiálise. Métodos: Estudo de corte transversal, analítico, realizado com 110 indivíduos com idade ≥ 20 anos,em tratamento hemodialítico em duas clínicas de Cuiabá, Mato Grosso, Brasil, no período de junho a outubro de 2018. Os dados foram coletados por meio de entrevista, aferições e consulta ao prontuário clínico. Avaliou-se a associação entre o desfecho pontuação do Malnutrition Inflammation Score (MIS) e as variáveis socioeconômicas, demográficas, clínicas, de comportamentos de risco relacionados à saúde e de estado nutricional. Realizou-se análise bivariada pelo teste de qui-quadrado de Pearson e regressão logística binária bruta e ajustada, considerando significativo p≤0,05. Resultados: Foi observada elevada frequência de indivíduos com alto RN (n=73; 66,36%), sendo maior entre os pacientes com tempo de diálise ≥ 4 anos, volume de urina/24