RESUMO
AIM: The present cohort study explored whether specific gut microbiota (GM) profile would predict the development of impaired glucose tolerance (IGT) in individuals with normal glucose tolerance (NGT). METHODS: A total of 114 study subjects with NGT in Kumejima island, Japan participated in the present study and underwent 75 g oral glucose tolerance tests at baseline and one year later. We compared the profile of GM at baseline between individuals who consistently maintained NGT (NRN, n = 108) and those who transitioned from NGT to IGT (NTI, n = 6). RESULTS: Within-individual bacterial richness and evenness as well as inter-individual bacterial composition showed no significant differences between NRN and NTI. Of note, however, partial least squares discriminant analyses revealed distinct compositions of GM between groups, with no overlap in their 95 % confidence interval ellipses. Multi-factor analyses at the genus level demonstrated that the proportions of CF231, Corynebacterium, Succinivibrio, and Geobacillus were significantly elevated in NTI compared to NRN (p < 0.005, FDR < 0.1, respectively) after adjusting for age, sex, HbA1c level, and BMI. CONCLUSIONS: Our data suggest that increased proportion of specific GM is linked to the future deterioration of glucose tolerance, thereby serving as a promising predictive marker for type 2 diabetes mellitus.
Assuntos
Microbioma Gastrointestinal , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Intolerância à Glucose/microbiologia , Intolerância à Glucose/sangue , Feminino , Masculino , Microbioma Gastrointestinal/fisiologia , Pessoa de Meia-Idade , Estudos de Coortes , Japão/epidemiologia , Glicemia/metabolismo , Glicemia/análise , Adulto , Idoso , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/sangueRESUMO
A recent animal study demonstrated that administration of Lactobacillus plantarum HAC01 isolated from Korean kimchi improved glycemic control in type 2 diabetic mice. In the present study, we evaluated Lactobacillus plantarum HAC01's effects on metabolic parameters of prediabetic human subjects. Forty subjects with isolated impaired glucose tolerance were randomly assigned to receive a daily placebo (n = 20) or a dose of Lactobacillus plantarum HAC01 (n = 20) over eight weeks. The primary endpoint was a change in 2 h postprandial glucose (2h-PPG) levels and the secondary endpoints were assessment of other glucose metabolism parameters, including HbA1c, gut microbiota composition, and fecal short-chain fatty acids (SCFAs). The group with a diet supplemented with Lactobacillus plantarum HAC01 saw a significant reduction in 2h-PPG and HbA1c levels compared to the placebo group. Fasting plasma glucose, insulin, HOMA-IR, QUICKI, microbiota composition, and fecal SCFAs, however, were not significantly altered. No serious adverse effects were reported. This is the first clinical trial to show a beneficial effect of single-strain probiotic supplementation administered over eight weeks on HbA1c levels in prediabetic subjects.
Assuntos
Intolerância à Glucose/microbiologia , Controle Glicêmico/métodos , Lactobacillus plantarum , Estado Pré-Diabético/microbiologia , Probióticos/administração & dosagem , Adulto , Glicemia/metabolismo , Método Duplo-Cego , Ácidos Graxos Voláteis/análise , Fezes/química , Feminino , Microbioma Gastrointestinal , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Estado Pré-Diabético/sangue , Resultado do TratamentoRESUMO
Consumption of different types of high-calorie foods leads to the development of various metabolic disorders. However, the effects of multi-strain probiotics on different types of diet-induced obesity and intestinal dysbiosis remain unclear. In this study, mice were fed a control diet, high-fat diet (HFD; 60% kcal fat and 20% kcal carbohydrate), or western diet (WD; 40% kcal fat and 43% kcal carbohydrate) and administered with multi-strain AB-Kefir containing six strains of lactic acid bacteria and a Bifidobacterium strain, at 109 CFU per mouse for 10 weeks. Results demonstrated that AB-Kefir reduced body weight gain, glucose intolerance, and hepatic steatosis with a minor influence on gut microbiota composition in HFD-fed mice, but not in WD-fed mice. In addition, AB-Kefir significantly reduced the weight and size of adipose tissues by regulating the expression of CD36, Igf1, and Pgc1 in HFD-fed mice. Although AB-Kefir did not reduce the volume of white adipose tissue, it markedly regulated CD36, Dgat1 and Mogat1 mRNA expression. Moreover, the abundance of Eubacterium_coprostanoligenes_group and Ruminiclostridium significantly correlated with changes in body weight, liver weight, and fasting glucose in test mice. Overall, this study provides important evidence to understand the interactions between probiotics, gut microbiota, and diet in obesity treatment.
Assuntos
Dieta da Carga de Carboidratos/métodos , Dieta Hiperlipídica/métodos , Kefir/microbiologia , Obesidade/dietoterapia , Probióticos/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Animais , Peso Corporal , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental , Sacarose Alimentar/administração & dosagem , Modelos Animais de Doenças , Disbiose/dietoterapia , Disbiose/microbiologia , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Intolerância à Glucose/dietoterapia , Intolerância à Glucose/microbiologia , Inflamação , Fígado/patologia , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/microbiologia , Aumento de Peso/efeitos dos fármacosRESUMO
The ketogenic diet (KD), which can induce changes in gut microbiota, has shown benefits for epilepsy and several neurodegenerative diseases. However, the effects of a KD on glucose and lipid metabolism remain inconclusive. Using two formulas of ketogenic diets (KDR with 89.5% fat and KDH with 91.3% fat), which are commonly used in mouse trials, we found that KDR but not KDH induced insulin resistance and damaged glucose homeostasis, while KDH induced more fat accumulation in mice. Further study showed that KD impacted glucose metabolism, which was related to the sources of fat, while both the sources and proportions of fat affected lipid metabolism. And the KD widely used in human studies still induced insulin resistance and fat accumulation in mice. Moreover, KDs changed the gut microbiota and metabolites in mice, and the sources and proportions of fat in the diets respectively changed the abundance of specific bacteria and metabolites which were correlated with parameters related to glucose intolerance and lipid accumulation. Overall, our study demonstrated that the metabolic disorders induced by KDs are closely related to the source and proportion of fat in the diet, which may be associated with the changes of the gut microbiota and metabolites.IMPORTANCE The ketogenic diet with extremely high fat and very low carbohydrate levels is very popular in society today. Although it has beneficial effects on epilepsy and neurodegenerative diseases, how ketogenic diets impact host glucose and lipid metabolism and gut microbiota still needs further investigation. Here, we surveyed the effects of two ketogenic diets which are commonly used in mouse trials on metabolic phenotypes, gut microbiota, and metabolites in mice. We found that both ketogenic diets impaired glucose and lipid metabolism in mice, and this may be due to the sources and proportions of fat in the diets. This work highlights the potential risk of glucose and lipid metabolism disorders and the importance of evaluating the sources and proportions of fat in the diets, when using ketogenic diets for weight loss and the treatment of diseases.
Assuntos
Bactérias/metabolismo , Dieta Cetogênica/efeitos adversos , Microbioma Gastrointestinal , Intolerância à Glucose/etiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
AIMS: To identify fecal microbiota profiles associated with metabolic abnormalities belonging to the metabolic syndrome (MS), high count of white blood cells (WBCs) and insulin resistance (IR). METHODS: Sixty-eight young patients with obesity were stratified for percentile distribution of MS abnormalities. A MS risk score was defined as low, medium, and high MS risk. High WBCs were defined as a count ≥ 7.0 103/µL; severe obesity as body mass index Z-score ≥ 2 standard deviations; IR as homeostatic assessment model algorithm of IR (HOMA) ≥ 3.7. Stool samples were analyzed by 16S rRNA-based metagenomics. RESULTS: We found reduced bacterial richness of fecal microbiota in patients with IR and high diastolic blood pressure (BP). Distinct microbial markers were associated to high BP (Clostridium and Clostridiaceae), low high-density lipoprotein cholesterol (Lachnospiraceae, Gemellaceae, Turicibacter), and high MS risk (Coriobacteriaceae), WBCs (Bacteroides caccae, Gemellaceae), severe obesity (Lachnospiraceae), and impaired glucose tolerance (Bacteroides ovatus and Enterobacteriaceae). Conversely, taxa such as Faecalibacterium prausnitzii, Parabacterodes, Bacteroides caccae, Oscillospira, Parabacterodes distasonis, Coprococcus, and Haemophilus parainfluenzae were associated to low MS risk score, triglycerides, fasting glucose and HOMA-IR, respectively. Supervised multilevel analysis grouped clearly "variable" patients based on the MS risk. CONCLUSIONS: This was a proof-of-concept study opening the way at the identification of fecal microbiota signatures, precisely associated with cardiometabolic risk factors in young patients with obesity. These evidences led us to infer, while some gut bacteria have a detrimental role in exacerbating metabolic risk factors some others are beneficial ameliorating cardiovascular host health.
Assuntos
Fezes/microbiologia , Inflamação/microbiologia , Resistência à Insulina/fisiologia , Síndrome Metabólica/microbiologia , Microbiota/fisiologia , Obesidade , Adolescente , Bactérias/classificação , Bactérias/genética , Biomarcadores/sangue , Criança , Feminino , Intolerância à Glucose/microbiologia , Humanos , Hipertensão/microbiologia , Masculino , Metagenômica , Obesidade/complicações , Projetos Piloto , RNA Ribossômico 16S/análise , Fatores de Risco , Triglicerídeos/sangueRESUMO
Studies suggest the gut microbiota contributes to the development of obesity and metabolic syndrome. Exercise alters microbiota composition and diversity and is protective of these maladies. We tested whether the protective metabolic effects of exercise are mediated through fecal components through assessment of body composition and metabolism in recipients of fecal microbiota transplantation (FMT) from exercise-trained (ET) mice fed normal or high-energy diets. Donor C57BL/6J mice were fed a chow or high-fat, high-sucrose diet (HFHS) for 4 wk to induce obesity and glucose intolerance. Mice were divided into sedentary (Sed) or ET groups (6 wk treadmill-based ET) while maintaining their diets, resulting in four donor groups: chow sedentary (NC-Sed) or ET (NC-ET) and HFHS sedentary (HFHS-Sed) or ET (HFHS-ET). Chow-fed recipient mice were gavaged with feces from the respective donor groups weekly, creating four groups (NC-Sed-R, NC-ET-R, HFHS-Sed-R, HFHS-ET-R), and body composition and metabolism were assessed. The HFHS diet led to glucose intolerance and obesity in the donors, whereas exercise training (ET) restrained adiposity and improved glucose tolerance. No donor group FMT altered recipient body composition. Despite unaltered adiposity, glucose levels were disrupted when challenged in mice receiving feces from HFHS-fed donors, irrespective of donor-ET status, with a decrease in insulin-stimulated glucose clearance into white adipose tissue and large intestine and specific changes in the recipient's microbiota composition observed. FMT can transmit HFHS-induced disrupted glucose metabolism to recipient mice independently of any change in adiposity. However, the protective metabolic effect of ET on glucose metabolism is not mediated through fecal factors.
Assuntos
Dieta Hiperlipídica , Sacarose Alimentar , Transplante de Microbiota Fecal , Intolerância à Glucose/microbiologia , Obesidade/microbiologia , Condicionamento Físico Animal , Comportamento Sedentário , Adiposidade , Animais , Microbioma Gastrointestinal , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Masculino , Camundongos , Obesidade/metabolismo , Distribuição AleatóriaRESUMO
Results from epidemiological and prospective studies indicate a close association between periodontitis and diabetes. However the mechanisms by which periodontal pathogens influence the development of prediabetes/diabetes are not clear. We previously reported that oral administration of a periodontal pathogen, Porphyromonas gingivalis (Pg) to WT mice results in insulin resistance, hyperinsulinemia, and glucose intolerance and that Pg translocates to the pancreas. In the current study, we determined the specific localization of Pg in relation to mouse and human pancreatic α- and ß-cells using 3-D confocal and immunofluorescence microscopy and orthogonal analyses. Pg/gingipain is intra- or peri-nuclearly localized primarily in ß-cells in experimental mice and also in human post-mortem pancreatic samples. We also identified bihormonal cells in experimental mice as well as human pancreatic samples. A low percentage of bihormonal cells has intracellular Pg in both humans and experimental mice. Our data show that the number of Pg translocated to the pancreas correlates with the number of bihormonal cells in both mice and humans. Our findings suggest that Pg/gingipain translocates to pancreas, particularly ß-cells in both humans and mice, and this is strongly associated with emergence of bihormonal cells.
Assuntos
Ilhotas Pancreáticas/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/isolamento & purificação , Animais , Infecções por Bacteroidaceae/microbiologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/microbiologia , Modelos Animais de Doenças , Estudos Epidemiológicos , Intolerância à Glucose/microbiologia , Humanos , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Periodontite/complicações , Estado Pré-Diabético/etiologia , Estado Pré-Diabético/microbiologia , Estudos ProspectivosRESUMO
BACKGROUND: Probiotics are defined as microorganisms that can exert health benefits for the host. Among the recognized probiotics, Bifidobacterium are the most frequently used probiotics in humans. The aim of this study was to evaluate the antidiabetic activity of Bifidobacterium strains isolated from breastfed infant faeces, both in vitro, using the Caco-2 monolayer transwell model, and in vivo, using a mice model of impaired glucose tolerance induced by a high-fat diet (HFD). RESULTS: The cell-free supernatant of Bifidobacterium lactis A12 showed better inhibitory activity of α-glucosidase and inhibited the glucose absorption and transport than B. lactis BB12, which is a typical probiotic with antidiabetic capabilities. B. lactis A12 improved the impaired glucose intolerance, restored islet function and morphology with insulin resistance induced by the HFD in C57BL/6J mice. Furthermore, in small intestine tissues, the cell-free supernatant of B. lactis A12 decreased the messenger RNA expressions of sucrase-isomaltase, live B. lactis A12 cells decreased glucose transporters 2. B. lactis A12 significantly stimulated the glucagon like peptide-1 (GLP-1) secretion and upregulated proglucagon messenger RNA levels. CONCLUSION: B. lactis A12 protect against the deleterious effects of HFD-induced diabetes by inhibiting the utilization, absorption, and transport of glucose by intestinal epithelial cells and promoting the expression and secretion of GLP-1. © 2020 Society of Chemical Industry.
Assuntos
Bifidobacterium/metabolismo , Fezes/microbiologia , Intolerância à Glucose/prevenção & controle , Glucose/metabolismo , Incretinas/metabolismo , Probióticos/administração & dosagem , Animais , Bifidobacterium/genética , Bifidobacterium/isolamento & purificação , Aleitamento Materno , Dieta Hiperlipídica , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: Gut microbiota and their metabolites play an important role in the development of type 2 diabetes mellitus (T2DM). This research was designed to study the relationship between gut microbiota and faecal metabolites of Uyghur newly onset T2DM and impaired glucose regulation (IGR) patients. MATERIALS AND METHODS: A total of 60 different glycemic Uyghur subjects were enrolled and divided into T2DM, IGR, and normal glucose tolerance (NGT) groups. Metagenomics and LC-MS-based untargeted faecal metabolomics were employed. Correlations between bacterial composition and faecal metabolomics were evaluated. RESULTS: We discovered that the composition and diversity of gut microbiota in newly onset T2DM and IGR were different from those in NGT. The α-diversity was higher in NGT than in T2DM and IGR; ß-diversity analysis revealed apparent differences in the bacterial community structures between patients with T2DM, IGR, and NGT. LC-MS faecal metabolomics analysis discovered different metabolomics features in the three groups. Alchornoic acid, PE (14 : 0/20 : 3), PI, L-tyrosine, LysoPC (15 : 0), protorifamycin I, pimelic acid, epothilone A, 7-dehydro-desmosterol, L-lysine, LysoPC (14 : 1), and teasterone are the most significant differential enriched metabolites. Most of the differential enriched metabolites were involved in metabolic processes, including carbohydrate metabolism, starch and sucrose metabolism, phenylpropanoid biosynthesis, and biosynthesis of amino acids. Procrustes analysis and correlation analysis identified correlations between gut microbiota and faecal metabolites. Matricin was positively correlated with Bacteroides and negatively correlated with Actinobacteria; protorifamycin I was negatively correlated with Actinobacteria; epothilone A was negatively correlated with Actinobacteria and positively correlated with Firmicutes; PA was positively correlated with Bacteroides and negatively correlated with Firmicutes; and cristacarpin was positively correlated with Actinobacteria; however, this correlation relationship does not imply causality. CONCLUSIONS: This study used joint metagenomics and metabolomics analyses to elucidate the relationship between gut microbiota and faecal metabolites in different glycemic groups, and the result suggested that metabolic disorders and gut microbiota dysbiosis occurred in Uyghur T2DM and IGR. The results provide a theoretical basis for studying the pathological mechanism for further research.
Assuntos
Diabetes Mellitus Tipo 2/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/genética , Intolerância à Glucose/microbiologia , Metabolômica , Metagenômica , Actinobacteria , Adulto , Bacteroides , Estudos de Casos e Controles , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Disbiose/epidemiologia , Disbiose/metabolismo , Fezes/química , Fezes/microbiologia , Feminino , Firmicutes , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Background The enterosalivary nitrate-nitrite-nitric oxide pathway is an alternative pathway of nitric oxide generation, potentially linking the oral microbiome to insulin resistance and blood pressure (BP). We hypothesized that increased abundance of nitrate-reducing oral bacteria would be associated with lower levels of cardiometabolic risk cross-sectionally. Methods and Results ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study) enrolled 300 diabetes mellitus-free adults aged 20 to 55 years (mean=34±10 years) (78% women). Microbial DNA was extracted from subgingival dental plaque (n=281) and V3-V4 regions of the 16S rRNA gene were sequenced to measure the relative abundances of 20 a priori-selected taxa with nitrate-reducing capacity. Standardized scores of each taxon's relative abundance were summed, producing a nitrate-reducing taxa summary score (NO3TSS) for each participant. Natural log-transformed homeostatic model assessment of insulin resistance, plasma glucose, systolic BP, and diastolic BP were regressed on NO3TSS in multivariable linear regressions; prediabetes mellitus and hypertension prevalence were regressed on NO3TSS using modified Poisson regression models. Nitrate-reducing bacterial species represented 20±16% of all measured taxa. After multivariable adjustment, a 1-SD increase in NO3TSS, was associated with a -0.09 (95% CI, -0.15 to -0.03) and -1.03 mg/dL (95% CI, -1.903 to -0.16) lower natural log-transformed homeostatic model assessment of insulin resistance and plasma glucose, respectively. NO3TSS was associated with systolic BP only among patients without hypertension; 1-SD increase in NO3TSS was associated with -1.53 (95% CI, -2.82 to -0.24) mm Hg lower mean systolic BP. No associations were observed with prediabetes mellitus and hypertension. Conclusions A higher relative abundance of oral nitrate-reducing bacteria was associated with lower insulin resistance and plasma glucose in the full cohort and with mean systolic BP in participants with normotension.
Assuntos
Bactérias/metabolismo , Intolerância à Glucose/microbiologia , Hipertensão/microbiologia , Resistência à Insulina , Doenças da Boca/microbiologia , Boca/microbiologia , Nitratos/metabolismo , Estado Pré-Diabético/microbiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Adulto JovemRESUMO
INTRODUCTION: Environmental factors have a key role in the control of gut microbiota and obesity. TLR2 knockout (TLR2-/-) mice in some housing conditions are protected from diet-induced insulin resistance. However, in our housing conditions these animals are not protected from diet-induced insulin-resistance. AIM: The aim of the present study was to investigate the influence of our animal housing conditions on the gut microbiota, glucose tolerance and insulin sensitivity in TLR2-/- mice. MATERIAL AND METHODS: The microbiota was investigated by metagenomics, associated with hyperinsulinemic euglycemic clamp and GTT associated with insulin signaling through immunoblotting. RESULTS: The results showed that TLR2-/- mice in our housing conditions presented a phenotype of metabolic syndrome characterized by insulin resistance, glucose intolerance and increase in body weight. This phenotype was associated with differences in microbiota in TLR2-/- mice that showed a decrease in the Proteobacteria and Bacteroidetes phyla and an increase in the Firmicutesphylum, associated with and in increase in the Oscillospira and Ruminococcus genera. Furthermore there is also an increase in circulating LPS and subclinical inflammation in TLR2-/-. The molecular mechanism that account for insulin resistance was an activation of TLR4, associated with ER stress and JNK activation. The phenotype and metabolic behavior was reversed by antibiotic treatment and reproduced in WT mice by microbiota transplantation. CONCLUSIONS: Our data show, for the first time, that the intestinal microbiota can induce insulin resistance and obesity in an animal model that is genetically protected from these processes.
Assuntos
Microbioma Gastrointestinal , Resistência à Insulina , Insulina/metabolismo , Receptor 2 Toll-Like/genética , Animais , Estresse do Retículo Endoplasmático , Deleção de Genes , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Abrigo para Animais , Resistência à Insulina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 2 Toll-Like/metabolismoRESUMO
Development of obesity-associated comorbidities is related to chronic inflammation, which has been linked to gut microbiota dysbiosis. Thus, modulating gut microbiota composition could have positive effects for metabolic disorders, supporting the use of probiotics as potential therapeutics in vivo, which may be enhanced by a microencapsulation technique. Here we investigated the effects of non-encapsulated or pectin-encapsulated probiotic supplementation (Lactobacillus paracasei subsp. paracasei L. casei W8®; L. casei W8) on gut microbiota composition and metabolic profile in high-fat (HF) diet-fed rats. Four male Wistar rat groups (n = 8/group) were fed 10% low-fat, 45% HF, or HF with non-encapsulated or encapsulated L. casei W8 (4 × 107 CFU/g diet) diet for seven weeks. Microbiota composition, intestinal integrity, inflammatory profiles, and glucose tolerance were assessed. Non-encapsulated and pectin-encapsulated probiotic supplementation positively modulated gut microbiota composition in HF-fed male rats. These changes were associated with improvements in gut barrier functions and local and systemic inflammation by non-encapsulated probiotics and improvement in glucose tolerance by encapsulated probiotic treatment. Thus, these findings suggest the potential of using oral non-encapsulated or encapsulated probiotic supplementation to ameliorate obesity-associated metabolic abnormalities.
Assuntos
Glicemia/metabolismo , Dieta Hiperlipídica , Microbioma Gastrointestinal , Intolerância à Glucose/prevenção & controle , Inflamação/prevenção & controle , Intestinos/microbiologia , Lactobacillus/crescimento & desenvolvimento , Probióticos/administração & dosagem , Animais , Modelos Animais de Doenças , Disbiose , Metabolismo Energético , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Intolerância à Glucose/microbiologia , Inflamação/sangue , Inflamação/etiologia , Inflamação/microbiologia , Mediadores da Inflamação/sangue , Insulina/sangue , Masculino , Permeabilidade , Ratos WistarRESUMO
The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Metformina/administração & dosagem , Obesidade/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/genética , Bacteroides/efeitos dos fármacos , Bacteroides/patogenicidade , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Intolerância à Glucose/microbiologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/microbiologia , Hiperglicemia/patologia , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Metagenômica/métodos , Obesidade/genética , Obesidade/microbiologia , Obesidade/patologia , Ácido Ursodesoxicólico/análogos & derivadosRESUMO
OBJECTIVE: To investigate the impact of gut microbiota manipulation on fasting and postprandial skeletal muscle metabolism in humans. METHODS: 40 obese, insulin-resistant males were randomized to amoxicillin (broad-spectrum antibiotic), vancomycin (narrow-spectrum antibiotic), or placebo (7 days, 1,500 mg/day). Before and after treatment, forearm blood flow and metabolite fluxes across forearm muscle were measured under fasting and postprandial (high-fat mixed-meal) conditions. RESULTS: Vancomycin decreased bacterial diversity, reduced the abundance of Gram-positive Firmicutes, and increased the abundance of Gram-negative Proteobacteria, whereas amoxicillin did not affect microbial composition. Neither vancomycin nor amoxicillin treatment affected fasting and postprandial plasma glucose, free fatty acid (FFA), triacylglycerol (TAG), glycerol, lactate, and insulin concentrations or forearm blood flow. Fasting and postprandial net forearm muscle glucose uptake and the release of lactate were not significantly altered by antibiotic treatment as compared to placebo. Finally, antibiotic treatment did not change fasting and postprandial glycerol, FFA, and TAG fluxes across forearm muscle. CONCLUSION: The present study demonstrates that short-term antibiotic treatment has no effects on fasting and postprandial forearm substrate metabolism and blood flow in obese men with impaired glucose metabolism. These data suggest that short-term strategies targeting the gut microbiota to improve metabolic health may not be effective in obese humans.
Assuntos
Amoxicilina/farmacologia , Antebraço , Microbioma Gastrointestinal/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Obesidade/microbiologia , Vancomicina/farmacologia , Antibacterianos/farmacologia , Método Duplo-Cego , Jejum , Ácidos Graxos não Esterificados/metabolismo , Intolerância à Glucose/complicações , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/química , Músculo Esquelético/efeitos dos fármacos , Obesidade/complicações , Placebos , Período Pós-PrandialRESUMO
High fat diet-induced changes in gut microbiota have been linked to intestinal permeability and metabolic endotoxemia, which is related to metabolic disorders. However, the influence of a high-glucose (HGD) or high-fructose (HFrD) diet on gut microbiota is largely unknown. We performed changes of gut microbiota in HGD- or HFrD-fed C57BL/6J mice by 16S rRNA analysis. Gut microbiota-derived endotoxin-induced metabolic disorders were evaluated by glucose and insulin tolerance test, gut permeability, Western blot and histological analysis. We found that the HGD and HFrD groups had comparatively higher blood glucose and endotoxin levels, fat mass, dyslipidemia, and glucose intolerance without changes in bodyweight. The HGD- and HFrD-fed mice lost gut microbial diversity, characterized by a lower proportion of Bacteroidetes and a markedly increased proportion of Proteobacteria. Moreover, the HGD and HFrD groups had increased gut permeability due to alterations to the tight junction proteins caused by gut inflammation. Hepatic inflammation and lipid accumulation were also markedly increased in the HGD and HFrD groups. High levels of glucose or fructose in the diet regulate the gut microbiota and increase intestinal permeability, which precedes the development of metabolic endotoxemia, inflammation, and lipid accumulation, ultimately leading to hepatic steatosis and normal-weight obesity.
Assuntos
Bactérias/crescimento & desenvolvimento , Açúcares da Dieta , Dislipidemias/microbiologia , Frutose , Microbioma Gastrointestinal , Intolerância à Glucose/microbiologia , Glucose , Intestinos/microbiologia , Adiposidade , Animais , Bactérias/genética , Bactérias/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Peso Corporal , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Dislipidemias/fisiopatologia , Endotoxinas/sangue , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Intolerância à Glucose/fisiopatologia , Inflamação/sangue , Inflamação/microbiologia , Resistência à Insulina , Mucosa Intestinal/metabolismo , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Permeabilidade , Fatores de TempoRESUMO
Altering the gut microbiome may be beneficial to the host and recently arose as a promising strategy to manage obesity. Here, we investigated the relative contribution of ω3 polyunsaturated fatty acid (PUFA)-mediated alterations in the microbiota to metabolic parameter changes in mice. Four groups were compared: male fat-1 transgenic mice (with constitutive production of ω3 PUFAs) and male wild-type (WT) littermates fed an obesogenic (high fat/high sucrose [HFHS]) or a control diet. Unlike WT mice, HFHS-fed fat-1 mice were protected against obesity, glucose intolerance, and hepatic steatosis. Unlike WT mice, fat-1 mice maintained a normal barrier function, resulting in a significantly lower metabolic endotoxemia. The fat-1 mice displayed greater phylogenic diversity in the cecum, and fecal microbiota transplantation from fat-1 to WT mice was able to reverse weight gain and to normalize glucose tolerance and intestinal permeability. We concluded that the ω3 PUFA-mediated alteration of gut microbiota contributed to the prevention of metabolic syndrome in fat-1 mice. It occurred independently of changes in the PUFA content of host tissues and may represent a promising strategy to prevent metabolic disease and preserve a lean phenotype.
Assuntos
Ácidos Graxos Ômega-3/metabolismo , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Animais , Caderinas/genética , Caderinas/metabolismo , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Disbiose/microbiologia , Disbiose/fisiopatologia , Disbiose/terapia , Endotoxemia/etiologia , Endotoxemia/prevenção & controle , Transplante de Microbiota Fecal/efeitos adversos , Intolerância à Glucose/microbiologia , Intolerância à Glucose/patologia , Intolerância à Glucose/fisiopatologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Intestinos/microbiologia , Intestinos/patologia , Intestinos/fisiopatologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/microbiologia , Obesidade/patologia , Obesidade/fisiopatologia , Permeabilidade , FilogeniaRESUMO
OBJECTIVE: Gut microbiota modulates adiposity and glucose metabolism in humans and mice. Here we investigated how colonization of germ-free (GF) mice affects kinetics of adiposity and glucose metabolism. METHODS: Adiposity and glucose metabolism were evaluated at different time points in ex-GF and antibiotic treated mice after colonization with gut microbiota from a conventionally raised (CONV-R) mouse. Mouse physiology, microbiome configuration, serum cytokine levels, and gene expression for inflammatory markers were performed in different tissues. RESULTS: Colonization resulted in a bi-phasic glucose impairment: the first phase occurring within 3 days of colonization (early phase) and the second 14-28 days after colonization (delayed phase). The early phase co-occurred with an inflammatory response and was independent of adiposity, while the delayed phase was mostly ascribed to adipose tissue expansion and inflammation. Importantly, re-colonization of antibiotic treated mice displays only the delayed phase of glucose impairment and adiposity, suggesting that the early phase may be unique to colonization of the immature GF mice gut. CONCLUSIONS: Our results provide new insights on host-microbiota interaction during colonization of GF mice and the resulting effects on adiposity and glucose metabolism in a time resolved fashion.
Assuntos
Adiposidade/fisiologia , Glucose/metabolismo , Interações entre Hospedeiro e Microrganismos/fisiologia , Tecido Adiposo , Animais , Citocinas/sangue , Microbioma Gastrointestinal/fisiologia , Expressão Gênica , Vida Livre de Germes , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Inflamação/metabolismo , Inflamação/microbiologia , Masculino , Camundongos , Microbiota , ObesidadeRESUMO
Evidence suggests that altered gut microbiota composition may be involved in the development of obesity. Studies using mice made obese with refined high-fat diets have supported this; however, these have commonly used chow as a control diet, introducing confounding factors from differences in dietary composition that have a key role in shaping microbiota composition. We compared the effects of feeding a refined high-fat diet with those of feeding either a refined low-fat diet or a chow diet on gut microbiota composition and host physiology. Feeding both refined low- or high-fat diets resulted in large alterations in the gut microbiota composition, intestinal fermentation, and gut morphology, compared to a chow diet. However, body weight, body fat, and glucose intolerance only increased in mice fed the refined high-fat diet. The choice of control diet can dissociate broad changes in microbiota composition from obesity, raising questions about the previously proposed relationship between gut microbiota and obesity.
Assuntos
Microbioma Gastrointestinal/fisiologia , Obesidade/etiologia , Animais , Bacteroidetes/genética , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/isolamento & purificação , Glicemia/análise , Peso Corporal , Ceco/microbiologia , Cromatografia Líquida de Alta Pressão , Dieta Hiperlipídica , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Firmicutes/genética , Firmicutes/crescimento & desenvolvimento , Firmicutes/isolamento & purificação , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Intolerância à Glucose/patologia , Íleo/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , RNA Ribossômico 16S/química , RNA Ribossômico 16S/isolamento & purificação , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNARESUMO
Several studies have demonstrated the beneficial impact of dried peas and their components on glucose tolerance; however, the role of gut microbiota as a potential mediator is not fully examined. In this study, we investigated the effect of dietary supplementation with raw and cooked pea seed coats (PSC) on glucose tolerance, microbial composition of the gut, select markers of intestinal barrier function, and short chain fatty acid profile in glucose intolerant rats. Male Sprague Dawley rats were fed high fat diet (HFD) for six weeks to induce glucose intolerance, followed by four weeks of feeding PSC-supplemented diets. Cooked PSC improved glucose tolerance by approximately 30% (p < 0.05), and raw and cooked PSC diets reduced insulin response by 53% and 56% respectively (p < 0.05 and p < 0.01), compared to HFD (containing cellulose as the source of dietary fiber). 16S rRNA gene sequencing on fecal samples showed a significant shift in the overall microbial composition of PSC groups when compared to HFD and low fat diet (LFD) controls. At the family level, PSC increased the abundance of Lachnospiraceae and Prevotellaceae (p < 0.001), and decreased Porphyromonadaceae (p < 0.01) compared with HFD. This was accompanied by increased mRNA expression of mucin genes Muc1, Muc2, and Muc4 in ileal epithelium (p < 0.05). Serum levels of acetate and propionate increased with raw PSC diet (p < 0.01). These results indicate that supplementation of HFD with PSC fractions can improve glycemia and may have a protective role against HFD-induced alterations in gut microbiota and mucus layer.
Assuntos
Bactérias/crescimento & desenvolvimento , Glicemia/metabolismo , Fibras na Dieta/administração & dosagem , Suplementos Nutricionais , Ácidos Graxos Voláteis/sangue , Microbioma Gastrointestinal , Intolerância à Glucose/dietoterapia , Íleo/metabolismo , Íleo/microbiologia , Mucinas/metabolismo , Pisum sativum , Animais , Bactérias/classificação , Bactérias/genética , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Intolerância à Glucose/sangue , Intolerância à Glucose/genética , Intolerância à Glucose/microbiologia , Insulina/sangue , Masculino , Mucinas/genética , Ocludina/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo , Receptores Toll-Like/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.