Metformin acts in the gut and induces gut-liver crosstalk.

Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.

Proton Pump Inhibitor Pantoprazole Modulates Intestinal Microbiota and Induces TLR4 Signaling and Fibrosis in Mouse Liver.

Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal models. However, since PPIs can induce microbiota modulation despite the absence of a high-fat diet or weight gain, it is an interesting model to correlate microbiota modulation with the establishment of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of pantoprazole treatment on TLR4 signaling and liver histology in C57BL/6J mice for 60 days, trying to correlate microbiota modulation with some aspects of liver injury. We performed glucose (GTT) and insulin (ITT) tolerance tests, serum lipopolysaccharide (LPS) dosage, liver histology, liver and intestine extraction for Western blot and qPCR. Fecal microbiota were investigated via metagenomics. Chronic treatment with pantoprazole induced microbiota modulation and impaired ileum barrier integrity, without an association with insulin resistance. Furthermore, increased circulating LPS and increased Toll-like receptor 4 (TLR4) and TGFß downstream signaling may have an important role in the development of the observed liver microvesicular steatosis and fibrosis. Finally, this model of PPI-induced changes in microbiota might be useful to investigate liver microvesicular steatosis and fibrosis.

Wheat-durum pasta added of inactivated Bifidobacterium animalis decreases glucose and total cholesterol levels and modulates gut microbiota in healthy rats.

This study investigated the effects of consumption of wheat-durum pasta added of Bifidobacterium animalis inactivated by gamma-irradiation (paraprobiotic) on health and gut microbiota of rats. Twenty-one male rats were divided into three groups as follow: control (Control) receiving standard diet; pasta control (PC) receiving diet containing pasta, and paraprobiotic pasta Bifidobacterium-irradiated (PPBI), receiving paraprobiotic pasta. The serum levels of glucose and total cholesterol were reduced (p < 0.05) in PPBI when compared to the Control (p < 0.05). PPBI showed high abundance (p ˂ 0.05) of Firmicutes and Actinobacteria and a lower abundance of Bacteriodes compared to Control and PC. Besides, the PPBI showed high abundance (p ˂ 0.05) of Clostridiales, Lactobacillales; Bifidobacteriales, Bacillales, and Coriobacteriales in comparison to Control. Specific genera such as Bifibacterium, Lactobacillus, Ruminococcus, Allobaculum, and Blautia were more related to PPBI. Findings reveal wheat-durum pasta as a potential vehicle for delivering paraprobiotics B. animalis.

Paraprobiotics obtained by six different inactivation processes: impacts on the biochemical parameters and intestinal microbiota of Wistar male rats.

This study investigated the effects of feeding paraprobiotics obtained by six processes [heat, ultrasound, high pH, low pH, irradiation and supercritical carbon dioxide (CO2)] on biochemical parameters and intestinal microbiota of Wistar male rats. Daily administration of paraprobiotics did not affect (p ≥ 0.05) the food intake, body weight, glucose and triglycerides levels, expression of antioxidant enzymes or thermal shock proteins in comparison to the control. Bifidobacterium lactis inactivated by irradiation and supercritical CO2 decreased the total cholesterol levels in serum (p < 0.05). Bifidobacterium lactis inactivated by supercritical CO2 increased the albumin and creatinine levels, while decreased the HDL-cholesterol levels (p < 0.05). Clostridiales (45.6-56%), Bacteroidales (31.9-44.2%) and Lactobacillales (3.9-7.8%) corresponded to the major orders in paraprobiotic groups. The properties of paraprobiotics are dependent on the method of inactivation, the intensity of the method employed and on the strain used.

Assessment of antioxidant system, cholinesterase activity and histopathology in Lithobates catesbeianus tadpoles exposed to water from an urban stream.

Anthropogenic activities promote changes in community structure and decrease the species abundance of amphibians. The aim of this study was to assess potential alterations in the antioxidant system and cholinesterase activity, histopathological and oxidative damage in Lithobates catesbeianus tadpoles exposed to water from the Cascavel River, in Southern Brazil. Water samples (140 L each) were collected from the headwater, urban and rural areas of the river. Tadpoles were acclimated for seven days. After acclimatization tadpoles were reared in water from the river, except for the control aquarium. After seven days, a portion of the liver was removed and prepared for cholinesterase (ChE), superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LPO) analysis; another part of the tissue was prepared for histological examination. An elevation of CAT activity was observed for water from both urban and rural environments. A decrease in LPO reaction was detected, mainly among the tadpoles exposed to water from the rural area. These alternations can cause delay the metamorphosis and lead to metabolic dysfunction, interfering in survival capacity and diminishing, not only individual fitness, but that of the whole population.

Helminth infection in mice improves insulin sensitivity via modulation of gut microbiota and fatty acid metabolism.

Intestinal helminths are prevalent in individuals who live in rural areas of developing countries, where obesity, type 2 diabetes, and metabolic syndrome are rare. In the present study, we analyzed the modulation of the gut microbiota in mice infected with the helminth Strongyloides venezuelensis, and fed either a standard rodent chow diet or high-fat diet (HFD). To investigate the effects of the microbiota modulation on the metabolism, we analyzed the expression of tight-junction proteins present in the gut epithelium, inflammatory markers in the serum and tissue and quantified glucose tolerance and insulin sensitivity and resistance. Additionally, the levels of lipids related to inflammation were evaluated in the feces and serum. Our results show that infection with Strongyloides venezuelensis results in a modification of the gut microbiota, most notably by increasing Lactobacillus spp. These modifications in the microbiota alter the host metabolism by increasing the levels of anti-inflammatory cytokines, switching macrophages from a M1 to M2 pattern in the adipose tissue, increasing the expression of tight junction proteins in the intestinal cells (thereby reducing the permeability) and decreasing LPS in the serum. Taken together, these changes correlate with improved insulin signaling and sensitivity, which could also be achieved with HFD mice treated with probiotics. Additionally, helminth infected mice produce higher levels of oleic acid, which participates in anti-inflammatory pathways. These results suggest that modulation of the microbiota by helminth infection or probiotic treatment causes a reduction in subclinical inflammation, which has a positive effect on the glucose metabolism of the host.

BCR-ABL1 Transcript Levels at 3 and 6 Months Are Better for Identifying Chronic Myeloid Leukemia Patients with Poor Outcome in Response to Second-Line Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure: A Report from a Single Institution.

Early reduction of BCR-ABL1 transcript levels has been associated with improved outcome in chronic myeloid leukemia (CML) treatment. We evaluated 54 chronic-phase CML patients treated with imatinib who switched therapy to dasatinib (n = 33) or nilotinib (n = 21). BCR-ABL1 transcript levels were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) every 3 months from the start of second-line treatment. Patients with BCR-ABL transcript levels >10% at 3 months and >1% at 6 months had significantly inferior progression-free (PFS) and event-free survival (EFS) than patients with RQ-PCR <10% at 3 months and <1% at 6 months (66 vs. 100%, p = 0.01, and 33 vs. 73%, p = 0.02, respectively). Patients with RQ-PCR <10% at 3 months and >1% at 6 months also had inferior PFS and EFS than patients with RQ-PCR <10% at 3 months and <1% at 6 months (48 vs. 100%, p = 0.002, and 25 vs. 73%, p < 0.0001, respectively). Two measurements of BCR-ABL levels were better than a single one to stratify chronic-phase CML patients as failure after second-line therapy.

Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression.

Pyrimidine-5'-nucleotidase type I (P5'NI) deficiency is an autosomal recessive condition that causes nonspherocytic hemolytic anemia, characterized by marked basophilic stippling and pyrimidine nucleotide accumulation in erythrocytes. We herein present two African descendant patients, father and daughter, with P5'N deficiency, both born from first cousins. Investigation of the promoter polymorphism of the uridine diphospho glucuronosyl transferase 1A (UGT1A) gene revealed that the father was homozygous for the allele (TA7) and the daughter heterozygous (TA6/TA7). P5'NI gene (NT5C3) gene sequencing revealed a further change in homozygosity at amino acid position 56 (p.R56G), located in a highly conserved region. Both patients developed gallstones; however the father, who had undergone surgery for the removal of stones, had extremely severe intrahepatic cholestasis and, liver biopsy revealed fibrosis and siderosis grade III, leading us to believe that the homozygosity of the UGT1A polymorphism was responsible for the more severe clinical features in the father. Moreover, our results show how the clinical expression of hemolytic anemia is influenced by epistatic factors and we describe a new mutation in the P5'N gene associated with enzyme deficiency, iron overload, and severe gallstone formation. To our knowledge, this is the first description of P5'N deficiency in South Americans.

Predictors of autosomal dominant polycystic kidney disease progression: a Brazilian single-center cohort.

INTRODUCTION: Identifying risk factors for autosomal dominant polycystic kidney disease (ADPKD) progression is important. However, studies that have evaluated this subject using a Brazilian sample is sparce. Therefore, the aim of this study was to identify risk factors for renal outcomes and death in a Brazilian cohort of ADPKD patients. METHODS: Patients had the first medical appointment between January 2002 and December 2014, and were followed up until December 2019. Associations between clinical and laboratory variables with the primary outcome (sustained decrease of at least 57% in the eGFR from baseline, need for dialysis or renal transplantation) and the secondary outcome (death from any cause) were analyzed using a multiple Cox regression model. Among 80 ADPKD patients, those under 18 years, with glomerular filtration rate <30 mL/min/1.73 m2, and/or those with missing data were excluded. There were 70 patients followed. RESULTS: The factors independently associated with the renal outcomes were total kidney length - adjusted Hazard Ratio (HR) with a 95% confidence interval (95% CI): 1.137 (1.057-1.224), glomerular filtration rate - HR (95% CI): 0.970 (0.949-0.992), and serum uric acid level - HR (95% CI): 1.643 (1.118-2.415). Diabetes mellitus - HR (95% CI): 8.115 (1.985-33.180) and glomerular filtration rate - HR (95% CI): 0.957 (0.919-0.997) were associated with the secondary outcome. CONCLUSIONS: These findings corroborate the hypothesis that total kidney length, glomerular filtration rate and serum uric acid level may be important prognostic predictors of ADPKD in a Brazilian cohort, which could help to select patients who require closer follow up.

Impact of cholecystectomy on the gut-liver axis and metabolic disorders.

Cholecystectomy is considered as a safe procedure to treat patients with gallstones. However, epidemiological studies highlighted an association between cholecystectomy and metabolic disorders, such as type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD), independently of the gallstone disease. Following cholecystectomy, bile acids flow directly from the liver into the intestine, leading to changes in the entero-hepatic circulation of bile acids and their metabolism. The changes in bile acids metabolism impact the gut microbiota. Therefore, cholecystectomized patients display gut dysbiosis characterized by a reduced diversity, a loss of bacteria producing short-chain fatty acids and an increase in pro-inflammatory bacteria. Alterations of both bile acids metabolism and gut microbiota occurring after cholecystectomy can promote the development of metabolic disorders. In this review, we discuss the impact of cholecystectomy on bile acids and gut microbiota and its consequences on metabolic functions.

INTERACTION BETWEEN FOOD PYRAMID AND GUT MICROBIOTA. A NEW NUTRITIONAL APPROACH.

The food pyramid is a pre-established nutritional education tool. The integration between the intestinal microbiome, food groups, and SCFA-producing bacteria, which benefit from the ingestion of these foods, has the potential to further improve and innovate healthy eating. The diet-microbiome interaction needs to be incorporated into nutrition science, and the food pyramid might assist in this interaction and nutritional learning. Against this context, this brief communication proposes through the food pyramid, the interactions between the intestinal microbiota, food groups, and SCFAs-producing bacteria.

Maternal exposure to air pollution alters energy balance transiently according to gender and changes gut microbiota.

Introduction: The timing of maternal exposure to air pollution is crucial to define metabolic changes in the offspring. Here we aimed to determine the most critical period of maternal exposure to particulate matter (PM2.5) that impairs offspring's energy metabolism and gut microbiota composition. Methods: Unexposed female and male C57BL/6J mice were mated. PM2.5 or filtered air (FA) exposure occurred only in gestation (PM2.5/FA) or lactation (FA/PM2.5). We studied the offspring of both genders. Results: PM2.5 exposure during gestation increased body weight (BW) at birth and from weaning to young in male adulthood. Leptin levels, food intake, Agrp, and Npy levels in the hypothalamus were also increased in young male offspring. Ikbke, Tnf increased in male PM2.5/FA. Males from FA/PM2.5 group were protected from these phenotypes showing higher O2 consumption and Ucp1 in the brown adipose tissue. In female offspring, we did not see changes in BW at weaning. However, adult females from PM2.5/FA displayed higher BW and leptin levels, despite increased energy expenditure and thermogenesis. This group showed a slight increase in food intake. In female offspring from FA/PM2.5, BW, and leptin levels were elevated. This group displayed higher energy expenditure and a mild increase in food intake. To determine if maternal exposure to PM2.5 could affect the offspring's gut microbiota, we analyzed alpha diversity by Shannon and Simpson indexes and beta diversity by the Linear Discriminant Analysis (LDA) in offspring at 30 weeks. Unlike males, exposure during gestation led to higher adiposity and leptin maintenance in female offspring at this age. Gestation exposure was associated with decreased alpha diversity in the gut microbiota in both genders. Discussion: Our data support that exposure to air pollution during gestation is more harmful to metabolism than exposure during lactation. Male offspring had an unfavorable metabolic phenotype at a young age. However, at an older age, only females kept more adiposity. Ultimately, our data highlight the importance of controlling air pollution, especially during gestation.

A red wine intervention does not modify plasma trimethylamine N-oxide but is associated with broad shifts in the plasma metabolome and gut microbiota composition.

BACKGROUND: Gut microbiota profiles are closely related to cardiovascular diseases through mechanisms that include the reported deleterious effects of metabolites, such as trimethylamine N-oxide (TMAO), which have been studied as diagnostic and therapeutic targets. Moderate red wine (RW) consumption is reportedly cardioprotective, possibly by affecting the gut microbiota. OBJECTIVES: To investigate the effects of RW consumption on the gut microbiota, plasma TMAO, and the plasma metabolome in men with documented coronary artery disease (CAD) using a multiomics assessment in a crossover trial. METHODS: We conducted a randomized, crossover, controlled trial involving 42 men (average age, 60 y) with documented CAD comparing 3-wk RW consumption (250 mL/d, 5 d/wk) with an equal period of alcohol abstention, both preceded by a 2-wk washout period. The gut microbiota was analyzed via 16S rRNA high-throughput sequencing. Plasma TMAO was evaluated by LC-MS/MS. The plasma metabolome of 20 randomly selected participants was evaluated by ultra-high-performance LC-MS/MS. The effect of RW consumption was assessed by individual comparisons using paired tests during the abstention and RW periods. RESULTS: Plasma TMAO did not differ between RW intervention and alcohol abstention, and TMAO concentrations showed low intraindividual concordance over time, with an intraclass correlation coefficient of 0.049 during the control period. After RW consumption, there was significant remodeling of the gut microbiota, with a difference in ß diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella. Plasma metabolomic analysis revealed significant changes in metabolites after RW consumption, consistent with improved redox homeostasis. CONCLUSIONS: Modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate RW consumption. The low intraindividual concordance of TMAO presents challenges regarding its role as a cardiovascular risk biomarker at the individual level. This study was registered at clinical trials.gov as NCT03232099.

Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model.

Production of recombinant B-domain-deleted canine factor VIII (cFVIII-BDD) unexpectedly revealed superior protein yields with 3-fold increased specific activity relative to human FVIII-BDD (hFVIII-BDD). We also determined that activated cFVIII-BDD is more stable than activated hFVIII-BDD. Furthermore, cFVIII-BDD is efficient at inducing hemostasis in human plasma containing FVIII inhibitors. Infusion of cFVIII-BDD in hemophilia A dogs resulted in correction of the disease phenotype with a pharmacokinetic profile similar to clinical experience with hFVIII-BDD. Notably, immune tolerance challenges with cFVIII-BDD in young and adult hemophilia A dogs did not induce the formation of neutralizing or nonneutralizing antibodies to cFVIII. These data establish the framework to quantitatively investigate the efficacy and safety in preclinical studies of novel therapies for hemophilia A.

Diabetes, obesity, and insulin resistance in COVID-19: molecular interrelationship and therapeutic implications.

BACKGROUND: Our understanding of the pathophysiology of the COVID-19 manifestations and evolution has improved over the past 10 months, but the reasons why evolution is more severe in obese and diabetic patients are not yet completely understood. MAIN TEXT: In the present review we discuss the different mechanisms that may contribute to explain the pathophysiology of COVID-19 including viral entrance, direct viral toxicity, endothelial dysfunction, thromboinflammation, dysregulation of the immune response, and the renin-angiotensin-aldosterone system. CONCLUSIONS: We show that the viral infection activates an integrated stress response, including activations of serine kinases such as PKR and PERK, which induce IRS-1 serine phosphorylation and insulin resistance. In parallel, we correlate and show the synergy of the insulin resistance of COVID-19 with this hormonal resistance of obesity and diabetes, which increase the severity of the disease. Finally, we discuss the potential beneficial effects of drugs used to treat insulin resistance and diabetes in patients with COVID-19.

Orange Juice and Yogurt Carrying Probiotic Bacillus coagulans GBI-30 6086: Impact of Intake on Wistar Male Rats Health Parameters and Gut Bacterial Diversity.

This study aimed to investigate the impact of the food matrix (orange juice and yogurt) on the effects of the spore-forming probiotic microorganism Bacillus coagulans GBI-30 6086 in health parameters and gastrointestinal tract (gut) bacterial diversity in Wistar male rats. Rats (n = 48) were randomly distributed into six groups. The groups were the Control (which received sterile distilled water), Juice (which received orange juice), Yogurt (which received yogurt), Probiotic Bacillus (which received B. coagulans GBI-30 6086 in distilled water), Probiotic Juice (which received orange juice with B. coagulans GBI-30 6086), and Probiotic Yogurt (which received yogurt with B. coagulans GBI-30 6086). Each animal belonging to the different groups was treated for 21 days. The daily administration of probiotic juice or probiotic yogurt did not affect the rats' food or body weight. Rats fed with Probiotic Yogurt showed lower glucose and triglycerides levels (p < 0.05) in comparison to the control group (p < 0.05), while no changes in these parameters were observed in the rats fed with Probiotic Juice. Rats fed with Probiotic Yogurt showed a higher gut bacterial diversity than the control group (p < 0.05), and higher abundance (p < 0.05) of Vibrionales, Enterobacteriales, Burkholderiales, Erysipelotrichales, and Bifidobacteriales compared to all other groups. No changes were observed in the expression levels of antioxidant enzymes or heat shock protein 70 of rats fed with probiotic yogurt or probiotic juice. Results reveal that the consumption of yogurt containing B. coagulans GBI-30 6086 decreases triglycerides and glucose levels and positively impacts the gut bacterial ecology in healthy rats. These animal model findings indicate that the matrix also impacts the functionality of foods carrying spore-forming probiotics. Besides, this research indicates that yogurt is also a suitable food carrier of Bacillus coagulans GBI-30 6086.

Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-γ Expression in Pulmonary Artery.

Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator-activated receptor (PPAR-γ) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-γ expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-γ in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity.

Colonic neuronal loss and delayed motility induced by high-fat diet occur independently of changes in the major groups of microbiota in Swiss mice.

BACKGROUND: Obesity has been linked to gastrointestinal disorders, and the loss of myenteric neurons in the intestine caused by high-fat diets (HFD) has been attributed to changes in microbiota and lipotoxicity. We investigated whether the prebiotic inulin modulates bacterial populations and alleviates neuronal loss in mice fed HFD. METHODS: Swiss mice were fed purified rodent diet or HFD (59% kcal fat), or both diets supplemented with inulin for 17 weeks. Intestinal motility was assessed and a metagenome analysis of the colonic microbiota was performed. The gene expression of inflammatory markers was evaluated, and immunofluorescence was performed for different types of myenteric neurons and glial cells in the distal colon. KEY RESULTS: The HFD caused obesity and delayed colonic motility. The loss of myenteric neurons and glial cells in obese mice affected all of the studied neuronal populations, including neurons positive for myosin-V, neuronal nitric oxide synthase, vasoactive intestinal peptide, and calretinin. Although obese mice supplemented with inulin exhibited improvements in colonic motility, neuronal, and glial cell loss persisted. The HFD did not altered the expression levels of inflammatory cytokines in the intestine or the prevalence of the major groups in microbiota, but inulin increased the proportion of the genus Akkermansia in the obese mice. CONCLUSIONS AND INFERENCES: In Swiss mice, the HFD-induced neuronal loss but did not change the major groups in microbiota. This suggests that, despite the increase in the beneficial bacteria, other factors that are directly linked to excess dietary lipid intake affect the enteric nervous system.

Gut Microbiota Modifications and Weight Regain in Morbidly Obese Women After Roux-en-Y Gastric Bypass.

INTRODUCTION: The relationship between late post-bariatric surgery weight regain and gut microbiota is not completely understood. OBJECTIVE: To analyze the profile of gut microbiota among patients with and without late weight regain after post-Roux-en-Y gastric bypass (RYGB) and to compare it with a control group (CG) comprised of obese Brazilian individuals. METHODS: This is a cross-sectional study which enrolled 34 morbidly obese women divided into 3 groups: post-Roux-en-Y gastric bypass without (RYGB_non-regain), and with weight regain (RYGB_regain) at least 5 years after surgery, and a CG of preoperative individuals. Gut microbiota was determined by metagenomic analyses. RESULTS: The alpha diversity was higher in groups RYGB non-regain and RYGB regain when compared with CG (p < 0.05). Both RYGB non-regain and RYGB regain groups showed a lower abundance of the phylum Bacteroidetes when compared with CG (p < 0.01). The genera Bacteroides and SMB53 were increased in CG (p < 0.05). Group RYGB non-regain showed more abundance of the Akkermansia genus when compared with CG and group RYGB regain (p < 0.05). RYGB non-regain showed a greater abundance of the Phascolarctobacterium genus and lower of the SMB53 genus when compared with CG (p < 0.05). RYGB non-regain showed a greater abundance of the Phascolarctobacterium genus and a lower of the SMB53 genus when compared with CG (p < 0.05). CONCLUSION: The gut microbiota of individuals which presented late weight regain after RYGB was significantly different in comparison to individuals with a successful weight loss, a finding that points towards a significant role of gut microbiota on weight loss and maintenance after surgery.

Microbiota determines insulin sensitivity in TLR2-KO mice.

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.