RESUMO
Background: High-fat diet (HFD) induced obesity is characterized with chronic low-grade inflammation in various tissues and organs among which colon is the first to display pro-inflammatory features associated with alterations of the gut microbiota. Sleeve gastrectomy (SG) is currently one of the most effective treatments for obesity. Although studies reveal that SG results in decreased levels of inflammation in multiple tissues such as liver and adipose tissues, the effects of surgery on obesity related pro-inflammatory status in the colon and its relation to the microbial changes remain unknown. Methods: To determine the effects of SG on the colonic pro-inflammatory condition and the gut microbiota, SG was performed on HFD-induced obese mice. To probe the causal relationship between alterations of the gut microbiota and improvements of pro-inflammatory status in the colon following SG, we applied broad-spectrum antibiotics cocktails on mice that received SG to disturb the gut microbial changes. The pro-inflammatory shifts in the colon were assessed based on morphology, macrophage infiltration and expressions of a variety of cytokine genes and tight junction protein genes. The gut microbiota alterations were analyzed using 16s rRNA sequencing. RNA sequencing of colon was conducted to further explore the role of the gut microbiota in amelioration of colonic pro-inflammation following SG at a transcriptional level. Results: Although SG did not lead to pronounced changes of colonic morphology and macrophage infiltration in the colon, there were significant decreases in the expressions of several pro-inflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, IL-18, and IL-23 as well as increased expressions of some tight junction proteins in the colon following SG, suggesting an improvement of pro-inflammatory status. This was accompanied by changing populations of the gut microbiota such as increased richness of Lactobacillus subspecies following SG. Importantly, oral administrations of broad-spectrum antibiotics to delete most intestinal bacteria abrogated surgical effects to relieve colonic pro-inflammation. This was further confirmed by transcriptional analysis of colon indicating that SG regulated inflammation related pathways in a manner that was gut microbiota relevant. Conclusion: These results support that SG decreases obesity related colonic pro-inflammatory status through the gut microbial alterations.
Assuntos
Colo , Dieta Hiperlipídica , Gastrectomia , Obesidade , Humanos , Animais , Camundongos , Microbioma Gastrointestinal , Inflamação , Dieta Hiperlipídica/efeitos adversos , Colo/metabolismo , Cirurgia Bariátrica , CitocinasRESUMO
AIMS: To examine how metabolic status is associated with microvascular phenotype and to identify variables associated with vascular remodeling after bariatric surgery, using noninvasive optical coherence tomography angiography (OCTA). METHODS: The study included 136 obese subjects scheduled for bariatric surgery and 52 normal-weight controls. Patients with obesity were divided into metabolically healthy obesity (MHO) and metabolic syndrome (MetS) groups according to the diagnosis criteria of the Chinese Diabetes Society. Retinal microvascular parameters were measured by OCTA, including superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel densities. Follow-ups were performed at the baseline and 6 months after bariatric surgery. RESULTS: Fovea SCP, average DCP, fovea DCP, parafovea DCP, and perifovea DCP vessel densities were significantly lower in the MetS group, compared to controls (19.91% vs. 22.49%, 51.60% vs. 54.20%, 36.64% vs. 39.14%, 56.24% vs. 57.65% and 52.59% vs. 55.58%, respectively, all p < .05). Parafovea SCP, average DCP, parafovea DCP, and perifovea DCP vessel densities significantly improved in patients with obesity 6 months after surgery, compared to baseline (54.21% vs. 52.97%, 54.43% vs. 50.95%, 58.29% vs. 55.54% and 55.76% vs. 51.82%, respectively, all p < .05). Multivariable analyses showed that baseline blood pressure and insulin were independent predictors of vessel density changes 6 months after surgery. CONCLUSIONS: Retinal microvascular impairment occurred mainly in MetS rather than MHO patients. Retinal microvascular phenotype improved 6 months after bariatric surgery and baseline blood pressure and insulin status may be key determinants. OCTA may be a reliable method to evaluate the microvascular complications associated with obesity.
Assuntos
Insulinas , Vasos Retinianos , Humanos , Angiofluoresceinografia/métodos , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Obesidade/complicações , Obesidade/cirurgiaRESUMO
Changing composition of the gut microbiome is an important component of the gut adaptation to various environments, which have been implicated in various metabolic diseases including obesity and type 2 diabetes, but the mechanisms by which the microbiota influence host physiology remain contentious. Here we find that both diets high in the fermentable fiber inulin and vertical sleeve gastrectomy increase intestinal expression and circulating levels of the anti-microbial peptide Reg3g. Moreover, a number of beneficial effects of these manipulations on gut function, energy balance, and glucose regulation are absent in Reg3g knockout mice. Peripheral administration of various preparations of Reg3g improves glucose tolerance, and this effect is dependent on the putative receptor Extl3 in the pancreas. These data suggest Reg3g acts both within the lumen and as a gut hormone to link the intestinal microbiome to various aspects of host physiology that may be leveraged for novel treatment strategies.
Assuntos
Diabetes Mellitus Tipo 2 , Microbiota , Camundongos , Animais , Intestino Delgado/metabolismo , Glucose/metabolismo , Peptídeos , Camundongos Knockout , N-Acetilglucosaminiltransferases , Proteínas Associadas a PancreatiteRESUMO
Gastric bypass and vertical sleeve gastrectomy (VSG) remain the most potent and durable treatments for obesity and type 2 diabetes but are also associated with iron deficiency. The transcription factor HIF2α, which regulates iron absorption in the duodenum, increases following these surgeries. Increasing iron levels by means of dietary supplementation or hepatic hepcidin knockdown does not undermine the effects of VSG, indicating that metabolic improvements following VSG are not secondary to lower iron levels. Gut-specific deletion of Vhl results in increased constitutive duodenal HIF2α signaling and produces a profound lean, glucose-tolerant phenotype that mimics key effects of VSG. Interestingly, intestinal Vhl deletion also results in increased intestinal secretion of GLP-1, which is essential for these metabolic benefits. These data demonstrate a role for increased duodenal HIF2α signaling in regulating crosstalk between iron-regulatory systems and other aspects of systemic physiology important for metabolic regulation.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Duodeno/metabolismo , Gastroplastia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Animais , Gastrectomia/métodos , Gastroplastia/métodos , Camundongos , RatosRESUMO
OBJECTIVE: Vertical Sleeve Gastrectomy (VSG) is one of the most efficacious treatments for obesity and its comorbidities. Although a range of evidence suggests that alterations of the microbiota in the distal gut following VSG are pivotal to these metabolic improvements, the effect of surgery to alter the microbiota of the proximal intestine and its effect on host physiology remain largely unknown. As the main bacteria in the upper small intestine, Lactobacillus subspecies have been appreciated as important regulators of gut function. These bacteria also regulate intestinal Hypoxia- Inducible Factor 2α (HIF2α) signaling that plays an integral role in gut physiology and iron absorption. In the present study, we sought to determine the impact of VSG on Lactobacillus spp. in the small intestine and potential downstream impacts of Lactobacillus spp. on HIF2α, specifically in the duodenum. METHODS: To determine the effects of VSG on the microbiota and HIF2α signaling in the duodenum, VSG surgeries were performed on diet-induced obese mice. To further probe the relationship between Lactobacillus spp. and HIF2α signaling in the duodenum, we applied a customized high-fat but iron-deficient diet on mice to increase duodenal HIF2α signaling and determined alterations of gut bacteria. To explore the causal role of Lactobacillus spp. in duodenal HIF2α signaling activation, we chronically administered probiotics containing Lactobacillus spp. to high-fat-fed obese mice. Lastly, we studied the effect of lactate, the major metabolite of Lactobacilli, on HIF2α in ex vivo duodenal organoids. RESULTS: There were pronounced increases in the abundance of Lactobacillus spp. in samples isolated from duodenal epithelium in VSG-operated mice as compared to sham-operated mice. This was accompanied by an increase in the expression of genes that are targets of HIF2α in the duodenum of VSG-treated mice. Activating HIF2α signaling with a high-fat but iron-deficient diet resulted in weight loss, improvements in glucose regulation, and increased Lactobacillus spp. richness in the duodenum as compared to mice on an iron-replete diet. Chronic administration of probiotics containing Lactobacillus spp. not only increased HIF2α signaling in the duodenum such as occurs after VSG but also resulted in reduced weight gain and improved glucose tolerance in high-fat-fed mice. Furthermore, lactate was able to activate HIF2α in ex vivo duodenal organoids. CONCLUSIONS: These results support a model whereby VSG increases duodenal Lactobacillus richness and potentially stimulates intestinal HIF2α signaling via increased lactate production.
Assuntos
Gastrectomia , Lactobacillus , Animais , Duodeno/metabolismo , Gastrectomia/métodos , Camundongos , Obesidade/metabolismo , Redução de PesoRESUMO
Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.
Assuntos
Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Gastrectomia/efeitos adversos , Tecido Adiposo , Animais , Cirurgia Bariátrica , Ácidos e Sais Biliares/sangue , Glicemia , Densidade Óssea , Medula Óssea , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/cirurgia , Redução de PesoRESUMO
BACKGROUND: /Objective: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and effective treatments are lacking. Bariatric surgery, including sleeve gastrectomy (SG), is a potential therapeutic strategy for NAFLD, but the molecular mechanisms underlying its effects are not fully understood. In this study, the effects of SG and the underlying mechanisms were evaluated in a mouse model of high-fat diet (HFD)-induced NAFLD. METHODS: C57BL/6 mice were randomly divided into three groups: normal diet with sham operation (NC-Sham group), HFD with sham operation (HFD-Sham group), and HFD with sleeve gastrectomy (HFD-SG group). Glucose metabolism and fat accumulation in the body and liver were analyzed before and after SG. Lipid metabolism and inflammation in the liver were evaluated. Nicotinamide adenine dinucleotide (NAD+) levels as well as nicotinamide riboside kinase (NRK1) and Sirtuin-1 (SIRT1) expression levels were evaluated. RESULTS: SG attenuated the HFD-induced increases in glucose and insulin levels, fat accumulation, and lipid droplet accumulation. Fatty acid biosynthesis, the expression of the metabolism-related genes ACC1, FASN, SCD1, and DGAT1, and the levels of inflammatory factors were higher in HFD mice than in NC mice and decreased after SG. NAD + concentrations were 54.9 ± 13.4 µmol/mg in NC-Sham mice, 37.6 ± 8.1 µmol/mg in HFD-Sham mice, and 79.9 ± 13.0 µmol/mg in HFD-SG mice (p < 0.05). NRK1 and SIRT1 expression increased dramatically after SG at both the RNA and protein levels. CONCLUSION: SG significantly alleviated NAFLD in HFD-induced obese mice with increasing the hepatic NAD + levels and upregulating the NRK1/NAD+/SIRT1 pathway.
Assuntos
Cirurgia Bariátrica/métodos , Dieta Hiperlipídica/efeitos adversos , Gastrectomia/métodos , Expressão Gênica/genética , NAD/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/cirurgia , Transdução de Sinais/genética , Sirtuína 1/metabolismo , Regulação para Cima/genética , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
OBJECTIVE: To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance. BACKGROUND DATA: Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention. METHODS: A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained. RESULTS: All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested. CONCLUSIONS: The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.
Assuntos
Cirurgia Bariátrica/métodos , Glicemia/metabolismo , Esvaziamento Gástrico/fisiologia , Obesidade/cirurgia , Estômago/diagnóstico por imagem , Redução de Peso/fisiologia , Animais , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Teste de Tolerância a Glucose , Incretinas/farmacologia , Masculino , Obesidade/sangue , Obesidade/fisiopatologia , Tamanho do Órgão , Ratos , Ratos Long-Evans , Estômago/fisiopatologia , Estômago/cirurgiaRESUMO
Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.
Assuntos
Adipócitos/metabolismo , Células da Medula Óssea/metabolismo , Reabsorção Óssea/sangue , Gastroplastia , Fator Estimulador de Colônias de Granulócitos/sangue , Obesidade/sangue , Complicações Pós-Operatórias/sangue , Adipócitos/patologia , Adolescente , Adulto , Animais , Medula Óssea/patologia , Células da Medula Óssea/patologia , Reabsorção Óssea/etiologia , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Feminino , Gastrectomia , Humanos , Estudos Longitudinais , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Obesidade/cirurgia , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/patologiaRESUMO
BACKGROUND: Disruptions of the composition and diurnal oscillation of gut microbiota are involved in metabolic disorders. OBJECTIVES: To identify alterations in both the composition and diurnal oscillation of gut microbiota after high-fat diet (HFD) feeding and sleeve gastrectomy (SG) related to host metabolic status. SETTING: University laboratories. METHODS: Twenty-one 6-week-old male C57 BL/6 J mice were randomized on an HFD (n = 14) or normal chow (NC, n = 7). After 14 weeks of feeding, HFD-induced obese mice were randomized to receive either SG or sham surgery (n = 7 in each group). Fecal samples were collected every 6 hours over a 24-hour period at 14 weeks of NC or HFD feeding and subsequently 8 weeks after surgery. The composition and diurnal oscillation of gut microbiota were characterized using next-generation Illumina sequencing of 16 S rDNA. RESULTS: HFD feeding led to adiposity, disrupted composition, and impaired diurnal oscillation of gut microbiota relative to NC. After surgery, SG mice had considerable weight loss, improved glucose tolerance, and insulin sensitivity compared with sham mice. SG restored the reduced richness and disruptions in the composition of gut microbiota. The diminished diurnal oscillation of gut microbiota was improved after SG. CONCLUSION: SG not only changed the disrupted composition of gut microbiota toward that of NC feeding, but also improved the dampened diurnal oscillation of gut microbiota due to HFD feeding.
Assuntos
Cirurgia Bariátrica/métodos , Gastrectomia/métodos , Microbioma Gastrointestinal/fisiologia , Adiposidade/fisiologia , Animais , Glicemia/metabolismo , Ritmo Circadiano/fisiologia , Dieta Hiperlipídica , Fezes/química , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Resistência à Insulina/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Distribuição Aleatória , Redução de Peso/fisiologiaRESUMO
BACKGROUND: The objective of the study was to compare gut microbiota post Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). METHODS: Sprague-Dawley rats were randomized to RYGB, SG, or sham surgery. Body weight was measured. Fecal samples were collected before and 1, 3, 6, and 9 weeks postoperatively. Fecal microbiota was profiled by 16S ribosomal DNA gene sequencing and analyzed using Quantitative Insights into Microbial Ecology (QIIME) to determine the α and ß diversities of gut microbiota. RESULTS: The body weight of the RYGB and SG group was significantly lower than that of the sham group. Unweighted UniFrac-based principal coordinate analysis of 5,323,091 sequences from 85 fecal samples from 17 rats revealed a distinct cluster of gut microbiota post RYGB from SG and sham surgery. The percentage of Proteobacteria in the SG and sham group remained markedly lower than that of the RYGB group from 3 weeks postoperatively, while the proportion of Gammaproteobacteria in the RYGB group was significantly higher than that of the SG group and the sham group from 3 weeks postoperatively. Furthermore, the RYGB group was postoperatively enriched for Gammaproteobacteria and Bacteroidaceae, whereas the SG group was postoperatively enriched for Desulfovibrionaceae and Cyanobacteria. Compared to the pre-operative parameters, the RYGB group had a persistent increase in the relative abundance of Gammaproteobacteria and a decrease in the Shannon index, while the SG group only transiently exhibited these changes within the first week after surgery. The relative abundance of Gammaproteobacteria was negatively correlated, whereas the Shannon index was positively correlated with weight after surgery. CONCLUSIONS: RYGB, but not SG, alters the gut microbiota of Sprague-Dawley rats. RYGB also reduces the diversity of gut microbiota. Furthermore, the abundance of Gammaproteobacteria negatively correlates with postoperative body weight and may be one of the potential contributors to stable weight loss after bariatric surgery.
Assuntos
Gastrectomia , Derivação Gástrica , Microbioma Gastrointestinal/fisiologia , Obesidade Mórbida/cirurgia , Animais , Gastrectomia/métodos , Derivação Gástrica/métodos , Masculino , Obesidade Mórbida/microbiologia , Período Pós-Operatório , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: We compared the therapeutic effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and duodenal-jejunal bypass (DJB) on type-2 diabetes mellitus (T2DM) in non-obese rats using clamp testing. METHODS: Goto-Kakizaki rats (non-obese rats with T2DM) underwent surgery: RYGB, SG, or DJB. Rats were observed for 8 weeks after surgery to evaluate weight changes. Levels of glucose, insulin, and glucagon-like peptide (GLP)-1 were determined 2, 4, 6, and 8 weeks after surgery. An oral glucose tolerance test (OGTT) and clamp test was used to evaluate glucose tolerance and insulin resistance. RESULTS: Rats in RYGB, SG, and DJB groups weighed significantly less than sham-group rats 6 and 8 weeks after surgery. Fasting blood glucose levels of RYGB, SG, and DJB rats were significantly lower than preoperative levels. One month after surgery, the area under the curve of the OGTT (in mmolâ¢h/L) for RYGB, SG, DJB, and sham surgery groups was 38.9 ± 5.9, 50.9 ± 2.9, 46.8 ± 3.3, and 67.4 ± 6.0, respectively; there was no significant difference in glucose levels of SG and DJB groups. Glucose infusion rates (in mg/(kgâ¢min)) were 18.3 ± 2.7, 17.2 ± 2.1, and 16.8 ± 1.9 in hyperinsulinemic-euglycemic-clamped RYGB, DJB, and SG rats, respectively, 8 weeks after surgery. The rate in the sham surgery group was 6.3 ± 0.9. Area under plasma insulin curves 8 weeks after surgery in hyperglycemic-clamped RYGB, DJB, SG, and sham surgery rats (in mUâ¢h/L) were 98.8 ± 7.0, 84.4 ± 6.1, 89.0 ± 7.1, and 22.6 ± 2.6, respectively. CONCLUSIONS: The three surgical methods described alleviated T2DM and reduced insulin resistance in non-obese rats with T2DM.
Assuntos
Cirurgia Bariátrica/métodos , Diabetes Mellitus Tipo 2/cirurgia , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Duodeno/cirurgia , Gastrectomia , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/sangue , Técnica Clamp de Glucose , Insulina/sangue , Resistência à Insulina , Jejuno/cirurgia , Masculino , Ratos , Ratos EndogâmicosRESUMO
Bariatric surgery is the most effective treatment for obesity and its comorbidities, but mechanisms of bariatric surgery remain unknown. In addition to volume restriction and malabsorption, gut hormones, bile acids, adipokines, intestinal microbiome and central nervous system may be the potential mechanisms.