Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: a Randomized Double-blind Placebo-controlled Trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76003 | GEO | 2016/07/15
SECONDARY ACCESSION(S): PRJNA305937
REPOSITORIES: GEO
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Project description:The gut microbiota has been implicated in obesity and cardiometabolic diseases, although evidence in humans is scarce. We investigated how gut microbiota manipulation by antibiotics (7-day administration of amoxicillin, vancomycin, or placebo) affects host metabolism in 57 obese, prediabetic men. Vancomycin, but not amoxicillin, decreased bacterial diversity and reduced Firmicutes involved in short-chain fatty acid and bile acid metabolism, concomitant with altered plasma and/or fecal metabolite concentrations. Adipose tissue gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. Antibiotics did not affect tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability, and adipocyte size. Importantly, energy harvest, adipocyte size, and whole-body insulin sensitivity were not altered at 8-week follow-up, despite a still considerably altered microbial composition, indicating that interference with adult microbiota by 7-day antibiotic treatment has no clinically relevant impact on metabolic health in obese humans. This randomized, placebo-controlled, double-blind study had a 3-armed parallel design. Overweight/obese participants were randomized to oral intake of amoxicillin, vancomycin or placebo for 7 consecutive days. After an overnight fast, subcutaneous adipose tissue biopsies were taken that were subjected to gene expression profiling by array.
2016-07-15 | E-GEOD-76003 | biostudies-arrayexpress
Project description:<p>Emerging evidence that the gut microbiota may contribute in important ways to human health and disease has led us and others to hypothesize that both symbiotic and pathological relationships between gut microbes and their host may be key contributors to obesity and the metabolic complications of obesity. Our "Thrifty Microbiome Hypothesis" poses that gut microbiota play a key role in human energy homeostasis. Specifically, constituents of the gut microbial community may introduce a survival advantage to its host in times of nutrient scarcity, promoting positive energy balance by increasing efficiency of nutrient absorption and improving metabolic efficiency and energy storage. However, in the presence of excess nutrients, fat accretion and obesity may result, and in genetically predisposed individuals, increased fat mass may result in preferential abdominal obesity, ectopic fat deposition (liver, muscle), and metabolic complications of obesity (insulin resistance, hypertension, hyperlipidemia). Furthermore, in the presence of excess nutrients, a pathological transition of the gut microbial community may occur, causing leakage of bacterial products into the intestinal lymphatics and portal circulation, thereby inducing an inflammatory state, further aggravating metabolic syndrome traits and accelerating atherosclerosis. This pathological transition and the extent to which antimicrobial leakage occurs and causes inflammatory and other maladaptive sequelae of obesity may also be influenced by host factors, including genetics. In the proposed study, we will directly test the Thrifty Microbiome Hypothesis by performing detailed genomic and functional assessment of gut microbial communities in intensively phenotyped and genotyped human subjects before and after intentional manipulation of the gut microbiome. To address these hypotheses, five specific aims are proposed: (1) enroll three age- and sex-matched groups from the Old Order Amish: (i) 50 obese subjects (BMI > 30 kg/m2) with metabolic syndrome, (ii) 50 obese subjects (BMI > 30 kg/m2) without metabolic syndrome, and (iii) 50 non-obese subjects (BMI < 25 kg/m2) without metabolic syndrome and characterize the architecture of the gut microbiota from the subjects enrolled in this study by high-throughput sequencing of 16S rRNA genes; (2) characterize the gene content (metagenome) to assess the metabolic potential of the gut microbiota in 75 subjects to determine whether particular genes or pathways are correlated with disease phenotype; (3) characterize the transcriptome in 75 subjects to determine whether differences in gene expression in the gut microbiota are correlated with disease phenotype, (4) determine the effect of manipulation of the gut microbiota with antibiotics on energy homeostasis, inflammation markers, and metabolic syndrome traits in 50 obese subjects with metabolic syndrome and (5) study the relationship between gut microbiota and metabolic and cardiovascular disease traits, weight change, and host genomics in 1,000 Amish already characterized for these traits and in whom 500K Affymetrix SNP chips have already been completed. These studies will provide our deepest understanding to date of the role of gut microbes in terms of 'who's there?', 'what are they doing?', and 'how are they influencing host energy homeostasis, obesity and its metabolic complications? PUBLIC HEALTH RELEVANCE: This study aims to unravel the contribution of the bacteria that normally inhabit the human gastrointestinal tract to the development of obesity, and its more severe metabolic consequences including cardiovascular disease, insulin resistance and Type II diabetes. We will take a multidisciplinary approach to study changes in the structure and function of gut microbial communities in three sets of Old Order Amish patients from Lancaster, Pennsylvania: obese patients, obese patients with metabolic syndrome and non-obese individuals. The Old Order Amish are a genetically closed homogeneous Caucasian population of Central European ancestry ideal for genetic studies. These works have the potential to provide new mechanistic insights into the role of gut microflora in obesity and metabolic syndrome, a disease that is responsible for significant morbidity in the adult population, and may ultimately lead to novel approaches for prevention and treatment of this disorder.</p>
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Project description:The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a critical process that maintains metabolic fitness, while dysbiosis contributes to the development of obesity and insulin resistance (IR). However, how the gut microbiota controls WAT functions remain largely unknown. Herein, we show that tryptophan-derived metabolites produced by the microbiota control the expression of the miR-181 family in white adipocytes to regulate energy expenditure and insulin sensitivity. Moreover, we show that dysregulation of the microbiota-miR-181 axis is required for the development of obesity, IR, and WAT inflammation. Thus, our results indicate that regulation of miRNA levels in WAT by microbiota-derived cues is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As MIR-181 is dysregulated in WAT from obese human individuals, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.
2019-04-03 | GSE126135 | GEO
Project description:Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Using a mouse model mimicking pediatric antibiotic use, we found that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide altered both host and microbiota development. Early-life PAT accelerated total mass and bone growth, and resulted in progressive changes in gut microbiome diversity, population structure, and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. While control microbiota rapidly adapted to a change in diet, PAT slowed the ecological progression, with delays lasting several months in response to the macrolide. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. C57BL/6J mice received three antibiotic courses: at days 10-15, 28-31, and 37-40 of life, amoxicillin or tylosin.Livers were collected at age 22 weeks, RNA was extracted, and transcriptional differences were measured by microarray analysis.
2015-05-07 | E-GEOD-68603 | biostudies-arrayexpress
Project description:Gut microbiota dysbiosis characterizes systemic metabolic alteration, yet its causality is debated. To address this issue, we transplanted antibiotic-free conventional wild-type mice with either dysbiotic (“obese”) or eubiotic (“lean”) gut microbiota and fed them either a NC or a 72%HFD. We report that, on NC, obese gut microbiota transplantation reduces hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-transplanted mice. Of note, this phenotype is blunted in conventional NOD2KO mice. By contrast, lean microbiota transplantation did not affect hepatic gluconeogenesis. In addition, obese microbiota transplantation changed both gut microbiota and microbiome of recipient mice. Interestingly, hepatic gluconeogenesis, PEPCK and G6Pase activity were reduced even once mice transplanted with the obese gut microbiota were fed a 72%HFD, together with reduced fed glycaemia and adiposity compared to non-transplanted mice. Notably, changes in gut microbiota and microbiome induced by the transplantation were still detectable on 72%HFD. Finally, we report that obese gut microbiota transplantation may impact on hepatic metabolism and even prevent HFD-increased hepatic gluconeogenesis. Our findings may provide a new vision of gut microbiota dysbiosis, useful for a better understanding of the aetiology of metabolic diseases. all livers are from NC-fed mice only.
2017-03-16 | GSE81318 | GEO
Project description:Improper use of antibiotics in swine could reduce commensal bacteria and possibly increase pathogen infections via the gut resistome. This study aimed to compare the metaproteomic profiles of gut resistome and related metabolism in the cecal microbiota of fattening pigs raised under antibiotic-free (ABF) conditions with those of ordinary industrial pigs (CTRL).
2023-10-09 | PXD037218 | JPOST Repository
Project description:Insect gut microbiota plays important roles in acquiring nutrition, preventing pathogens infection, immune responses, and communicating with the environment. Gut microbiota can be affected by some external factors such as foods, temperature, and antibiotics. Spodoptera frugiperda (Lepidoptera: Noctuidae) is an important destructive pest of grain crops all over the world. The function of gut microbiota in S. frugiperda remains to be investigated. In this study, we fed the S. frugiperda with the antibiotic mixture (penicillin, gentamicin, rifampicin, and streptomycin) to perturb the gut microbiota, and further examined the effect of dysbiosis in gut microbiota on the gene expression of S. frugiperda by RNA sequencing. We found the composition and diversity of the gut bacterial community were changed in S. frugiperda after antibiotics treatmen, and the expression of genes related to energy and metabolic process were affected after antibiotics exposure in S. frugiperda. Our work will help understand the role of gut microbiota in insects.
2021-08-06 | GSE175476 | GEO
Project description:The early life microbiome plays important roles in host immunological and metabolic development. Because type 1 diabetes (T1D) incidence has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota that predisposes to disease. Using NOD mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and T reg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating T1D onset in NOD mice.
2016-05-20 | GSE81648 | GEO
Project description:We analyzed the effects of antibiotics using a popular model of gut microbiota depletion in mice by a cocktail of antibiotics. We combined intestinal transcriptome together with metagenomic analysis of the gut microbiota to develop a new bioinformatics approach that probes the links between microbial components and host functions. We found that most antibiotic-induced alterations can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues; and the effects of remaining antibiotic-resistant microbes. While microbe depletion led to down-regulation of immunity, the two other factors primarily inhibited mitochondrial gene expression and amounts of active mitochondria, and induced cell death. By reconstructing and analyzing a transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria. This series includes gene expression in the ileum of control, antibiotics (ABx)-treated, germfree, germfree-ABx-treated and mice colonized with normal or Abx-resistant microbiota. common reference design with a pool of small intestine RNA labeled with Cy3
2015-01-26 | E-GEOD-60566 | biostudies-arrayexpress
Project description:Inappropriate cross talk between mammals and their gut microbiota may trigger intestinal inflammation and drive extra-intestinal immune-mediated diseases. Studies with germ-free or gnotobiotic animals represent the gold standard for research on bacterial-host interaction but they are not readily accessible to the wide scientific community. We aimed at refining a protocol that in a robust manner would deplete murine intestinal microbiota and prove to have significant biologic validity. Previously published protocols for depleting mice of their intestinal microbiota by administering broad-spectrum antibiotics in drinking water were difficult to reproduce. We show that twice daily delivery of antibiotics by gavage depleted mice of their cultivable fecal microbiota and reduced the fecal bacterial DNA load by approximately 400 fold while ensuring the animals’ health. Mice subjected to the protocol for 17 days displayed enlarged ceca, reduced Peyer’s patches and small spleens. Antibiotic treatment significantly reduced the expression of antimicrobial factors and altered the expression of 517 genes in total in the colonic epithelium. Genes involved in cell cycle were significantly altered concomitant with reduced epithelial proliferative activity in situ assessed by Ki-67 expression, suggesting that commensal microbiota drives cellular proliferation in colonic epithelium. We present a robust protocol for depleting mice of their cultivatable intestinal microbiota with antibiotics by gavage and show that the biological effect of this depletion is phenotypic characteristics and epithelial gene expression profile similar to those of germ-free mice. Comparison of genome-wide gene expression of colon intestinal epithelial cells from mice subjected to microbiota depletion protocol against to control mice.
2011-08-14 | E-GEOD-22648 | biostudies-arrayexpress