Multi-omics analysis reveals gut-brain interactions mediating the anti-obesity effect of Akkermansia muciniphila
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212491 | GEO | 2022/09/03
REPOSITORIES: GEO
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Project description:The crucial role of nutrition for cerebral health and the impact of dietary habits on brain structure and function have been long far recognized. To date a major health concern is associated with the increased consumption of fructose as added sugar in many types of drinks and processed foods, especially among young people. High-fructose intake has been pointed out as the possible culprit for the raised incidence of chronic diseases, such as obesity, cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabete. Further, it has been reported that high-fructose intake is associated with the over-activation of its cerebral metabolism, which was proposed to negatively impact on whole brain physiology and cognitive function. Notably, we previously reported that short-term fructose-rich diet induces mitochondrial dysfunction, oxidative stress, and neuroinflammation in hippocampus of young rats, as well as the imbalance of redox homeostasis, autophagic mechanisms and representation of synaptic markers in frontal cortex of both adult and young rats. Animal studies have also revealed the damaging effect of high-fructose diets on hippocampal functions during periods of neurocognitive development, such as childhood and adolescence. Hypothalamus plays a crucial role in maintaining whole body homeostasis. Long-term fructose overfeeding was reported to alter hypothalamic-pituitary-adrenal axis, leading to elevations in glucocorticoids in peri-adolescent rats [22]. Further, fructose overconsumption was associated with impairment of hypothalamic insulin signalling, oxidative stress and inflammation , and it was proposed that fructose-driven perturbations of hypothalamic function may compromise the potential for satiety, thereby increasing the prospect of developing obesity. Data currently available on hypothalamic dysfunctions related to a high-fructose diet essentially refer to the effects of long-term sugar feeding, while information on corresponding alterations associated with a short-term dietary treatment, particularly in the critical period of adolescence, is still lacking. Due to complexity and multiplicity of hypothalamic functions, there is also the need for a holistic characterization aimed at unveiling the general picture of hypothalamic dysfunctions associated with a high-fructose diet. To fill this gap, we investigated adolescent rats fed a fructose-rich or control diet, for 3 weeks. To verify whether the fructose-driven changes are rescued after the switch to a control diet, half of the rats from both animal groups were then fed a control diet for additional 3 weeks until young adulthood phase. Quantitative proteomics on hypothalamic extracts of all animal groups was used to identify molecular alterations triggered by fructose-rich diet and to obtain insights into the relationship between sugar feeding and possible dysfunctions of hypothalamus.
2023-03-11 | PXD038834 | Pride
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>
| phs000258 | dbGaP
Project description:Obesity is characterized by central leptin resistance. Celastrol has been identified to reduce leptin resistance in diet-induced obese and leptin resistant mice. Current microarray data provide the hypothalamic gene expression profiles from mice treated with Celastrol or Withaferin A.
2016-07-08 | GSE84156 | GEO
Project description:Maternal obesity programs the offspring to cardiovascular disease, insulin resistance, and obesity. We sequenced and profiled the cardiac miRNAs that were dysregulated in the hearts of baboon fetuses born to a high fat / high fructose diet fed mothers compared to a regular diet fed mothers. Fetal hearts were collected from baboon fetuses born to obese and lean mothers, total RNA was isolated, and fetal cardiac miRNA were sequenced and profiled
2013-02-01 | E-GEOD-43323 | biostudies-arrayexpress
Project description:Kees2018 - Genome-scale constraint-based
model of the mucin-degrader Akkermansia
muciniphila
This model is described in the article:
Model-driven design of a
minimal medium for Akkermansia muciniphila confirms mucus
adaptation.
van der Ark KCH, Aalvink S,
Suarez-Diez M, Schaap PJ, de Vos WM, Belzer C.
Microb Biotechnol 2018 Jan; :
Abstract:
The abundance of the human intestinal symbiont Akkermansia
muciniphila has found to be inversely correlated with several
diseases, including metabolic syndrome and obesity.
A. muciniphila is known to use mucin as sole carbon and
nitrogen source. To study the physiology and the potential for
therapeutic applications of this bacterium, we designed a
defined minimal medium. The composition of the medium was based
on the genome-scale metabolic model of A. muciniphila and
the composition of mucin. Our results indicate that
A. muciniphila does not code for GlmS, the enzyme that
mediates the conversion of fructose-6-phosphate (Fru6P) to
glucosamine-6-phosphate (GlcN6P), which is essential in
peptidoglycan formation. The only annotated enzyme that could
mediate this conversion is Amuc-NagB on locus Amuc_1822. We
found that Amuc-NagB was unable to form GlcN6P from Fru6P at
physiological conditions, while it efficiently catalyzed the
reverse reaction. To overcome this inability,
N-acetylglucosamine needs to be present in the medium for
A. muciniphila growth. With these findings, the
genome-scale metabolic model was updated and used to accurately
predict growth of A. muciniphila on synthetic media. The
finding that A. muciniphila has a necessity for GlcNAc,
which is present in mucin further prompts the adaptation to its
mucosal niche.
This model is hosted on
BioModels Database
and identified by:
MODEL1710040000.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2021-02-15 | MODEL1710040000 | BioModels
Project description:Roux-en-Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, but it has a ~20% failure rate. We used our established RYGB model in diet-induced obese (DIO) Sprague-Dawley rats, which reproduces human bi-phasic body weight (BW) loss pattern, to determine mechanisms contributing to success (RGYB-S) or failed (RYGB-F) RYGB. DIO rats were randomized to RYGB, sham operated Obese, and sham operated obese pair fed-linked to RYGB (PF) groups. BW, caloric intake (CI) and fecal output (FO) were recorded daily for 90 days, food efficiency (FE) was calculated, and morphologic changes were determined. Gut, adipose and thyroid hormones were measured in plasma. Mitochondrial respiratory complexes in skeletal muscle, expression of energy-related hypothalamic and fat peptides, receptors and enzymes were quantified. A 25% failure rate occurred. RYGB-S, RYGB-F and PF rats vs. Obese showed rapid BW decrease, followed by sustained BW loss in RYGB-S. RYGB-F and PF gradually increased BW. Expression profiling of both CNS (hypothalamus) and peripheral tissues (subcutaneous abdominal fat) strongly supported the involvement of a number of metabolic and feeding-related genes in the differential outcomes. Experiment Overall Design: 3 biological replicate RNA samples were prepared from 2 tissues (the subcutaneous abdominal fat or the hypothalamus) from rats in 3 treatment groups (rats losing weight successfully after gastric bypass surgery, rats gaining weight, and rats that were fed the same amount as the treated rats)
2008-06-16 | E-GEOD-8314 | biostudies-arrayexpress
Project description:Obesity is a risk factor for Osteoarthritis (OA), the greatest cause of disability in the US. The impact of obesity on OA is driven by systemic inflammation, now understood to be caused by an altered gut microbiome. Oligofructose, a non-digestible prebiotic fiber, can correct the obese gut microbiome, suggesting a novel approach to treat the OA of obesity. Here we report that in the obese murine gut, beneficial Bifidobacteria are lost while key proinflammatory species gain in abundance. A downstream systemic inflammatory signature culminates with accelerated knee OA. Oligofructose supplementation corrects the obese gut microbiome in part by supporting key commensal microflora, particularly Bifidobacterium pseudolongum. This leads to reduced inflammation in the colon, circulation and knee, and protection from OA. This novel recognition of a gut microbiome-OA connection sets the stage for discovery of new OA therapeutics targeting specific microbes inhabiting the intestinal space to inhibit disease pathology.
2018-06-22 | GSE98287 | GEO
Project description:Roux-en-Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, but it has a ~20% failure rate. We used our established RYGB model in diet-induced obese (DIO) Sprague-Dawley rats, which reproduces human bi-phasic body weight (BW) loss pattern, to determine mechanisms contributing to success (RGYB-S) or failed (RYGB-F) RYGB. DIO rats were randomized to RYGB, sham operated Obese, and sham operated obese pair fed-linked to RYGB (PF) groups. BW, caloric intake (CI) and fecal output (FO) were recorded daily for 90 days, food efficiency (FE) was calculated, and morphologic changes were determined. Gut, adipose and thyroid hormones were measured in plasma. Mitochondrial respiratory complexes in skeletal muscle, expression of energy-related hypothalamic and fat peptides, receptors and enzymes were quantified. A 25% failure rate occurred. RYGB-S, RYGB-F and PF rats vs. Obese showed rapid BW decrease, followed by sustained BW loss in RYGB-S. RYGB-F and PF gradually increased BW. Expression profiling of both CNS (hypothalamus) and peripheral tissues (subcutaneous abdominal fat) strongly supported the involvement of a number of metabolic and feeding-related genes in the differential outcomes. Keywords: gene expression analysis
2007-06-30 | GSE8314 | GEO
Project description:Background: The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. The negative impact of poor dietary patterns on brain development and neurological function may be related to gut microbiota disturbance. The role of phlorizin in mitigating glucose and lipid metabolism disorders is well documented. However, the protective effect of phlorizin on diabetes-related cognitive dysfunction is unclear. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. Results: Dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Moreover, integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Conclusions: These results indicate that gut microbiota and their metabolites mediate the ameliorative effect of phlorizin on HFFD-induced cognitive impairment. Therefore, phlorizin can be used as an easy-to-implement nutritional therapy to prevent and alleviate metabolism-related neurodegenerative diseases by targeting the regulation of the microbiome-gut-brain axis.
2024-03-20 | GSE261887 | GEO
Project description:Fructose consumption has increased by over 25% since 1970, and excess consumption has deleterious metabolic effects. Additionally, fructose can alter hypothalamic pituitary adrenal axis function, potentially resulting in increased vulnerability to mood disorders. Adolescents are the greatest consumers of fructose and also at a critical period of development. Here, we examine the effects of consumption of a 55% fructose diet from weaning until adulthood on the hypothalamic transcriptome.
2015-03-25 | GSE56238 | GEO