Metabolic and gut microbiome changes following GLP-1 or dual GLP-1/GLP-2 receptor agonist treatment in diet-induced obese mice

Abstract Enteroendocrine L-cell derived peptide hormones, notably glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), have become important targets in the treatment of type 2 diabetes, obesity and intestinal diseases. As gut microbial imbalances and maladaptive host responses have been implicated in the pathology of obesity and diabetes, this study aimed to determine the effects of pharmacologically stimulated GLP-1 and GLP-2 receptor function on the gut microbiome composition in diet-induced obese (DIO) mice. DIO mice received treatment with a selective GLP-1 receptor agonist (liraglutide, 0.2 mg/kg, BID) or dual GLP-1/GLP-2 receptor agonist (GUB09–145, 0.04 mg/kg, BID) for 4 weeks. Both compounds suppressed caloric intake, promoted a marked weight loss, improved glucose tolerance and reduced plasma cholesterol levels. 16S rDNA sequencing and deep-sequencing shotgun metagenomics was applied for comprehensive within-subject profiling of changes in gut microbiome signatures. Compared to baseline, DIO mice assumed phylogenetically similar gut bacterial compositional changes following liraglutide and GUB09-145 treatment, characterized by discrete shifts in low-abundant species and related bacterial metabolic pathways. The microbiome alterations may potentially associate to the converging biological actions of GLP-1 and GLP-2 receptor signaling on caloric intake, glucose metabolism and lipid handling.

Download Full-text

Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake

Gut ◽

10.1136/gutjnl-2019-320438 ◽

2020 ◽

Vol 69 (7) ◽

pp. 1258-1268 ◽

Cited By ~ 26

Author(s):

Victoria Meslier ◽

Manolo Laiola ◽

Henrik Munch Roager ◽

Francesca De Filippis ◽

Hugo Roume ◽

...

Keyword(s):

Mediterranean Diet ◽

Energy Intake ◽

Gut Microbiome ◽

Plasma Cholesterol ◽

Controlled Trial ◽

Metabolic Health ◽

Blood Cholesterol ◽

Shotgun Metagenomics ◽

Lifestyle Risk Factors ◽

Obese Subjects

ObjectivesThis study aimed to explore the effects of an isocaloric Mediterranean diet (MD) intervention on metabolic health, gut microbiome and systemic metabolome in subjects with lifestyle risk factors for metabolic disease.DesignEighty-two healthy overweight and obese subjects with a habitually low intake of fruit and vegetables and a sedentary lifestyle participated in a parallel 8-week randomised controlled trial. Forty-three participants consumed an MD tailored to their habitual energy intakes (MedD), and 39 maintained their regular diets (ConD). Dietary adherence, metabolic parameters, gut microbiome and systemic metabolome were monitored over the study period.ResultsIncreased MD adherence in the MedD group successfully reprogrammed subjects’ intake of fibre and animal proteins. Compliance was confirmed by lowered levels of carnitine in plasma and urine. Significant reductions in plasma cholesterol (primary outcome) and faecal bile acids occurred in the MedD compared with the ConD group. Shotgun metagenomics showed gut microbiome changes that reflected individual MD adherence and increase in gene richness in participants who reduced systemic inflammation over the intervention. The MD intervention led to increased levels of the fibre-degrading Faecalibacterium prausnitzii and of genes for microbial carbohydrate degradation linked to butyrate metabolism. The dietary changes in the MedD group led to increased urinary urolithins, faecal bile acid degradation and insulin sensitivity that co-varied with specific microbial taxa.ConclusionSwitching subjects to an MD while maintaining their energy intake reduced their blood cholesterol and caused multiple changes in their microbiome and metabolome that are relevant in future strategies for the improvement of metabolic health.

Download Full-text

Characteristics of the Gut Microbiome and IL-13/TGF-β1 Mediated Fibrosis in Post-Kasai Cholangitis of Biliary Atresia

Frontiers in Pediatrics ◽

10.3389/fped.2021.751204 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lingdu Meng ◽

Jia Liu ◽

Junfeng Wang ◽

Min Du ◽

Shouhua Zhang ◽

...

Keyword(s):

Biliary Atresia ◽

Gut Microbiome ◽

Expression Patterns ◽

Rna Seq ◽

Microbiome Composition ◽

Kasai Procedure ◽

Rdna Sequencing ◽

Liver Organoids ◽

Tgf Β1

Aims: Cholangitis in biliary atresia (BA), which accelerates liver fibrosis progression, is among the most common serious complications after Kasai surgery; however, its etiology remains elusive. Gut microbiome migration may contribute to post-Kasai cholangitis. Further, there is no appropriate model of BA post-Kasai cholangitis for use in investigation of its pathogenesis.Methods: We explored the characteristics of gut microbiome in patients with BA before and after Kasai procedure based on 16S rDNA sequencing. We isolated the dominant strain from patient stool samples and established an in vitro model by infecting patient-derived liver organoids. Bulk RNA-seq was performed, and we conducted qPCR, ELISA, and western blot to explore the mechanism of fibrosis.Results: Gut microbiome diversity was lower in patients after, relative to before, Kasai procedure, while the relative abundance of Klebsiella was higher. Patients who developed cholangitis within 1 month after discharge tended to have simpler gut microbiome composition, dominated by Klebsiella. Klebsiella pneumoniae (KPN) was isolated and used for modeling. RNA-seq showed that BA liver organoids expressed markers of hepatic progenitor cells (KRT19, KRT7, EPCAM, etc.) and that organoids were more stable and less heterogeneous among individuals than liver tissues. After infection with KPN, gene expression patterns in BA liver organoids were enriched in pathways related to infection, apoptosis, and fibrosis. Preliminary experiments indicated the presence of IL-13/TGF-β1-mediated fibrosis in post-Kasai cholangitis.Conclusions: Our findings using a newly-developed model, demonstrate a key role for Klebsiella, and a potential mechanism underlying fibrosis in post-Kasai cholangitis, mediated by the IL-13/TGF-β1 pathway.

Download Full-text

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

Frontiers in Endocrinology ◽

10.3389/fendo.2021.626359 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laila Silamiķele ◽

Ivars Silamiķelis ◽

Monta Ustinova ◽

Zane Kalniņa ◽

Ilze Elbere ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiome ◽

High Fat Diet ◽

Abundant Species ◽

Metformin Treatment ◽

High Fat ◽

Microbiome Composition ◽

Before And After ◽

Diabetes Mouse

Effects of metformin, the first-line drug for type 2 diabetes therapy, on gut microbiome composition in type 2 diabetes have been described in various studies both in human subjects and animals. However, the details of the molecular mechanisms of metformin action have not been fully understood. Moreover, there is a significant lack of information on how metformin affects gut microbiome composition in female mouse models, depending on sex and metabolic status in well controlled experimental setting. Our study aimed to examine metformin-induced alterations in gut microbiome diversity, composition, and functional implications of high-fat diet-induced type 2 diabetes mouse model, using, for the first time in mice study, the shotgun metagenomic sequencing that allows estimation of microorganisms at species level. We also employed a randomized block, factorial study design, and including 24 experimental units allocated to 8 treatment groups to systematically evaluate the effect of sex and metabolic status on metformin interaction with microbiome. We used DNA obtained from fecal samples representing gut microbiome before and after ten weeks-long metformin treatment. We identified 100 metformin-related differentially abundant species in high-fat diet-fed mice before and after the treatment, with most of the species relative abundances increased. In contrast, no significant changes were observed in control diet-fed mice. Functional analysis targeted to carbohydrate, lipid, and amino acid metabolism pathways revealed 14 significantly altered hierarchies. We also observed sex-specific differences in response to metformin treatment. Males experienced more pronounced changes in metabolic markers, while in females the extent of changes in gut microbiome representatives was more marked, indicated by 53 differentially abundant species with more remarkable Log fold changes compared to the combined-sex analysis. The same pattern manifested regarding the functional analysis, where we discovered 5 significantly affected hierarchies in female groups but not in males. Our results suggest that both sexes of animals should be included in future studies focusing on metformin effects on the gut microbiome.

Download Full-text

Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy and the host’s genotype upon microbiome composition

10.1101/571430 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jian Yin ◽

Peter R. Sternes ◽

Mingbang Wang ◽

Mark Morrison ◽

Jing Song ◽

...

Keyword(s):

Ankylosing Spondylitis ◽

Gut Microbiome ◽

Bacterial Species ◽

Tnf Inhibitor ◽

Hla B27 ◽

Clinical Genetic ◽

Host Genotype ◽

Shotgun Metagenomics ◽

Microbiome Composition ◽

Immune Mediated

ABSTRACTDiverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). To further investigate this we performed metagenomic analysis of a case-control cohort of 250 Han-Chinese subjects. Previous reports of gut dysbiosis in AS were re-confirmed and several notable bacterial species and functional categories were differentially abundant. TNF-inhibitor (TNFi) therapy at least partially restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of AS patients, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy of AS patients was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. An AS-associated SNP in RUNX3 significantly influenced the microbiome in two independent cohorts, highlighting a host genotype (other than HLA-B27) potentially influencing AS via the microbiome. These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS.

Download Full-text

Metformin strongly affects gut microbiome composition in high-fat diet-induced type 2 diabetes mouse model of both sexes

10.1101/2020.10.30.362095 ◽

2020 ◽

Author(s):

Laila Silamiķele ◽

Ivars Silamiķelis ◽

Monta Ustinova ◽

Zane Kalniņa ◽

Ilze Elbere ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiome ◽

High Fat Diet ◽

Abundant Species ◽

Metformin Treatment ◽

High Fat ◽

Microbiome Composition ◽

Before And After ◽

Diabetes Mouse

AbstractEffects of metformin, the first-line drug for type 2 diabetes therapy, on gut microbiome composition in type 2 diabetes have been described in various studies both in human subjects and animals. However, the details of the molecular mechanisms of metformin action have not been fully understood. Moreover, there is a significant lack of information on how metformin affects gut microbiome composition in female mice models, as most of the existing studies have focused on males only.Our study aimed to examine metformin-induced alterations in gut microbiome diversity and composition of high-fat diet-induced type 2 diabetes mouse model, employing a randomized block, factorial study design, and including 24 experimental units allocated to 8 treatment groups. We performed shotgun metagenomic sequencing using DNA obtained from fecal samples representing gut microbiome before and after ten weeks-long metformin treatment.We identified 100 metformin-related differentially abundant species in high-fat diet-fed mice before and after the treatment, with most of the species abundances increased. In contrast, no significant changes were observed in control diet-fed mice.We also observed sex-specific differences in response to metformin treatment. Males experienced more pronounced changes in metabolic markers, while, in females, the extent of changes in gut microbiome representatives was more marked, indicated by 53 differentially abundant species with more remarkable Log fold changes compared to the combined-sex analysis. Our results suggest that both sexes of animals should be included in future studies focusing on metformin effects on the gut microbiome.

Download Full-text

Shotgun metagenomics reveals significant gut microbiome features in different grades of acute pancreatitis

10.21203/rs.3.rs-34718/v1 ◽

2020 ◽

Author(s):

Shanshan Yu ◽

Yangyang Xiong ◽

Yangyang Fu ◽

Guorong Chen ◽

Huadong Zhu ◽

...

Keyword(s):

Acute Pancreatitis ◽

Gut Microbiota ◽

Severe Acute Pancreatitis ◽

Gut Microbiome ◽

Glutathione Metabolism ◽

Shotgun Metagenomics ◽

Microbiome Composition ◽

Considerable Morbidity ◽

Mild Acute Pancreatitis ◽

And Function

Abstract Background: Acute pancreatitis (AP) has a broad spectrum of severity and is associated with considerable morbidity and mortality. We aimed to evaluate the composition and functional effects of gut microbiota in different grades of AP severity. Results: Gut microbiota in AP patients was characterized by decreased species richness. The most representative gut microbiota in mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis (SAP) was Streptococcus, Escherichia-coli, and Enterococcus, respectively. Each of the three AP-associated genera could differentiate AP from healthy control population. Representative pathways associated with the glutathione metabolism, lipopolysaccharide biosynthesis, and amino acid metabolism (valine, leucine and isoleucine degradation) were enriched in MAP, MSAP, and SAP, respectively. Conclusions: Our findings indicate that in patients with AP, the gut microbiome composition and function are correlated with different severity of AP from a whole-genome perspective, and new changes are observed.

Download Full-text

Projection of gut microbiome pre and post bariatric surgery to predict surgery outcome

10.21203/rs.2.18879/v1 ◽

2019 ◽

Author(s):

yoram louzoun ◽

Meirav Ben Izhak ◽

Ruti Cohen ◽

Liora Madar Shapiro ◽

Hamutal Meiri ◽

...

Keyword(s):

Bariatric Surgery ◽

Gut Microbiome ◽

Eating Habits ◽

Sugar Metabolism ◽

Microbiome Composition ◽

Surgery Outcome ◽

Post Surgery ◽

Obesity And Diabetes ◽

Before And After ◽

Main Components

Abstract Background: Bariatric surgery is often the preferred method to resolve obesity and diabetes, with ~800,000 cases worldwide yearly and high outcome variability. The ability to predict the long-term BMI change following surgery has important implications on individuals and the health care system in general. Given the tight connection between eating habits, sugar consumption, BMI and the gut microbiome, we tested whether the microbiome before any treatment is associated with different treatment outcomes, as well as other intakes (HDL, Triglycerides, etc.).Results: A projection of the gut microbiome composition of obese (sampled before and after bariatric surgery) and slim patients into principal components was performed and the relation between this projection and surgery outcome was studied. The projection reveals 3 different microbiome profiles belonging to slim, obese and obese who underwent bariatric surgery, with post-surgery more different from the slim than the obese. The same projection allows for a prediction of BMI loss following bariatric surgery, using only the pre-surgery microbiome. A different projection is associated with sugar metabolism and A1C levels. Conclusions: - the gut microbiome can be naturally decomposed into main components depicting the patient's development and predicting in advance the outcome. Those may be translated into a better clinical management of obese individuals planning to undergo metabolic surgery.

Download Full-text

Human and rat gut microbiome composition is maintained following sleep restriction

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1620673114 ◽

2017 ◽

Vol 114 (8) ◽

pp. E1564-E1571 ◽

Cited By ~ 37

Author(s):

Shirley L. Zhang ◽

Lei Bai ◽

Namni Goel ◽

Aubrey Bailey ◽

Christopher J. Jang ◽

...

Keyword(s):

Gut Microbiome ◽

Metabolic Diseases ◽

Human Microbiome ◽

Modern Society ◽

Sleep Restriction ◽

Medical Problems ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Operational Taxonomic Units ◽

Obesity And Diabetes

Insufficient sleep increasingly characterizes modern society, contributing to a host of serious medical problems. Loss of sleep is associated with metabolic diseases such as obesity and diabetes, cardiovascular disorders, and neurological and cognitive impairments. Shifts in gut microbiome composition have also been associated with the same pathologies; therefore, we hypothesized that sleep restriction may perturb the gut microbiome to contribute to a disease state. In this study, we examined the fecal microbiome by using a cross-species approach in both rat and human studies of sleep restriction. We used DNA from hypervariable regions (V1-V2) of 16S bacteria rRNA to define operational taxonomic units (OTUs) of the microbiome. Although the OTU richness of the microbiome is decreased by sleep restriction in rats, major microbial populations are not altered. Only a single OTU, TM7-3a, was found to increase with sleep restriction of rats. In the human microbiome, we find no overt changes in the richness or composition induced by sleep restriction. Together, these results suggest that the microbiome is largely resistant to changes during sleep restriction.

Download Full-text

Gut microbiome composition is predictive of incident type 2 diabetes

10.1101/2021.11.10.21266163 ◽

2021 ◽

Author(s):

Matti O. Ruuskanen ◽

Pande P. Erawijantari ◽

Aki S. Havulinna ◽

Yang Liu ◽

Guillaume Meric ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiome ◽

Incident Diabetes ◽

Shotgun Metagenomics ◽

Incident Type ◽

Microbiome Composition ◽

Incident Type 2 Diabetes

OBJECTIVE: To examine the previously unknown long-term association between gut microbiome composition and incident type 2 diabetes in a representative population cohort. RESEARCH DESIGN AND METHODS: We collected fecal samples of 5 572 Finns (mean age 48.7 years, 54.1% women) in 2002 who were followed up for incident type 2 diabetes until Dec 31 st , 2017. The samples were sequenced using shotgun metagenomics. We examined associations between gut microbiome compositions and incident diabetes using multivariable- adjusted Cox regression models. We first used the Eastern Finland sub-population to obtain initial findings and validated these in the Western Finland sub-population. RESULTS: Altogether 432 cases of incident diabetes occurred over the median follow-up of 15.8 years. We detected 4 species and 2 clusters consistently associated with incident diabetes in the validation models. These 4 species were Clostridium citroniae (HR, 1.21; 95% CI, 1.04- 1.42), C. bolteae (HR, 1.20; 95% CI, 1.04-1.39), Tyzzerella nexilis (HR, 1.17; 95% CI, 1.01- 1.36), and Ruminococcus gnavus (HR = 1.17; 95% CI, 1.01-1.36). The positively associated clusters, cluster 1 (HR, 1.18; 95% CI, 1.02-1.38) and cluster 5 (HR, 1.18; 95% CI, 1.02-1.36), mostly consisted of these same species. CONCLUSIONS: We observed robust species-level taxonomic features predictive of incident type 2 diabetes over a long-term follow-up. These findings build on and extend previous mainly cross-sectional evidence and further support links between dietary habits, metabolic diseases, and type 2 diabetes that are modulated by the gut microbiome. The gut microbiome could potentially be used to improve risk prediction and to uncover novel therapeutic targets for diabetes.

Download Full-text

Projection of gut microbiome pre and post-bariatric surgery to predict surgery outcome

10.1101/2020.08.27.271312 ◽

2020 ◽

Author(s):

Meirav Ben Izhak ◽

Adi Eshel ◽

Ruti Cohen ◽

Liora Madar Shapiro ◽

Hamutal Meiri ◽

...

Keyword(s):

Bariatric Surgery ◽

Gut Microbiome ◽

Eating Habits ◽

High Density Lipoproteins ◽

List Type ◽

Microbiome Composition ◽

Surgery Outcome ◽

Post Surgery ◽

Obesity And Diabetes ◽

Before And After

AbstractBackgroundBariatric surgery is often the preferred method to resolve obesity and diabetes, with ~800,000 cases worldwide yearly and high outcome variability. The ability to predict the long-term Body Mass Index (BMI) change following surgery has important implications on individuals and the health care system in general. Given the tight connection between eating habits, sugar consumption, BMI, and the gut microbiome, we tested whether the microbiome before any treatment is associated with different treatment outcomes, as well as other intakes (high-density lipoproteins (HDL), Triglycerides, etc.).ResultsA projection of the gut microbiome composition of obese (sampled before and after bariatric surgery) and slim patients into principal components was performed and the relation between this projection and surgery outcome was studied. The projection reveals 3 different microbiome profiles belonging to slim, obese, and obese who underwent bariatric surgery, with post-surgery more different from the slim than the obese. The same projection allowed for a prediction of BMI loss following bariatric surgery, using only the pre-surgery microbiome.ConclusionsThe gut microbiome can be decomposed into main components depicting the patient’s development and predicting in advance the outcome. Those may be translated into better clinical management of obese individuals planning to undergo metabolic surgery.ImportanceBMI and diabetes can affect the gut microbiome composition.Bariatric surgery has large variabilities in outcome.The microbiome was previously shown to be a good predictor for multiple diseases.We analyzed here the gut microbiome before and after bariatric surgery and show that: The microbiome before surgery can be used to predict surgery outcome.Post-surgery microbiome drifts further away from the slim microbiome than pre-surgery obese patients.These results can lead to a microbiome-based pre-surgery decision whether to perform surgery.

Download Full-text