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Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects.

ABSTRACT: Introduction:Metformin and glucagon-like peptide-1 (GLP-1) agonists are widely used for treating type two diabetes mellitus (T2DM). While recent studies suggest these drugs might modify the gastrointestinal tract (GIT) microbiome, further confirmation is required from human clinical trials. Materials and methods:Here, we compare, in patients with T2DM, the effects of metformin (n = 18 subjects) and liraglutide (n = 19), a GLP-1 agonist, on their GIT microbiomes over a 42 day period (n = 74 samples) using 16S ribosomal RNA (rRNA) sequencing. Results:We found that these drugs had markedly different effects on the microbiome composition. At both baseline and Day 42, subjects taking metformin had a significant increase (Baseline adj. P = .038, Day 42 adj. P = .041) in the relative abundance of the bacterial genus Sutterella, whereas liraglutide dosing is associated with a significant increase (Baseline adj. P = .048, Day 42 adj. P = .003) in the genus Akkermansia, a GIT bacteria positively associated with gut barrier homoeostasis. Bacteroides and Akkermansia relative abundances were also significantly associated with duration of subject diabetes (adj P < .05). Specifically, there was a significantly higher abundance of Akkermansia in subjects with short and medium durations than those with long duration of diabetes. Discussion:To our knowledge, this is the first report of GLP-1 agonist-associated changes in the human microbiome and its differentiating effects to metformin. Our study suggests that modulation of the GIT microbiome is a potentially important component in the mechanism of action of these drugs.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6360918 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects.

Wang Zhang Z Saha Somdutta S Van Horn Stephanie S Thomas Elizabeth E Traini Christopher C Sathe Ganesh G Rajpal Deepak K DK Brown James R JR

Endocrinology, diabetes & metabolism 20171228 1

<h4>Introduction</h4>Metformin and glucagon-like peptide-1 (GLP-1) agonists are widely used for treating type two diabetes mellitus (T2DM). While recent studies suggest these drugs might modify the gastrointestinal tract (GIT) microbiome, further confirmation is required from human clinical trials.<h4>Materials and methods</h4>Here, we compare, in patients with T2DM, the effects of metformin (n<i> </i>=<i> </i>18 subjects) and liraglutide (n<i> </i>=<i> </i>19), a GLP-1 agonist, on their GIT mic ...[more]

PMID: 30815546

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Project description:BackgroundTreatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease.MethodsIn a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS).ResultsIn total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism.ConclusionsCompared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted.Trial registrationNCT01425580.

Project description:A number of recent studies have shown the importance of the mammalian gut microbiome in host health. In the context of endangered species, a few studies have examined the relationship between the gut microbiome in wild versus captive populations due to digestive and other health issues. Unfortunately, the results seem to vary across taxa in terms of captive animals having higher, lower, or equivalent microbiome diversity relative to their wild counterparts. Here, we focus on the black rhinoceros as captive animals suffer from a number of potentially dietary related health effects. We compared gut microbiomes of wild and captive black rhinos to test for differences in taxonomic diversity (alpha and beta) and in functional diversity of the microbiome. We incorporated a more powerful metagenomic shotgun sequencing approach rather than a targeted amplification of the 16S gene for taxonomic assignment of the microbiome. Our results showed no significant differences in the alpha diversity levels between wild and captive black rhinos, but significant differences in beta diversity. We found that bacterial taxa traditionally associated with ruminant guts of domesticated animals had higher relative abundances in captive rhinos. Our metagenomic sequencing results suggest that unknown gut microbes of wild rhinos are being replaced by those found in conventional human-domesticated livestock. Wild rhinos have significantly different functional bacterial communities compared to their captive counterparts. Functional profiling results showed greater abundance of glycolysis and amino acid synthesis pathways in captive rhino microbiomes, representing an animal receiving sub-optimal nutrition with a readily available source of glucose but possibly an imbalance of necessary macro and micronutrients. Given the differences observed between wild and captive rhino gut microbiomes, we make a number of recommendations for potentially modifying captive gut microbiome to better reflect their wild counterparts and thereby hopefully improve overall rhino health in captivity.

Project description:The change of gut microbiome is associated with a serious of metabolic disorders, such as diabetes. As a glucagon-like peptide 1 analogue, liraglutide is a potent antidiabetic drug in clinical practice. However, the effect of liraglutide on the community of gut microbiota is still unknown. We aimed to determine the influence of liraglutide on fecal microbiota in diabetic male rats. Five-week-old male Sprague-Dawley rats were fed with a control diet or a high-fat diet for four weeks. By injecting streptozotocin, the diabetic rat model was performed. Diabetic male rats were injected subcutaneously with a low dose of liraglutide (liraglutide 0.2 mg/kg/day), a high dose of liraglutide (liraglutide 0.4 mg/kg/day), or normal saline for 12 weeks. Our data showed that liraglutide effectively prevented the development of diabetes in male rats. Pyrosequencing of the V3-V4 region of 16S rRNA genes manifested a remarkable transfer of gut microbiota construction in liraglutide-treated male rats compared with that of the diabetic male rats. Further analysis identified 879 liraglutide-treated specific operational taxonomic units. Some short-chain fatty acid (SCFA)-producing bacteria, including Bacteroides, Lachnospiraceae, and probiotic bacteria, Bifidobacterium, were selectively enhanced in liraglutide-treated diabetic male rats. Lactobacillus was negatively correlated with fasting blood glucose. To sum up, our findings propose that the prevention of diabetes by liraglutide in the diabetic male rats may be associated with the structural change of the gut microbiota, inflammation alleviation, and abundantly elevated SCFA-producing bacteria in the intestine. Impact statement Our findings suggest that significant changes in gut microbiota are associated with liraglutide treatment on the diabetic male rats, including enrichment of short-chain fatty acid producers and probiotic bacteria. This may help alleviate systemic inflammation and contribute to the beneficial effects of liraglutide against diabetes.

Project description:BackgroundGastrointestinal (GI) health is an important aspect of general health. Gastrointestinal symptoms are of specific importance for the elderly, an increasing group globally. Hence, promoting the elderly's health and especially gastrointestinal health is important. Gut microbiota can influence gastrointestinal health by modulation of the immune system and the gut-brain axis. Diverse gut microbiota have been shown to be beneficial; however, for the elderly, the gut microbiota is often less diverse. Nutrition and physical activity, in particular, are two components that have been suggested to influence composition or diversity.Materials and methodsIn this study, we compared gut microbiota between two groups of elderly individuals: community-dwelling older adults and physically active senior orienteering athletes, where the latter group has less gastrointestinal symptoms and a reported better well-being. With this approach, we explored if certain gut microbiota were related to healthy ageing. The participant data and faecal samples were collected from these two groups and the microbiota was whole-genome sequenced and taxonomically classified with MetaPhlAn.ResultsThe physically active senior orienteers had a more homogeneous microbiota within the group and a higher abundance of Faecalibacterium prausnitzii compared to the community-dwelling older adults. Faecalibacterium prausnitzii has previously shown to have beneficial properties. Senior orienteers also had a lower abundance of Parasutterella excrementihominis and Bilophila unclassified, which have been associated with impaired GI health. We could not observe any difference between the groups in terms of Shannon diversity index. Interestingly, a subgroup of community-dwelling older adults showed an atypical microbiota profile as well as the parameters for gastrointestinal symptoms and well-being closer to senior orienteers.ConclusionsOur results suggest specific composition characteristics of healthy microbiota in the elderly, and show that certain components of nutrition as well as psychological distress are not as tightly connected with composition or diversity variation in faecal microbiota samples.

Dataset Information

Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects.

Publications

Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects.

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