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

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. More...

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Autores principales: Silamiķele, Laila, Silamiķelis, Ivars, Ustinova, Monta, Kalniņa, Zane, Elbere, Ilze, Petrovska, Ramona, Kalniņa, Ineta, Kloviņš, Jānis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018580/
https://www.ncbi.nlm.nih.gov/pubmed/33815284
http://dx.doi.org/10.3389/fendo.2021.626359
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author Silamiķele, Laila
Silamiķelis, Ivars
Ustinova, Monta
Kalniņa, Zane
Elbere, Ilze
Petrovska, Ramona
Kalniņa, Ineta
Kloviņš, Jānis
author_facet Silamiķele, Laila
Silamiķelis, Ivars
Ustinova, Monta
Kalniņa, Zane
Elbere, Ilze
Petrovska, Ramona
Kalniņa, Ineta
Kloviņš, Jānis
author_sort Silamiķele, Laila
collection PubMed
description 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.
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spelling pubmed-80185802021-04-03 Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes Silamiķele, Laila Silamiķelis, Ivars Ustinova, Monta Kalniņa, Zane Elbere, Ilze Petrovska, Ramona Kalniņa, Ineta Kloviņš, Jānis Front Endocrinol (Lausanne) Endocrinology 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. Frontiers Media S.A. 2021-03-19 /pmc/articles/PMC8018580/ /pubmed/33815284 http://dx.doi.org/10.3389/fendo.2021.626359 Text en Copyright © 2021 Silamiķele, Silamiķelis, Ustinova, Kalniņa, Elbere, Petrovska, Kalniņa and Kloviņš http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Silamiķele, Laila
Silamiķelis, Ivars
Ustinova, Monta
Kalniņa, Zane
Elbere, Ilze
Petrovska, Ramona
Kalniņa, Ineta
Kloviņš, Jānis
Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title_full Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title_fullStr Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title_full_unstemmed Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title_short Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes
title_sort metformin strongly affects gut microbiome composition in high-fat diet-induced type 2 diabetes mouse model of both sexes
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018580/
https://www.ncbi.nlm.nih.gov/pubmed/33815284
http://dx.doi.org/10.3389/fendo.2021.626359
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