Paul M Ryan1, Elaine Patterson2, Ilaria Carafa3, Rupasri Mandal4, David S Wishart5, Timothy G Dinan6, John F Cryan7, Kieran M Tuohy3, Catherine Stanton2, R Paul Ross8. 1. School of Medicine, University College Cork, County Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, County Cork, Ireland; APC Microbiome Ireland, University College Cork, County Cork, Ireland. 2. Teagasc Food Research Centre, Moorepark, Fermoy, County Cork, Ireland; APC Microbiome Ireland, University College Cork, County Cork, Ireland. 3. Fondazione Edmund Mach - Istituto Agrario, San Michele All'adige, Italy. 4. Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada. 5. Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada; Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada; National Institute for Nanotechnology, Edmonton, Alberta, Canada. 6. APC Microbiome Ireland, University College Cork, County Cork, Ireland; Department of Psychiatry, University College Cork, County Cork, Ireland. 7. APC Microbiome Ireland, University College Cork, County Cork, Ireland; Department of Neuroscience, University College Cork, County Cork, Ireland. 8. APC Microbiome Ireland, University College Cork, County Cork, Ireland. Electronic address: p.ross@ucc.ie.
Abstract
OBJECTIVES: Recent evidence indicates that gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of 2 antidiabetic therapeutics on gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. METHODS: C57BL/6 mice were fed a high-fat diet for 24 weeks while receiving 1 of 2 antidiabetic therapeutics-metformin or dipeptidyl peptidase-4 (DPP-4) inhibitor, PKF-275-055-for the final 12 weeks. Mice were assessed for weight gain, glucose and cholesterol metabolism, and adiposity. In addition, cecal microbiota was analyzed by 16S compositional sequencing, and plasma metabolome was analyzed by liquid chromatography with tandem mass spectrometry. RESULTS: Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity and improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. Although both metformin and PKF-275-055 mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin harboured metabolic health-associated Akkermansia, Parabacteroides and Christensenella. Paradoxically, metformin also reduced α diversity, a metric frequently associated with host metabolic fitness. PKF-275-055 mice displayed elevated levels of butyrate-producing Ruminococcus and acetogen Dorea, with reduced levels of certain plasma sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities. In turn, metformin reduced levels of acylcarnitines, a functional group associated with systemic metabolic dysfunction. Finally, several associations were identified between metabolites and altered taxa. CONCLUSIONS: This study represents the first direct comparison of the microbiota-modifying effects of metformin and a DPP-4 inhibitor, and proposes several putative microbial targets both in terms of novel therapeutic development and adverse effect prevention.
OBJECTIVES: Recent evidence indicates that gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of 2 antidiabetic therapeutics on gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. METHODS: C57BL/6 mice were fed a high-fat diet for 24 weeks while receiving 1 of 2 antidiabetic therapeutics-metformin or dipeptidyl peptidase-4 (DPP-4) inhibitor, PKF-275-055-for the final 12 weeks. Mice were assessed for weight gain, glucose and cholesterol metabolism, and adiposity. In addition, cecal microbiota was analyzed by 16S compositional sequencing, and plasma metabolome was analyzed by liquid chromatography with tandem mass spectrometry. RESULTS: Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity and improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. Although both metformin and PKF-275-055 mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin harboured metabolic health-associated Akkermansia, Parabacteroides and Christensenella. Paradoxically, metformin also reduced α diversity, a metric frequently associated with host metabolic fitness. PKF-275-055 mice displayed elevated levels of butyrate-producing Ruminococcus and acetogen Dorea, with reduced levels of certain plasma sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities. In turn, metformin reduced levels of acylcarnitines, a functional group associated with systemic metabolic dysfunction. Finally, several associations were identified between metabolites and altered taxa. CONCLUSIONS: This study represents the first direct comparison of the microbiota-modifying effects of metformin and a DPP-4 inhibitor, and proposes several putative microbial targets both in terms of novel therapeutic development and adverse effect prevention.
Authors: Meghana D Gadgil; Alka M Kanaya; Caroline Sands; Matthew R Lewis; Namratha R Kandula; David M Herrington Journal: Diabet Med Date: 2020-12-25 Impact factor: 4.359
Authors: Lina A Dahabiyeh; Muhammad Mujammami; Tawfiq Arafat; Hicham Benabdelkamel; Assim A Alfadda; Anas M Abdel Rahman Journal: Front Pharmacol Date: 2021-07-15 Impact factor: 5.810