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      Bi-directional drug-microbiome interactions of anti-diabetics

      review-article
      Author(s): , , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: Diabetes, Drugs, Metformin, Microbiome, Type-2 diabetes, Probiotics, Prebiotics, AGIs, α-Glucosidase inhibitors, AMP, adenosine monophosphate, AMPK, AMP-kinases, BCCA, branched-chain amino acid, cAMP, cyclic AMP, DPP-4, Dipeptidyl peptidase-4, GLP-1, glucagon-like protein-1, HbA1c, hemoglobin A1c, HFD, high-fat diet, HFHSD, high-fat high-sucrose diet, IR, insulin resistance, LPS, lipopolysaccharide, MS, multiple sclerosis, PPAR, peroxisome proliferator-activated receptor, SCFAs, short-chain fatty acids, SGLT, sodium-glucose cotransporters, SGLT2, sodium-dependent glucose transport-2, T2D, type-2 diabetes, IR, insulin resistance, TLR, toll-like receptor, TZDs, thiazolidinediones

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          Abstract

          Type 2 diabetes (T2D) has become a global epidemic. Although several drugs are available to manage T2D, problems associated with person-to-person variability in drug efficacy and potential side-effects remain unresolved. Owing to the emerging role of the gut microbiome in obesity and T2D, the interaction between gut microbes and anti-diabetic drugs and its influence on drugs' functions remains of immediate research interest. On one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence drug metabolism and effects. Hence, understanding this bi-directional drug-microbiome interaction and how it influences the clinical outcomes of antidiabetic drugs can pave the way to develop next-generation strategies to ameliorate diabetes. This review presents evidences demonstrating the putative interactions between anti-diabetic drugs and the gut microbiome, and discusses the potential of microbiome modulators to manipulate drug-microbiome interactions and the drug metabolism.

          Graphical abstract

          Highlights

          • •

            Gut microbes interact with medications used to treat T2D, that at least partially mediates potential benefits of these drugs.

          • •

            Anti-diabetic drugs impact gut microbiome and its metabolic activity and vice-versa.

          • •

            Understanding the dynamics of drug-microbiome cross-talk would offer better therapeutic outcomes for diabetes.

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          Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.

          O Braissant, F Foufelle, C Scotto … (1996)
          Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.
          Article 0 comments Cited 353 times – based on 0 reviews     Review now
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            Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome.

            Siegfried Ussar, Nicholas W Griffin, Olivier Bezy … (2015)
            Obesity, diabetes, and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly used inbred strains of mice-obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ from Jackson Laboratory, and obesity-prone but diabetes-resistant 129S6/SvEvTac from Taconic-plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally normalized derivatives revealed strong interactions between microbiota, diet, breeding site, and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics, and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome.
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              Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats.

              Frank Duca, Clémence Côté, Brittany A Rasmussen … (2015)
              Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.
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                Author and article information

                Contributors
                Hariom Yadav
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 13 December 2018
                Publication date Collection: January 2019
                Publication date (Electronic): 13 December 2018
                Volume: 39
                Pages: 591-602
                Affiliations
                Department of Internal Medicine- Molecular Medicine, Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA
                Author notes
                [* ]Corresponding author at: Center for Diabetes, Obesity and Metabolism, Department of Internal Medicine-Molecular Medicine, Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. hyadav@ 123456wakehealth.edu
                Article
                Publisher ID: S2352-3964(18)30550-4
                DOI: 10.1016/j.ebiom.2018.11.046
                PMC ID: 6354569
                PubMed ID: 30553752
                SO-VID: e5b322c3-4a9f-445f-9cc6-f8829541d41b
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 6 July 2018
                Date revision received : 13 November 2018
                Date accepted : 21 November 2018
                Categories
                Subject: Review

                Keywords: diabetes,drugs,metformin,microbiome,type-2 diabetes,probiotics,prebiotics,agis, α-glucosidase inhibitors,amp, adenosine monophosphate,ampk, amp-kinases,bcca, branched-chain amino acid,camp, cyclic amp,dpp-4, dipeptidyl peptidase-4,glp-1, glucagon-like protein-1,hba1c, hemoglobin a1c,hfd, high-fat diet,hfhsd, high-fat high-sucrose diet,ir, insulin resistance,lps, lipopolysaccharide,ms, multiple sclerosis,ppar, peroxisome proliferator-activated receptor,scfas, short-chain fatty acids,sglt, sodium-glucose cotransporters,sglt2, sodium-dependent glucose transport-2,t2d, type-2 diabetes,tlr, toll-like receptor,tzds, thiazolidinediones
                Data availability:
                Keywords: diabetes, drugs, metformin, microbiome, type-2 diabetes, probiotics, prebiotics, agis, α-glucosidase inhibitors, amp, adenosine monophosphate, ampk, amp-kinases, bcca, branched-chain amino acid, camp, cyclic amp, dpp-4, dipeptidyl peptidase-4, glp-1, glucagon-like protein-1, hba1c, hemoglobin a1c, hfd, high-fat diet, hfhsd, high-fat high-sucrose diet, ir, insulin resistance, lps, lipopolysaccharide, ms, multiple sclerosis, ppar, peroxisome proliferator-activated receptor, scfas, short-chain fatty acids, sglt, sodium-glucose cotransporters, sglt2, sodium-dependent glucose transport-2, t2d, type-2 diabetes, tlr, toll-like receptor, tzds, thiazolidinediones

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