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Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.

ABSTRACT: BACKGROUND:The study was conducted to investigate the effects of metformin treatment on the human gut microbiome's taxonomic and functional profile in the Latvian population, and to evaluate the correlation of these changes with therapeutic efficacy and tolerance. METHODS:In this longitudinal observational study, stool samples for shotgun metagenomic sequencing-based analysis were collected in two cohorts. The first cohort included 35 healthy nondiabetic individuals (metformin dose 2x850mg/day) at three time-points during metformin administration. The second cohort was composed of 50 newly-diagnosed type 2 diabetes patients (metformin dose-determined by an endocrinologist) at two concordant times. Patients were defined as Responders if their HbA1c levels during three months of metformin therapy had decreased by ?12.6 mmol/mol (1%), while in Non-responders HbA1c were decreased by <12.6 mmol/mol (1%). RESULTS:Metformin reduced the alpha diversity of microbiota in healthy controls (p = 0.02) but not in T2D patients. At the species level, reduction in the abundance of Clostridium bartlettii and Barnesiella intestinihominis, as well as an increase in the abundance of Parabacteroides distasonis and Oscillibacter unclassified overlapped between both study groups. A large number of group-specific changes in taxonomic and functional profiles was observed. We identified an increased abundance of Prevotella copri (FDR = 0.01) in the Non-Responders subgroup, and enrichment of Enterococcus faecium, Lactococcus lactis, Odoribacter, and Dialister at baseline in the Responders group. Various taxonomic units were associated with the observed incidence of side effects in both cohorts. CONCLUSIONS:Metformin effects are different in T2D patients and healthy individuals. Therapy induced changes in the composition of gut microbiome revealed possible mediators of observed short-term therapeutic effects. The baseline composition of the gut microbiome may influence metformin therapy efficacy and tolerance in T2D patients and could be used as a powerful prediction tool.

SUBMITTER: Elbere I

PROVIDER: S-EPMC7598494 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.

Elbere Ilze I Silamikelis Ivars I Dindune Ilze Izabella II Kalnina Ineta I Ustinova Monta M Zaharenko Linda L Silamikele Laila L Rovite Vita V Gudra Dita D Konrade Ilze I Sokolovska Jelizaveta J Pirags Valdis V Klovins Janis J

PloS one 20201030 10

<h4>Background</h4>The study was conducted to investigate the effects of metformin treatment on the human gut microbiome's taxonomic and functional profile in the Latvian population, and to evaluate the correlation of these changes with therapeutic efficacy and tolerance.<h4>Methods</h4>In this longitudinal observational study, stool samples for shotgun metagenomic sequencing-based analysis were collected in two cohorts. The first cohort included 35 healthy nondiabetic individuals (metformin dos ...[more]

PMID: 33125401

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Project description:ObjectiveTo determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs).Research design and methodsWe conducted a 3-parallel-arm, randomized trial. We enrolled overweight/obese adults who had been treated for solid tumors but had no ongoing cancer treatment and randomized them (n = 121) to either 1) metformin (up to 2,000 mg), 2) coach-directed behavioral weight loss, or 3) self-directed care (control) for 12 months. We collected stool and serum at baseline (n = 114), 6 months (n = 109), and 12 months (n = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum.ResultsOf the 121 participants, 79% were female and 46% were Black, and the mean age was 60 years. Only metformin treatment significantly altered microbiota composition. Compared with control, metformin treatment increased amplicon sequence variants for Escherichia (confirmed as Escherichia coli by metagenomic sequencing) and Ruminococcus torques and decreased Intestinibacter bartlettii at both 6 and 12 months and decreased the genus Roseburia, including R. faecis and R. intestinalis, at 12 months. Effects were similar in comparison of the metformin group with the behavioral weight loss group. Metformin versus control also increased butyrate, acetate, and valerate at 6 months (but not at 12 months). Behavioral weight loss versus control did not significantly alter microbiota composition but did increase acetate at 6 months (but not at 12 months). Increases in acetate were associated with decreases in fasting insulin. Additional whole genome metagenomic sequencing of a subset of the metformin group showed that metformin altered 62 metagenomic functional pathways, including an acetate producing pathway and three pathways in glucose metabolism.ConclusionsMetformin, but not behavioral weight loss, impacted gut microbiota composition at 6 months and 12 months. Both metformin and behavioral weight loss altered circulating SCFAs at 6 months, including increasing acetate, which correlated with lower fasting insulin. Future research is needed to elucidate whether the gut microboime mediates or modifies metformin's health effects.

Project description:OBJECTIVE:To assess the efficacy and safety of short- term intensive hypoglycemic therapy with a triple regimen consisting of metformin, sagliptin and dapagliflozin in patients with newly diagnosed type 2 diabetes mellitus with hemoglobin Alc (HbA1c) of 9%-12%. METHODS:We prospectively enrolled 58 patients with newly diagnosed type 2 diabetes, who were treated with metformin combined with sagliptin and dapagliflozin for 12 weeks on the basis of diabetic diet and regular exercise. Blood glucose was monitored during the treatment and the changes in HbA1c, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 hPBG), fasting insulin (FINS), 2-hour postprandial insulin (2 hPINS), fasting C-peptide (F-CP), 2-hour postprandial C-peptide (2 hP-CP), and body weight after treatment as well as the incidence of hypoglycemia and adverse events associated with the treatment were recorded. RESULTS:Two patients withdrew from the study for intolerance of gastrointestinal reactions, and another 2 withdrew for inconvenience of access to the medicines. Fifty-four of the patients finally completed the study, including 34 male and 20 female patients. After 12 weeks of therapy, all the patients showed significant improvements in FBG, 2 hPBG, HbA1c, HOMA-beta and HOMA-IR (P < 0.001) with a mean reduction of HbA1c level by (4.19 ± 1.07)%, and the goal of HbA1c control to below 7.0% was achieved in 83.33% of the patients. The reduction of HbA1c was correlated with FBG (r=0.487, P=0.000), 2 hPBG (r=0.310, P=0.023), and HOMA-? (r=-0.398, P=0.003). The patients had a mean body weight loss by 2.47±3.38 kg (P < 0.001) and a mean decrease of body mass index (BMI) by 0.90± 1.18 kg/m2 (P < 0.001) after the therapy. The body weight-reducing effect was associated with the patients' baseline body weight (r=0.678, P=0.000), BMI (r=0.818, P=0.000), F-CP (r=0.282, P=0.039) and HOMA-IR (r=0.297, P=0.029). During the therapy 8 patients experienced hypoglycemic symptoms (10 times, 14.81%); 3 patients were diagnosed with hypoglycemia (blood glucose ?3.9 mmol/L, 3 times), and the overall incidence of hypoglycemia was 5.56%. No serious hypoglycemia or infections of the urinary and reproductive systems occurred in these patients. CONCLUSIONS:Short-term intensive oral hypoglycemic therapy with metformin combined with sagliptin and dapagliflozin is effective for treatment of patients with newly diagnosed type 2 diabetes with HbA1c of 9%-12% and shows a good weight-reducing effect with a low risk of hypoglycemia. The combined therapy can effectively improve ?-cell insulin secretion function, and is suitable for treatment of newly diagnosed type 2 diabetic patients with high blood glucose.

Dataset Information

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.

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Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.

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