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.

Comparative Evaluation of the Effect of Metformin and Insulin on Gut Microbiota and Metabolome Profiles of Type 2 Diabetic Rats Induced by the Combination of Streptozotocin and High-Fat Diet

“…We also found that the abundances of norank_f_Ruminococcaceae and unclassified_f_Ruminococcaceae were reduced by metformin. Elbere et al have shown that the metformin treatment can elevate the abundance of Oscillibacter in both healthy nondiabetic individuals and T2DM patients ( Elbere et al, 2020 ), which is opposite to our results. The alteration of Lactobacillus in our present work was also inconsistent with previous findings, in which its abundance is increased by metformin treatment in obese or diabetic rodents ( Zhang et al, 2015 ; Zhang M. et al, 2019 ; Cui et al, 2019 ).…”

Microbiome Changes after Type 2 Diabetes Treatment: A Systematic Review

“…Elbere et al and Sun et al found that metformin clinical benefits are partly mediated by bacteria-specific mechanisms such as glucose-SGLT1-sensing glucoregulatory pathway associated with Lactobacillus increase or B. fragilis —glycoursodeoxycholic acid (GUDCA)—intestinal farnesoid X receptor (FXR) [ 65 , 66 ]. Furthermore, higher abundances of Enterococcus faecium , Lactococcus lactis , Odoribacter , and Dialister were linked to a better response to metformin, while higher Prevotella copri suppresses it [ 65 ]. Based on these studies, microbiome preparation with proven gut-modulating interventions could improve response to first-line treatment.…”

Analyzing Type 2 Diabetes Associations with the Gut Microbiome in Individuals from Two Ethnic Backgrounds Living in the Same Geographic Area

“…Those cases could express a more severe diabetic phenotype compared to the untreated diabetes cases. However, previous studies have reported that metformin use itself affects gut microbiome composition, even in healthy normoglycemic individuals [ 9 , 22 , 23 , 24 , 59 , 60 ]. Therefore, disentangling the effect of metformin from the effect of type 2 diabetes on the gut microbiome in our datasets is difficult.…”

“…Interestingly, of all ASVs associated to Met-T2D in both ethnicities, almost all have been related to metformin use before in humans with the same direction. Clostridium sensu stricto 1 [ 23 ] and Peptostreptococcaceae Romboutsia [ 24 ], Terrisporobacter [ 23 ], and especially Intestinibacter bartlettii [ 9 , 22 , 23 , 60 ] were decreased, while Escherichia [ 9 , 22 , 23 , 24 ] showed an increase after metformin treatment in previous studies. In our study, Romboutsia was identified as a robust and strong biomarker in the relation between Met-T2D and the gut microbiome in both ethnicities.…”