Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects

Abstract

Introduction: Metformin and glucagon-like peptide-1 (GLP-1) agonists are widely used for treating type two diabetes mellitus (T2DM). While recent studies suggest these drugs might modify the gastrointestinal tract (GIT) microbiome, further confirmation is required from human clinical trials.

Materials and methods: Here, we compare, in patients with T2DM, the effects of metformin (n = 18 subjects) and liraglutide (n = 19), a GLP-1 agonist, on their GIT microbiomes over a 42 day period (n = 74 samples) using 16S ribosomal RNA (rRNA) sequencing.

Results: We found that these drugs had markedly different effects on the microbiome composition. At both baseline and Day 42, subjects taking metformin had a significant increase (Baseline adj. P = .038, Day 42 adj. P = .041) in the relative abundance of the bacterial genus Sutterella, whereas liraglutide dosing is associated with a significant increase (Baseline adj. P = .048, Day 42 adj. P = .003) in the genus Akkermansia, a GIT bacteria positively associated with gut barrier homoeostasis. Bacteroides and Akkermansia relative abundances were also significantly associated with duration of subject diabetes (adj P < .05). Specifically, there was a significantly higher abundance of Akkermansia in subjects with short and medium durations than those with long duration of diabetes.

Discussion: To our knowledge, this is the first report of GLP-1 agonist-associated changes in the human microbiome and its differentiating effects to metformin. Our study suggests that modulation of the GIT microbiome is a potentially important component in the mechanism of action of these drugs.

Keywords: liraglutide; metformin; microbiota.

Figure 1

Difference in microbiome composition in metformin or liraglutide‐treated T2DM subjects. A, Study design and stool sampling periods at baseline and Day 42 as adapted from Hodge et al.9 B, Comparison of alpha diversity (Shannon) and major bacterial taxa between samples from liraglutide and metformin‐treated patients, both at baseline and Day 42 and in concert with GSK2890457 and placebo treatment. C, PCoA plot of all samples based on weighted UniFrac distance showed significant differential distribution of metformin and liraglutide groups. D, Significantly differentially represented bacterial genera between metformin and liraglutide groups, at baseline and Day 42