Gut microbiota of patients with type 2 diabetes and gastrointestinal intolerance to metformin differs in composition and functionality from tolerant patients.

Abstract

Metformin modifies the gut microbiome in type 2 diabetes and gastrointestinal tolerance to metformin could be mediated by the gut microbiome. We enrolled 35 patients with type 2 diabetes not receiving treatment with metformin due to suspected gastrointestinal intolerance. Metformin was reintroduced at 425 mg, increasing 425 mg every two weeks until reaching 1700 mg per day. According to the occurrence of metformin-related gastrointestinal symptoms, patients were classified into three groups: early intolerance, non-tolerant, and tolerant. Gut microbiota was profiled with 16 S rRNA. This sequencing aimed to determine the differences in the baseline gut microbiota in all groups and prospectively in the tolerant and non-tolerant groups. The classification resulted in 15 early intolerant, 10 tolerant, and 10 non-tolerant subjects. Early tolerance was characterized by a higher abundance of Subdoligranulum; while Veillonella and Serratia were higher in the non-tolerant group. The tolerant group showed enrichment of Megamonas, Megamonas rupellensis, and Phascolarctobacterium spp; Ruminococcus gnavus was lower in the longitudinal analysis. At the end point Prevotellaceae, Prevotella stercorea, Megamonas funiformis, Bacteroides xylanisolvens, and Blautia producta had a higher relative abundance in the tolerant group compared to the non-tolerant group. Subdoligranulum, Ruminococcus torques_1, Phascolarctobacterium faecium, and Eubacterium were higher in the non-tolerant group. The PICRUSt analysis showed a lower activity of the amino acid biosynthesis pathways and a higher sugar degradation pathway in the intolerant groups. Gut microbiota of subjects with gastrointestinal intolerance depicted taxonomic and functional differences compared to tolerant patients, and this changed differently after metformin administration.