Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling

Abstract

Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world’s most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

“…This effect is consistent with the enrichment of short chain fatty acid (SCFA)-producing bacteria including Akkermansia, Bifidobacterium, Blautia, Butyrivibrio, Lactobacillus, Megasphaera, Prevotella or Shewanella species in metformintreated patients with T2DM, which results in increased SCFA in the colon, with potential metabolic benefits for the host 22,[187][188][189][190] . Interestingly, in silico analysis of the prevalent human gut bacterial metabolism using genome-scale metabolic models revealed important commensal and competing behavior following metformin treatment in the production of important SCFAs and their association with host cellular metabolism 191 .…”

Mechanisms of action of metformin with special reference to cardiovascular protection

“…Alterations in gut microbiota have been associated with dysglycaemia, including on people with prediabetes . Treatment with type 2 diabetes patients with metformin has been shown to alter the relative abundance of individual microbial species within the gut, particularly increasing the number of bacteria that produce short‐chain fatty acids or reduce the abundance of bacteria producing branched amino acids associated with insulin resistance . A recent randomized trial demonstrated altered gut microbiota during metformin treatment of antidiabetic drug‐naïve type 2 diabetes patients .…”

Reconstruction and dynamics of human intestinal microbiome observedin situ

“…Bacterial species as well as metabolic pathways can have distinct patterns when they are examined at DNA (“standing”) level and RNA (“active”) levels 25, 26 . In defecated fecal samples, a collection of bacterial species including Ruminococcus , Subdoligranulum and Faecalibacterium are highly active in terms of transcription and potentially metabolism, and they belong to the increasingly well-appreciated group of butyrate producers, and butyrate is known to be both metabolically as well as immunologically crucial for the host, especially in the context of several metabolic as well as auto-immune disorders 28, 29, 30, 31 . Except the top pathway being adenosine ribonucleotides de novo biosynthesis that is related to ATP production and thus energy cycling in both DNA and RNA, metabolic pathways related to nutrients metabolism (for instance glucose metabolism) are highly active in transcriptome data, even though pathways related cellular structures (for instance, components of cell walls) are most abundant in DNAs, suggesting a heterogeneous regulation of transcription in pathways aimed at different parts of microbial physiological activities.…”