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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.
Highlights
IntroductionDysbiosis in the gut bacterial community and concomitant metabolic changes have an impact on human health (Qin et al, 2012; Tremaroli and Bäckhed, 2012; Karlsson et al, 2013; Forslund et al, 2015; Mardinoglu et al, 2016; Magnusdottir et al, 2017)
Dysbiosis is one of the main features observed in metformintreated type 2 diabetes (T2D) patients, where there is higher relative abundance of Escherichia spp., A. muciniphila, S. variabile but lower of I. bartlettii (Forslund et al, 2015; Mardinoglu et al, 2016; Wu et al, 2017)
Larger concentrations of the short chain fatty acids (SCFAs) propionate and butyrate were reported under drug treatment (Forslund et al, 2015; Mardinoglu et al, 2016; Wu et al, 2017)
Summary
Dysbiosis in the gut bacterial community and concomitant metabolic changes have an impact on human health (Qin et al, 2012; Tremaroli and Bäckhed, 2012; Karlsson et al, 2013; Forslund et al, 2015; Mardinoglu et al, 2016; Magnusdottir et al, 2017). Compositional shifts in representative gut microbes were identified in T2D patients undergoing metformin treatment, the most prescribed antidiabetic drug These patients display increased abundance of Escherichia sp., Akkermansia muciniphila (A. muciniphila), and Subdoligranulum variabile (S. variabile) (Forslund et al, 2015; Mardinoglu et al, 2016; Wu et al, 2017), and lower of Intestinibacter bartlettii (Forslund et al, 2015; Wu et al, 2017), as well as increased levels of the SCFAs butyrate and propionate. The relationship between the metabolism of representative gut bacteria such as Escherichia sp., A. muciniphila, S. variabile and I. bartlettii, and compounds in the intestinal lumen such as SCFAs or amino acids is unclear
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