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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Front+Physiol
2018 ; 9
(ä): 775
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Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated
Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling
#MMPMID29988585
Rosario D
; Benfeitas R
; Bidkhori G
; Zhang C
; Uhlen M
; Shoaie S
; Mardinoglu A
Front Physiol
2018[]; 9
(ä): 775
PMID29988585
show ga
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.