Background&Aims: Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota but whether IGN intensity could shape it has not been investigated. Methods: To this aim, we studied gut microbiota and microbiome in wild-type and IGN-deficient mice which underwent GBP and were fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine

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... ome in NC-fed mice. Results: IGN and GBP had a peculiar effect on both gut microbiota and microbiome, on NC and HFHS diet. IGN inactivation induced Deltaproteobacteria on NC and higher Proteobacteria such as Helicobacter on HFHS diet. GBP induced higher Firmicutes and Proteobacteria on NC-fed WT mice and Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP induced higher Actinobacteria on NC and higher Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. Conclusions: IGN and GBP, alone and in combination, shape gut microbiota and microbiome on NC- and HFHS-fed mice, together with a change in fecal and urine metabolome.