ena-STUDY-CLEVELAND CLINIC LERNER RESEARCH INSTITUTE-19-05-2021-03:03:12:378-243
Gestational gut microbiome-IDO1 axis mediates pregnancy insulin resistance
Background and aims: Normal gestation involves reprogramming of maternal gut microbiome (GM) which has been established to contribute to maternal metabolic changes; however, by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM – maternal metabolism interaction.Methods: To identify novel associations, we characterized the GM and plasma metabolome of 3 strains of mice (CD1, NIH-Swiss and C57BL/6J) throughout gestation and postpartum.  Following identification of the tryptophan-kynurenine (Trp-Kyn) metabolite pathway and its rate limiting enzyme, indoleamine 2,3-dioxygenase (IDO1), as key players, pharmacologic and genetic knockout models of IDO1 were used to establish relationship of the pathway to pregnancy metabolic traits. Fecal microbial transplants were performed on pseudo germ free mice establishing the influence of the gestational GM on gut inflammation, Kyn levels and metabolic outcomes. Results: During different phases of pregnancy, we found significant variation in alpha diversity and strain specific enrichment of bacterial species/taxa. Machine learning analysis identified that bacterial taxa enriched in mice at gestation day 15/19 are distinct from those enriched pre or post pregnancy. Key identified taxa, like Anaeroplasma, Candidatus arthromitus, Sutterella, family Lachnospiraceae, enriched at gestation day 15/19 are associated with metabolic syndrome, diabetes and/or obesity. Untargeted and targeted metabolomics revealed elevated plasma Kyn at gestation day 15/19 in all the 3 mouse strains. Pharmacologic and genetic inhibition of indoleamine 2,3-dioxygenase (IDO1) revealed Kyn levels mediate insulin resistance (IR), and their levels are impacted by the GM.Conclusions: We show that during pregnancy IDO1 shifts Trp metabolism toward Kyn production, intestinal barrier disruption and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.
Background and aims: Normal gestation involves reprogramming of maternal gut microbiome (GM) which has been established to contribute to maternal metabolic changes; however, by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM – maternal metabolism interaction.Methods: To identify novel associations, we characterized the GM and plasma metabolome of 3 strains of mice (CD1, NIH-Swiss and C57BL/6J) throughout gestation and postpartum.  Following identification of the tryptophan-kynurenine (Trp-Kyn) metabolite pathway and its rate limiting enzyme, indoleamine 2,3-dioxygenase (IDO1), as key players, pharmacologic and genetic knockout models of IDO1 were used to establish relationship of the pathway to pregnancy metabolic traits. Fecal microbial transplants were performed on pseudo germ free mice establishing the influence of the gestational GM on gut inflammation, Kyn levels and metabolic outcomes. Results: During different phases of pregnancy, we found significant variation in alpha diversity and strain specific enrichment of bacterial species/taxa. Machine learning analysis identified that bacterial taxa enriched in mice at gestation day 15/19 are distinct from those enriched pre or post pregnancy. Key identified taxa, like Anaeroplasma, Candidatus arthromitus, Sutterella, family Lachnospiraceae, enriched at gestation day 15/19 are associated with metabolic syndrome, diabetes and/or obesity. Untargeted and targeted metabolomics revealed elevated plasma Kyn at gestation day 15/19 in all the 3 mouse strains. Pharmacologic and genetic inhibition of indoleamine 2,3-dioxygenase (IDO1) revealed Kyn levels mediate insulin resistance (IR), and their levels are impacted by the GM.Conclusions: We show that during pregnancy IDO1 shifts Trp metabolism toward Kyn production, intestinal barrier disruption and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.