Medha Priyadarshini1, Guadalupe Navarro1, Derek J Reiman2, Anukriti Sharma3, Kai Xu1, Kristen Lednovich1, Christopher R Manzella4, Md Wasim Khan1, Mariana Salas Garcia5, Sarah Allard5, Barton Wicksteed1, George E Chlipala6, Barbara Szynal1, Beatriz Penalver Bernabe2, Pauline M Maki7, Ravinder K Gill4, Gary H Perdew8, Jack Gilbert9, Yang Dai2, Brian T Layden10. 1. Division of Endocrinology, Diabetes, and Metabolism, University of Illinois, Chicago, Illinois. 2. Department of Biomedical Engineering, University of Illinois, Chicago, Illinois. 3. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Main Campus, Cleveland, Ohio. 4. Division of Gastroenterology and Hepatology, University of Illinois, Chicago, Illinois. 5. Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California. 6. Research Informatics Core, Research Resources Center, University of Illinois, Chicago, Illinois. 7. Department of Psychiatry, University of Illinois, Chicago, Illinois; Department of Psychology, University of Illinois, Chicago, Illinois; Department of Obstetrics and Gynecology, University of Illinois, Chicago, Illinois. 8. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, State College, Pennsylvania. 9. Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California; Scripps Institution of Oceanography, University of California San Diego, La Jolla, California. 10. Division of Endocrinology, Diabetes, and Metabolism, University of Illinois, Chicago, Illinois; Jesse Brown Veterans Affair Medical Center, Chicago, Illinois. Electronic address: blayde1@uic.edu.
Abstract
BACKGROUND & AIMS: Normal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of the GM-maternal metabolism interaction. METHODS: The GM and plasma metabolome of CD1, NIH-Swiss, and C57 mice were analyzed with the use of 16S rRNA sequencing and untargeted liquid chromatography-mass spectrometry throughout gestation. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM was studied with the use of fecal microbial transplants (FMTs). RESULTS: Significant variation in GM alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time point specific, with the species enriched at gestation day 15/19 (G15/19), a point of heightened IR, being distinct from those enriched before or after pregnancy. Metabolomics revealed elevated plasma kynurenine at G15/19 in all 3 mouse strains. IDO1, the rate-limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine level effects on IR derive from the GM in both mouse and human pregnancy. CONCLUSIONS: GM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation, and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1. (Gestational Gut Microbiome-IDO1 Axis Mediates Pregnancy Insulin Resistance; EMBL-ENA ID: PRJEB45047. MetaboLights ID: MTBLS3598). Published by Elsevier Inc.
BACKGROUND & AIMS: Normal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of the GM-maternal metabolism interaction. METHODS: The GM and plasma metabolome of CD1, NIH-Swiss, and C57 mice were analyzed with the use of 16S rRNA sequencing and untargeted liquid chromatography-mass spectrometry throughout gestation. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM was studied with the use of fecal microbial transplants (FMTs). RESULTS: Significant variation in GM alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time point specific, with the species enriched at gestation day 15/19 (G15/19), a point of heightened IR, being distinct from those enriched before or after pregnancy. Metabolomics revealed elevated plasma kynurenine at G15/19 in all 3 mouse strains. IDO1, the rate-limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine level effects on IR derive from the GM in both mouse and human pregnancy. CONCLUSIONS: GM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation, and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1. (Gestational Gut Microbiome-IDO1 Axis Mediates Pregnancy Insulin Resistance; EMBL-ENA ID: PRJEB45047. MetaboLights ID: MTBLS3598). Published by Elsevier Inc.
Entities:
Keywords:
Gut Microbiome; IDO1; Kynurenine; Pregnancy
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