Gestational Insulin Resistance Is Mediated by the Gut Microbiome–Indoleamine 2,3-Dioxygenase Axis

Priyadarshini, Medha; Navarro, Guadalupe; Reiman, Derek; Sharma, Anukriti; Xu, Kai; Lednovich, Kristen; Manzella, Christopher R.; Khan, Md Wasim; Garcia, Mariana Salas; Allard, Sarah; Wicksteed, Barton; Chlipala, George E.; Szynal, Barbara; Bernabé, Beatriz Peñalver; Maki, Pauline M.; Gill, Ravinder K.; Perdew, Gary H.; Gilbert, Jack A.; Dai, Yang; Layden, Brian T.

doi:10.1053/j.gastro.2022.01.008

Cited by 20 publications

(19 citation statements)

References 45 publications

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“…83 Insulin resistance, which occurs as pregnancy progresses, is characterized by lower ratio of tryptophan to kynurenine (T/K) and lower levels of T/K ratio are associated with greater inflammatory disorders such as preeclampsia and perinatal depression. 84–87 Tryptophan is a key regulator of neural plasticity. Adequate neural plastic is vital to the required coping and cognitive adaptations necessary for a healthy sense of Self-Efficacy.…”

Section: Discussionmentioning

confidence: 99%

Interactions between Perceived Stress and Microbial-Host Immune Components in Pregnancy

Bernabé

Maki

Cunningham

et al. 2022

Preprint

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BackgroundHigher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota reflects the environment, lifestyle, and the perinatal period. The gut microbiota, alongside host immune responses, has the potential to aid in identifying when stress is excessive.MethodsTwo U.S. cohorts, of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 (Emotional Distress and Self-Efficacy) in the two cohorts. Gut microbiota composition was measured by 16S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines.ResultsEmotional Distress levels were higher in the suburban compared to the urban cohort, but levels of Self-Efficacy were similar. Emotional Distress and Self-Efficacy levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of Self-Efficacy levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and Self-Efficacy.ConclusionsThe study identified links between distinct taxonomical and immunological signatures with perceived stress. The data is congruent with a model where gut microbiome and immune factors may modulate neural plasticity resulting in increased Self-Efficacy during pregnancy. The predictive value of these peripheral markers merit further study.

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Section: Discussionmentioning

confidence: 99%

Interactions between Perceived Stress and Microbial-Host Immune Components in Pregnancy

Bernabé

Maki

Cunningham

et al. 2022

Preprint

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“…The 16S rRNA gene amplicon sequencing and untargeted LC-MS were used to generate microbiome and metabolome profiles, respectively. Detailed experimental protocols for data collection and quantification procedures for microbiome and metabolomic features can be found in [4]. Briefly, the metabolic health characteristics are comprised of blood glucose and insulin levels, body weight, and change in weights of different types of adipose depots (subcutaneous and visceral) at the different time points of pregnancy.…”

Section: Datasets and Pre-processingmentioning

confidence: 99%

“…2 of 11 that the gestational gut microbiome mediates pregnancy metabolic adaptations through effects on the gut indoleamine-2,3 dioxygenase 1 activity and the production of kynurenine [4]. This multi-omics study collected pregnancy-specific physiological and metabolic response characteristics, gut microbiome, and plasma metabolome data on 3 genetically diverse strains of mice (C57BL/6J, CD1, and NIH-Swiss) during the gestational stage and postpartum pregnancy.…”

Section: Introductionmentioning

confidence: 99%

MOMMI-MP: A Comprehensive Database for Integrated Analysis of Metabolic and Microbiome Profiling of Mouse Pregnancy

Pachpor¹,

Priyadarshini²,

Reiman³

et al. 2022

Preprint

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Pregnancy is a dynamic state with multiple metabolic changes occurring including insulin resistance. Gestational diabetes mellitus (GDM), a form of diabetes that appears during pregnancy, develops if metabolic aberrations occur, in particular, in normal pregnancy-induced insulin resistance. Multi-omics is a powerful approach for uncovering the mechanisms driving metabolic change in different physiologic and pathologic states. A recent study demonstrated that the gestational gut microbiome mediates pregnancy metabolic adaptations through effects on gut indoleamine-2,3 dioxygenase 1 activity and the production of kynurenine. Using the dataset generated from this highly controlled study, we performed a comprehensive analysis of the pregnancy-specific physiological and metabolic profiles, 16S rRNA microbiome, and plasma untargeted LC-MS metabolome data. To facilitate the utilization of these analysis results by other researchers, we developed MOMMI-MP, a database that provides an easy-to-use platform to browse and search differential abundant microbial taxa and metabolites, and to examine metabolic pathways. The datasets consist of data collected from 3 genetically diverse strains of mice (C57BL/6J, CD1, and NIH-Swiss) over 6 time points during the gestational (days 0, 10, 15, and 19 during gestation) and postpartum (days 3 and 20 after delivery) states, totaling 180 samples for each strain. The computational results are presented in various tables and plots, and organized in MOMMI-MP to empower exploratory analyses by other researchers. In conclusion, MOMMI-MP is a resource to facilitate the investigation of novel mechanisms governing metabolic changes during pregnancy.

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“…The gut microbiota influences 5-HT through the production and metabolism of tryptophan, the rate-limiting precursor of 5-HT ( 12 – 15 ). Postprandial 5-HT concentrations have been associated with IBS subtypes ( 16 ), and patients with IBS can have decreased nocturnal levels of tryptophan metabolites ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Decreased Gut Microbiome Tryptophan Metabolism and Serotonergic Signaling in Patients With Persistent Mental Health and Gastrointestinal Symptoms After Covid-19

Blackett

Sun

Purpura

et al. 2022

Clin Transl Gastroenterol

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INTRODUCTION: An estimated 15%–29% of patients report new gastrointestinal (GI) symptoms after coronavirus-19 disease (COVID-19) while 4%–31% report new depressive symptoms. These symptoms may be secondary to gut microbiome tryptophan metabolism and 5-hydroxytryptamine (5-HT)-based signaling. METHODS: This study used specimens from 2 patient cohorts: (i) fecal samples from patients with acute COVID-19 who participated in a randomized controlled trial testing prebiotic fiber and (ii) blood samples from patients with acute COVID-19. Six months after recovering from COVID-19, both cohorts answered questions related to GI symptoms and anxiety or depression. Microbiome composition and function, focusing on tryptophan metabolism-associated pathways, and plasma 5-HT were assessed. RESULTS: In the first cohort (n = 13), gut microbiome L-tryptophan biosynthesis during acute COVID-19 was decreased among those who developed more severe GI symptoms (2.0-fold lower log activity comparing those with the most severe GI symptoms vs those with no symptoms, P = 0.06). All tryptophan pathways showed decreased activity among those with more GI symptoms. The same pathways were also decreased in those with the most severe mental health symptoms after COVID-19. In an untargeted analysis, 5 additional metabolic pathways significantly differed based on subsequent development of GI symptoms. In the second cohort (n = 39), plasma 5-HT concentration at the time of COVID-19 was increased 5.1-fold in those with GI symptoms alone compared with those with mental health symptoms alone ( P = 0.02). DISCUSSION: Acute gut microbiome-mediated reduction in 5-HT signaling may contribute to long-term GI and mental health symptoms after COVID-19. Future studies should explore modification of 5-HT signaling to reduce post-COVID symptoms.

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Gestational Insulin Resistance Is Mediated by the Gut Microbiome–Indoleamine 2,3-Dioxygenase Axis

Cited by 20 publications

References 45 publications

Interactions between Perceived Stress and Microbial-Host Immune Components in Pregnancy

Interactions between Perceived Stress and Microbial-Host Immune Components in Pregnancy

MOMMI-MP: A Comprehensive Database for Integrated Analysis of Metabolic and Microbiome Profiling of Mouse Pregnancy

Decreased Gut Microbiome Tryptophan Metabolism and Serotonergic Signaling in Patients With Persistent Mental Health and Gastrointestinal Symptoms After Covid-19

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