Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis

Abstract

Background and aims: Normal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM maternal metabolism interaction. Methods: The GM and plasma metabolome of CD1, NIH Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. 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 in the process was studied using fecal microbial transplants (FMT). Results: Significant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post-pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three 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 levels 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.

Gut Microbiota Reprogramming of Tryptophan Metabolism During Pregnancy Shapes Host Insulin Resistance

“…Depletion of circulating serotonin levels, as reported here in all mouse lines used by Priyadarshini and colleagues, 4 may also contribute to IR, as it has been found to be negatively correlated with body mass index and body fat in patients with metabolic syndrome. 13 Moreover, gutderived serotonin can induce satiety and hypophagia, 14 and genetic or pharmacological ablation of TpH1, the ratelimiting enzyme responsible for the production of serotonin, has a protective effect against obesity and IR in mice fed a high-fat diet.…”

“…19 Indole itself, as well as other AhR agonists, have been shown to stimulate the secretion of insulin in pancreatic b cells through production of glucagon-like peptide-1 by enteroendocrine L cells. 10,20 Thus, using a powerful approach, Priyadarshini et al's work 4 confirms and enhances the growing literature that identifies Trp metabolism as a cornerstone of host-microbiota interactions and a promising pharmacological target to treat IR in both metabolic syndrome and pregnancy. However, in an attempt to interfere in Trp metabolism, one should keep in mind the symbiotic nature of the human body.…”

“…During pregnancy, specific changes in the gut microbiota composition have been described previously, 2,3 but little was known on how they can impact host metabolism. In this issue, Priyadarshini and colleagues 4 aimed to understand the mechanisms underlying the gut microbiota-host metabolisms interactions during this specific condition. Taking advantage of 3 different mouse lines to avoid strain-specific bias, the authors showed that pregnancy is associated with changes in both gut microbiota composition and metabolic output.…”

“…6 An imbalance between these 3 metabolic pathways is known to be associated with multiple diseases, such as inflammatory bowel diseases, 7 irritable bowel syndrome, 8 celiac disease, 9 and metabolic syndrome. 10 Using both untargeted and targeted metabolomic analyses, Priyadarshini and colleagues 4 showed an activation of the kynurenine pathway during pregnancy in all 3 mouse strains used. In opposite, serotonin levels decreased and a reduced amount of AhR agonists was measured, confirming the global shift of the Trp metabolism toward kynurenines.…”

“…[14][15][16] Besides kynurenine and serotonin pathways, Trp metabolism by the gut microbiota into indoles leads to the production of AhR agonists that contribute to intestinal integrity, notably through interleukin-22 production. 4,12 In case of mucosal inflammation, the activation of IDO1 in the gut hijacks Trp metabolism toward the kynurenine pathway, inducing depletion of the Trp pool available for the gut microbiota. This leads to an amplifying loop worsening the decreased production of AhR agonists and interleukin-22 EDITORIALS Gastroenterology 2022;-:1-3 and promoting bacterial translocation.…”