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

See “Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis,” by Priyadarshini M, Navarroa G, Reimanb DJ, et al, on page 1675.Gut microbiota is a potent modulator of host metabolism,1Fan Y. Pedersen O. Gut microbiota in human metabolic health and disease.Nat Rev Microbiol. 2021; 19: 55-71Crossref PubMed Scopus (703) Google Scholar and the host–microbial cross-talk is a dynamic process impacted by the host physiological state. During pregnancy, specific changes in the gut microbiota composition have been described previously,2Wang J. Zheng J. Shi W. et al.Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus.Gut. 2018; 67: 1614-1625Crossref PubMed Scopus (178) Google Scholar,3Koren O. Goodrich J.K. Cullender T.C. et al.Host remodeling of the gut microbiome and metabolic changes during pregnancy.Cell. 2012; 150: 470-480Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar but little was known on how they can impact host metabolism. In this issue, Priyadarshini and colleagues4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. Tryptophan (Trp) catabolic pathway was especially increased, promoting low-grade mucosal inflammation and insulin resistance (IR).In the last decade, Trp metabolism appeared to be a key player of the host–microbiota symbiosis. In the intestine, Trp is metabolized through the following deeply interconnected pathways: the indole pathway in which Trp is transformed by the gut microbiota into several metabolites, among them ligands of the aryl hydrocarbon receptor (AhR), a potent transcription factor involved in the mucosal homeostasis5Zelante T. Iannitti R.G. Cunha C. et al.Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.Immunity. 2013; 39: 372-385Abstract Full Text Full Text PDF PubMed Scopus (1199) Google Scholar; the serotonin pathway, which occurred mainly within the enterochromaffin cells in which Trp is transformed into serotonin and its derivatives; and the kynurenine pathway within the immune, adipose, and epithelial cells, which leads to production of kynurenine and its derivatives through the dependence of indoleamine 2,3-dioxygenase (IDO1) (Figure 1).6Agus A. Planchais J. Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease.Cell Host Microbe. 2018; 23: 716-724Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar An imbalance between these 3 metabolic pathways is known to be associated with multiple diseases, such as inflammatory bowel diseases,7Nikolaus S. Schulte B. Al-Massad N. et al.Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases.Gastroenterology. 2017; 153: 1504-1516.e2Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar irritable bowel syndrome,8Mars R.A.T. Yang Y. Ward T. et al.Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome.Cell. 2020; 182: 1460-1473.e17Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar celiac disease,9Lamas B. Hernandez-Galan L. Galipeau H.J. et al.Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.Sci Transl Med. 2020; 12eaba062Crossref PubMed Scopus (54) Google Scholar and metabolic syndrome.10Natividad J.M. Agus A. Planchais J. et al.Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 2018; 28: 737-749.e4Abstract Full Text Full Text PDF PubMed Scopus (220) Google ScholarUsing both untargeted and targeted metabolomic analyses, Priyadarshini and colleagues4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. Interestingly, plasmatic kynurenine correlated with the IR phase of pregnancy with a maximum level at day 15 of gestation. Accordingly, IDO1, the rate-limiting enzyme of Trp degradation in the kynurenine pathway, was increased in the intestinal epithelium and correlated with the expression of pro-inflammatory cytokines, such as ifn-gamma in the ileum. This low-grade mucosal inflammation was associated with decreased expression of tight junction proteins involved in maintaining the intestinal barrier and an increase in bacterial translocation as assessed by plasmatic lipopolysaccharide levels. Combining both pharmacological and genetic deletion approaches, the authors showed that IDO1 inhibition can reverse these mucosal changes and IDO1 knockout mice were protected from developing pregnancy-induced IR. Finally, transferring the gut microbiota of pregnant mice to antibiotic-induced pseudo–germ-free ones was able to transfer part of the intestinal inflammation and IR phenotype, demonstrating the gut microbiota's causal role in the rewiring of Trp metabolism toward the kynurenine pathway. Confirming the relevance of these mechanisms in humans, similar results were found with the transfer of fecal microbiota samples from third-trimester pregnant women in antibiotic-treated pseudo–germ-free mice, with an increase of the kynurenine/Trp ratio and IR compared with mice transferred with feces from the same women at the first semester of pregnancy, when IR is not usually observed.A similar shift of Trp metabolism toward the kynurenine pathway has been described in metabolic syndrome11Mallmann N.H. Lima E.S. Lalwani P. Dysregulation of tryptophan catabolism in metabolic syndrome.Metab Syndr Relat Disord. 2018; 16: 135-142Crossref PubMed Scopus (31) Google Scholar with similar pro-inflammatory mucosal changes, increased intestinal permeability, and IR (Figure 1).12Laurans L. Venteclef N. Haddad Y. et al.Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.Nat Med. 2018; 24: 1113-1120Crossref PubMed Scopus (135) Google Scholar However, to understand the mechanisms involved, Trp metabolism has to be considered as a whole.Depletion of circulating serotonin levels, as reported here in all mouse lines used by Priyadarshini and colleagues,4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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.13Hodge S. Bunting B.P. Carr E. et al.Obesity, whole blood serotonin and sex differences in healthy volunteers.Obes Facts. 2012; 5: 399-407Crossref PubMed Scopus (23) Google Scholar Moreover, gut-derived serotonin can induce satiety and hypophagia,14Voigt J.-P. Fink H. Serotonin controlling feeding and satiety.Behav Brain Res. 2015; 277: 14-31Crossref PubMed Scopus (191) Google Scholar and genetic or pharmacological ablation of TpH1, the rate-limiting enzyme responsible for the production of serotonin, has a protective effect against obesity and IR in mice fed a high-fat diet.15Crane J.D. Palanivel R. Mottillo E.P. et al.Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.Nat Med. 2015; 21: 166-172Crossref PubMed Scopus (297) Google Scholar The mechanism involves an increased energy expenditure by thermogenic brown adipose tissue. However, these results might not apply to adult humans whose abundance of brown adipose tissue is low, and contradictory effects of serotonin on weight and glycemic control have been described, suggesting a complex role in pathogenesis.14Voigt J.-P. Fink H. Serotonin controlling feeding and satiety.Behav Brain Res. 2015; 277: 14-31Crossref PubMed Scopus (191) Google Scholar, 15Crane J.D. Palanivel R. Mottillo E.P. et al.Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.Nat Med. 2015; 21: 166-172Crossref PubMed Scopus (297) Google Scholar, 16Sumara G. Sumara O. Kim J.K. et al.Gut-derived serotonin is a multifunctional determinant to fasting adaptation.Cell Metab. 2012; 16: 588-600Abstract Full Text Full Text PDF PubMed Scopus (153) Google ScholarBesides 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.4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,12Laurans L. Venteclef N. Haddad Y. et al.Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.Nat Med. 2018; 24: 1113-1120Crossref PubMed Scopus (135) Google Scholar 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 and promoting bacterial translocation.17Lamas B. Richard M.L. Leducq V. et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.Nat Med. 2016; 22: 598-605Crossref PubMed Scopus (698) Google Scholar Circulating bacterial compounds then contribute to the chronic inflammation of liver and adipose tissues associated with IR.18Dabke K. Hendrick G. Devkota S. The gut microbiome and metabolic syndrome.J Clin Invest. 2019; 129: 4050-4057Crossref PubMed Scopus (229) Google ScholarIn line with these data, in a recent large-scale population study, circulating levels of kynurenine were positively associated with risk of type 2 diabetes, and indolepropionate, a microbial indole derivative, was inversely associated with the risk of developing the disease.19Qi Q, Li J, Yu B, et al. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies [published online ahead of print June 14, 2021]. Gut https://doi.org/10.1136/gutjnl-2021-324053.Google Scholar Indole itself, as well as other AhR agonists, have been shown to stimulate the secretion of insulin in pancreatic β cells through production of glucagon-like peptide-1 by enteroendocrine L cells.10Natividad J.M. Agus A. Planchais J. et al.Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 2018; 28: 737-749.e4Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar,20Chimerel C. Emery E. Summers D.K. et al.Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells.Cell Rep. 2014; 9: 1202-1208Abstract Full Text Full Text PDF PubMed Scopus (273) Google ScholarThus, using a powerful approach, Priyadarshini et al’s work4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. In the intestine, the biochemical reactions underlying Trp metabolism are under the close dependence of both microbial and host enzymatic machinery and compounds. Targeting only 1 of these compartments may not be sufficient to shift all of the ecological niches toward a healthy state of equilibrium. Combined approaches that will modulate both the gut microbiota composition and/or functions and host cells enzymatic activity might be more efficient and sustained over time. See “Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis,” by Priyadarshini M, Navarroa G, Reimanb DJ, et al, on page 1675. See “Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis,” by Priyadarshini M, Navarroa G, Reimanb DJ, et al, on page 1675. See “Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis,” by Priyadarshini M, Navarroa G, Reimanb DJ, et al, on page 1675. Gut microbiota is a potent modulator of host metabolism,1Fan Y. Pedersen O. Gut microbiota in human metabolic health and disease.Nat Rev Microbiol. 2021; 19: 55-71Crossref PubMed Scopus (703) Google Scholar and the host–microbial cross-talk is a dynamic process impacted by the host physiological state. During pregnancy, specific changes in the gut microbiota composition have been described previously,2Wang J. Zheng J. Shi W. et al.Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus.Gut. 2018; 67: 1614-1625Crossref PubMed Scopus (178) Google Scholar,3Koren O. Goodrich J.K. Cullender T.C. et al.Host remodeling of the gut microbiome and metabolic changes during pregnancy.Cell. 2012; 150: 470-480Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar but little was known on how they can impact host metabolism. In this issue, Priyadarshini and colleagues4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. Tryptophan (Trp) catabolic pathway was especially increased, promoting low-grade mucosal inflammation and insulin resistance (IR). In the last decade, Trp metabolism appeared to be a key player of the host–microbiota symbiosis. In the intestine, Trp is metabolized through the following deeply interconnected pathways: the indole pathway in which Trp is transformed by the gut microbiota into several metabolites, among them ligands of the aryl hydrocarbon receptor (AhR), a potent transcription factor involved in the mucosal homeostasis5Zelante T. Iannitti R.G. Cunha C. et al.Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.Immunity. 2013; 39: 372-385Abstract Full Text Full Text PDF PubMed Scopus (1199) Google Scholar; the serotonin pathway, which occurred mainly within the enterochromaffin cells in which Trp is transformed into serotonin and its derivatives; and the kynurenine pathway within the immune, adipose, and epithelial cells, which leads to production of kynurenine and its derivatives through the dependence of indoleamine 2,3-dioxygenase (IDO1) (Figure 1).6Agus A. Planchais J. Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease.Cell Host Microbe. 2018; 23: 716-724Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar An imbalance between these 3 metabolic pathways is known to be associated with multiple diseases, such as inflammatory bowel diseases,7Nikolaus S. Schulte B. Al-Massad N. et al.Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases.Gastroenterology. 2017; 153: 1504-1516.e2Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar irritable bowel syndrome,8Mars R.A.T. Yang Y. Ward T. et al.Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome.Cell. 2020; 182: 1460-1473.e17Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar celiac disease,9Lamas B. Hernandez-Galan L. Galipeau H.J. et al.Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.Sci Transl Med. 2020; 12eaba062Crossref PubMed Scopus (54) Google Scholar and metabolic syndrome.10Natividad J.M. Agus A. Planchais J. et al.Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 2018; 28: 737-749.e4Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Using both untargeted and targeted metabolomic analyses, Priyadarshini and colleagues4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. Interestingly, plasmatic kynurenine correlated with the IR phase of pregnancy with a maximum level at day 15 of gestation. Accordingly, IDO1, the rate-limiting enzyme of Trp degradation in the kynurenine pathway, was increased in the intestinal epithelium and correlated with the expression of pro-inflammatory cytokines, such as ifn-gamma in the ileum. This low-grade mucosal inflammation was associated with decreased expression of tight junction proteins involved in maintaining the intestinal barrier and an increase in bacterial translocation as assessed by plasmatic lipopolysaccharide levels. Combining both pharmacological and genetic deletion approaches, the authors showed that IDO1 inhibition can reverse these mucosal changes and IDO1 knockout mice were protected from developing pregnancy-induced IR. Finally, transferring the gut microbiota of pregnant mice to antibiotic-induced pseudo–germ-free ones was able to transfer part of the intestinal inflammation and IR phenotype, demonstrating the gut microbiota's causal role in the rewiring of Trp metabolism toward the kynurenine pathway. Confirming the relevance of these mechanisms in humans, similar results were found with the transfer of fecal microbiota samples from third-trimester pregnant women in antibiotic-treated pseudo–germ-free mice, with an increase of the kynurenine/Trp ratio and IR compared with mice transferred with feces from the same women at the first semester of pregnancy, when IR is not usually observed. A similar shift of Trp metabolism toward the kynurenine pathway has been described in metabolic syndrome11Mallmann N.H. Lima E.S. Lalwani P. Dysregulation of tryptophan catabolism in metabolic syndrome.Metab Syndr Relat Disord. 2018; 16: 135-142Crossref PubMed Scopus (31) Google Scholar with similar pro-inflammatory mucosal changes, increased intestinal permeability, and IR (Figure 1).12Laurans L. Venteclef N. Haddad Y. et al.Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.Nat Med. 2018; 24: 1113-1120Crossref PubMed Scopus (135) Google Scholar However, to understand the mechanisms involved, Trp metabolism has to be considered as a whole. Depletion of circulating serotonin levels, as reported here in all mouse lines used by Priyadarshini and colleagues,4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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.13Hodge S. Bunting B.P. Carr E. et al.Obesity, whole blood serotonin and sex differences in healthy volunteers.Obes Facts. 2012; 5: 399-407Crossref PubMed Scopus (23) Google Scholar Moreover, gut-derived serotonin can induce satiety and hypophagia,14Voigt J.-P. Fink H. Serotonin controlling feeding and satiety.Behav Brain Res. 2015; 277: 14-31Crossref PubMed Scopus (191) Google Scholar and genetic or pharmacological ablation of TpH1, the rate-limiting enzyme responsible for the production of serotonin, has a protective effect against obesity and IR in mice fed a high-fat diet.15Crane J.D. Palanivel R. Mottillo E.P. et al.Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.Nat Med. 2015; 21: 166-172Crossref PubMed Scopus (297) Google Scholar The mechanism involves an increased energy expenditure by thermogenic brown adipose tissue. However, these results might not apply to adult humans whose abundance of brown adipose tissue is low, and contradictory effects of serotonin on weight and glycemic control have been described, suggesting a complex role in pathogenesis.14Voigt J.-P. Fink H. Serotonin controlling feeding and satiety.Behav Brain Res. 2015; 277: 14-31Crossref PubMed Scopus (191) Google Scholar, 15Crane J.D. Palanivel R. Mottillo E.P. et al.Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.Nat Med. 2015; 21: 166-172Crossref PubMed Scopus (297) Google Scholar, 16Sumara G. Sumara O. Kim J.K. et al.Gut-derived serotonin is a multifunctional determinant to fasting adaptation.Cell Metab. 2012; 16: 588-600Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar 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.4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,12Laurans L. Venteclef N. Haddad Y. et al.Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.Nat Med. 2018; 24: 1113-1120Crossref PubMed Scopus (135) Google Scholar 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 and promoting bacterial translocation.17Lamas B. Richard M.L. Leducq V. et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.Nat Med. 2016; 22: 598-605Crossref PubMed Scopus (698) Google Scholar Circulating bacterial compounds then contribute to the chronic inflammation of liver and adipose tissues associated with IR.18Dabke K. Hendrick G. Devkota S. The gut microbiome and metabolic syndrome.J Clin Invest. 2019; 129: 4050-4057Crossref PubMed Scopus (229) Google Scholar In line with these data, in a recent large-scale population study, circulating levels of kynurenine were positively associated with risk of type 2 diabetes, and indolepropionate, a microbial indole derivative, was inversely associated with the risk of developing the disease.19Qi Q, Li J, Yu B, et al. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies [published online ahead of print June 14, 2021]. Gut https://doi.org/10.1136/gutjnl-2021-324053.Google Scholar Indole itself, as well as other AhR agonists, have been shown to stimulate the secretion of insulin in pancreatic β cells through production of glucagon-like peptide-1 by enteroendocrine L cells.10Natividad J.M. Agus A. Planchais J. et al.Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 2018; 28: 737-749.e4Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar,20Chimerel C. Emery E. Summers D.K. et al.Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells.Cell Rep. 2014; 9: 1202-1208Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Thus, using a powerful approach, Priyadarshini et al’s work4Priyadarshini M. Navarroa G. Reimanb D.J. et al.Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis.Gastroenterology. 2022; 162: 1675-1689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar 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. In the intestine, the biochemical reactions underlying Trp metabolism are under the close dependence of both microbial and host enzymatic machinery and compounds. Targeting only 1 of these compartments may not be sufficient to shift all of the ecological niches toward a healthy state of equilibrium. Combined approaches that will modulate both the gut microbiota composition and/or functions and host cells enzymatic activity might be more efficient and sustained over time. Gestational Insulin Resistance Is Mediated by the Gut Microbiome–Indoleamine 2,3-Dioxygenase AxisGastroenterologyVol. 162Issue 6PreviewThis study demonstrates that the gestational gut microbiome mediates metabolic adaptations in pregnancy through effects on gut IDO1 activity and the production of kynurenine. Full-Text PDF Open Access