Chunxia Lu1
Xiaoping Lei- 1Department of Neonatology, Children’s Medical Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- 2Sichuan Clinical Research Center for Birth Defects,The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
Gestational diabetes mellitus (GDM) represents a prevalent metabolic disorder related to pregnancy, posing significant risks to both the expecting mother and the developing fetus. Recent research indicates a potential connection between bile acids (BAs) and GDM, such as lithocholic acid (LCA), β-muricholic acid (β-MCA), and 6,7-diketolithocholic acid (6,7-diketoLCA), have been found to be significantly increased in GDM individuals, thereby with the potential to reveal their involvement in glucose metabolism and the underlying mechanisms of GDM development. Additionally, BAs have emerged as vital signaling molecules that regulate glucose and lipid metabolism by interacting with Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), highlighting their potential as novel therapeutic targets for GDM management. The aim of this manuscript is to comprehensively review the current understanding of the relationship between BAs and GDM, delving into their potential mechanistic roles, diagnostic significance, and possible therapeutic applications.
1 Introduction
Gestational diabetes mellitus (GDM) classically denotes abnormal glucose tolerance that manifests or is first identified during pregnancy, featuring glycemia and insulin disorders (1). The worldwide prevalence of GDM is escalating at a rapid pace (2). This condition is not only linked to adverse perinatal outcomes (3) but also increases women’s long-term risk of developing type 2 diabetes mellitus (T2DM) (4, 5) and metabolic syndrome (5, 6). Moreover, children born to mothers with GDM face a heightened risk of obesity, metabolic syndrome, future type diabetes (7), and brain development issues (8–10).
In recent years, numerous studies have delved deeper into the etiology and pathophysiology of GDM (11, 12). Emerging research has revealed a potential connection between bile acids (BAs) and GDM (13, 14) recently. BAs, amphipathic molecules synthesized in the liver from cholesterol and forming a crucial bile component (15), have traditionally been recognized for their role in the digestion and absorption of dietary fats (16). However, modern perspectives view BAs as more versatile molecules with diverse functions (17), including promoting intestinal epithelial regeneration (18, 19), regulating gene expression (20, 21), influencing insulin secretion (22, 23), epigenetic mechanisms (24, 25), fibrogenesis (26), lipid metabolism (27)and glucose metabolism (28). Consequently, alterations in BAs are strongly linked to metabolic disorders.
2 Bile acid metabolism
BAs encompass both primary and secondary types, as outlined in Table 1. The biosynthesis of BAs commences with the formation of primary BAs, predominantly in the liver. This process involves a sequence of 17 enzymes, including cytochrome p450, which alter the steroid ring of cholesterol. These enzymes eliminate the short aliphatic side chain and conjugate it primarily with glycine (75%) and taurine (25%). The end result is the conjugated primary BAs, specifically cholic acid (CA) and chenodeoxycholic acid (CDCA) (29, 30). Secondary BAs come into being through enzymatic modification of primary BAs by colon-dwelling bacteria, which utilize them as substrates for microbial metabolism (31). The BA pool, encompassing all BAs circulating within the enterohepatic circulation, comprises BAs present in the intestine (~85%–90%), gallbladder (~10%–15%), and liver (<1%) (32). The ratio of glycine (G)- to taurine (T)-conjugated BAs stands at approximately 3 to 1, establishing a hydrophobic pool (32).
Table 1. The classification of bile acids.
The synthesis of BAs can commence via several routes (Figure 1). The classic pathway involves the metabolism of cholesterol 7α-hydroxylase (CYP7A1) to form 7α-hydroxycholesterol, which is subsequently hydroxylated by sterol 12α-hydroxylase (CYP8B1) or sterol 27-hydroxylase (CYP27A1). Alternatively, the second (or alternate) pathway sees the formation of 27-hydroxycholesterol from cholesterol via CYP27A1, followed by hydroxylation via oxysterol 7α-hydroxylase (CYP7B1) (30). A third pathway involves the oxidation of cholesterol to 24- and 25-hydroxycholesterol by cholesterol 24-hydroxylase (CYP46A1), an enzyme predominantly expressed in the brain (33).
Figure 1. Bile Acid metabolism in liver. In the liver, cholesterol 7α-hydroxylase (CYP7A1) initiates the classical bile acid synthesis pathway by hydroxylation of the steroid rings at 7α-C for further modifications of the steroid rings, followed by steroid side chain oxidation and cleavage, whereas sterol 27-hydroxylase (CYP27A1) initiates the alternative bile acid synthesis pathway by oxidation of the steroid side chain followed by modifications of the steroid rings and cleavage of the side chain in the classic pathway. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the two major primary bile acids synthesized in the human liver.
3 Bile acids and glucose homeostasis
Recently, BAs have garnered attention due to their involvement in glucose metabolism and the secretion of glucoregulatory hormones (34, 35). Studies have shown that BAs regulate glucose homeostasis by directly interacting with the FXR (36) and the TGR5 (37, 38), or indirectly by promoting the synthesis of fibroblast growth factor 15 (FGF15) in the intestine, which is induced by FXR (39, 40). Specifically, certain BAs activate FXR in the intestine, triggering the production of FGF15/19 and enhancing the expression of pancreatic β cells (41). This mechanism exerts diverse effects on hepatic BA metabolism, lipid metabolism, protein metabolism, and glucose metabolism (42). Furthermore, BA-mediated TGR5 signaling boosts the release of intestinal glucagon-like peptide 1 (GLP-1), thereby increasing glucose-stimulated insulin secretion from pancreatic β cells (43). The receptors specific to BAs and the precise molecular mechanisms underlying their effects on glucose metabolism will be further explored (Table 2).
Table 2. Effects of BAs and receptors on glucose metabolism and mechanisms.
Given that different BAs exhibit unique affinities for FXR and TGR5, and they play varying roles in glucose metabolism, it becomes imperative to investigate whether the BA profile undergoes changes in patients with GDM. Determining the clinical significance of any such alterations is also crucial.
4 Bile acids in pregnant women with GDM and their offspring
The quantity of BAs differed significantly between mothers with GDM and those without. A study revealed that pregnant women with GDM had higher serum total bile acid (TBA) levels than their non-GDM counterparts during the first trimester (52). Notably, elevated serum TBA concentrations during pregnancy have been positively correlated with an augmented risk of GDM (13, 14).Although a causal relationship between GDM and serum TBA levels has not been conclusively established, it is apparent that GDM is often associated with higher serum TBA levels. Additionally, when maternal serum TBA levels surpass 40 mmol/L, the likelihood of fetal complications increases by 1%-2% for every additional mmol/L (53). Consequently, we postulate that altered serum TBA could be a potential influencing factor in the relationship between GDM and complications in offspring. However, some studies found no significant differences in TBA levels between GDM and non-GDM groups when measured in the second or third trimester (54). The substantial heterogeneity observed across studies, primarily attributable to variations in the timing of TBA measurement, suggests that the relationship between TBA levels and GDM is not straightforward. This indicates that the role of TBA as a biomarker for GDM may be highly sensitive to the gestational period during which it is measured (55).
Pregnant women with GDM not only encounter elevated serum TBA levels, but also demonstrate alterations in their BA profiles when compared to those without GDM. Research indicates that, in GDM pregnancies, serum concentrations of glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), CA, dehydro-lithocholic acid (dehydro-LCA), and iso-deoxycholic acid (iso-DCA) are notably diminished (56). Conversely, certain BAs, such as glycohyodeoxycholic acid (GHDCA), taurohyodeoxycholic acid (THDCA), hyodeoxycholic acid (HDCA), LCA, β-MCA, and 6,7-diketoLCA, have been found to be significantly increased in GDM individuals (56). In summary, the modifications in BAs associated with GDM are intricate, underscoring the importance of understanding these changes to gain further insight into GDM.
Although numerous studies have established that the serum BA profiles of mothers with GDM undergo changes, the impact on fetal/neonatal serum BA profiles remains unclear. Recent studies have indicated that a higher prevalence of GDM among women with intrahepatic cholestasis of pregnancy (ICP), offering potential insights into this issue (57, 58). Previous studies have revealed that umbilical cord from ICP pregnancies exhibits elevated levels of CDCA, CA and LCA compared to controls (59). Based on these findings, we hypothesize that variations in BAs among GDM mothers may also lead to alterations in BA metabolism in their offspring. Furthermore, a study has documented significant changes in BA metabolism within the amniotic fluid (AF) during the second trimester of GDM-diagnosed pregnancies (60). Given that the AF primarily consists of fetal urine, this study lends credence to our hypothesis. However, direct evidence remains lacking and further investigation is warranted to elucidate the specific changes occurring.
5 Predictive value of BAs in GDM
Currently, the oral glucose tolerance test (OGTT) is widely regarded as the gold standard for diagnosing GDM (1). However, it is important to note that OGTT typically diagnoses GDM between 24–28 gestational weeks. By this time, irreversible fetal changes, such as epigenetic modifications (61), may have already occurred. Therefore, the identification of early predictors would be beneficial in improving the management of GDM and minimizing adverse outcomes for both the mother and the fetus.
ICP, characterized by elevated TBA levels, is strongly associated with an increased vulnerability to GDM (57, 58). This suggests a potential link between BA changes and the development of GDM. Based on this, we hypothesize that BAs could serve as valuable biomarkers for GDM diagnosis and risk stratification. Indeed, studies have shown that pregnant women with higher serum TBA levels during the first to second trimester face an increased risk of developing GDM. This indicates that TBA may represent a new risk factor for GDM (13), likely due to its correlation with insulin sensitivity (62). However, it’s worth noting that Zhu et al. have found TBA levels to remain stable in the GDM group when compared to those with normal glucose tolerance (63). This discrepancy could be partially attributed to methodological differences, specifically the distinction between TBA measured by enzymatic cycling assay and individual BAs detected via mass spectrometry (MS). This finding underscores the importance of focusing on individual BA components related to glucose metabolism.
Individual BAs have emerged as promising biomarkers for the diagnosis and risk stratification of GDM (Table 3). Gao et al. have specifically highlighted β-MCA as a potential biomarker that can distinguish between GDM patients and healthy controls (54). Notably, β-MCA levels are elevated in GDM patients, possibly due to enhanced α-muricholic acid (α-MCA) C7-isomerase activity. This activity subsequently leads to increases in terminal GHDCA and THDCA levels through specific metabolic channels (54). GDCA, on the other hand, shows a significant decline in GDM patients. Its level is inversely correlated with insulin sensitivity and positively correlated with β-cell compensation, making it a valuable biomarker candidate for assessing these factors (63). Van Nierop et al. have indeed linked GDCA to insulin secretion and resistance, with increased GDCA triggering insulin secretion in a GLP-1-dependent manner (66). This explains why, despite an elevation in GDCA levels after glucose intake in GDM patients, the lower baseline GDCA levels are insufficient to promote insulin secretion via GLP-1, ultimately leading to glycemic dysregulation. Importantly, these markers have been identified post-diagnosis, and further studies are warranted to determine if they are altered in early pregnancy serum samples of women with GDM.
Table 3. The predictive value of BAs in GDM.
Recent evidence also suggests that BAs could serve as early diagnostic marker for GDM. Circulating BAs levels during early pregnancy are associated with GDM risk. Specifically, taurocholic acid (TCA) is positively, while LCA negatively associated with GDM risk (64). Additionally, low serum levels of glycoursodeoxycholic acid (GUDCA) and deoxycholic acid (DCA) during early pregnancy are independently linked to an increased risk of GDM development (65). Secondary BAs are converted from primary BAs by gut microbiota (22), and an abnormal gut microbiome may reduce this conversion, particularly of GUDCA and DCA, which may contribute to the etiology of GDM. Furthermore, in a rodent model, an elevated serum CA concentration, coupled with reduced BA receptors, such as FXR and TGR5, is associated with GDM (67). Therefore, further validating the diagnostic value of these BA metabolites in the early stages of GDM through animal experiments holds significant promise for early and timely intervention in GDM, potentially reducing poor outcomes.
6 Potential values for BA intervention in the GDM
The treatment of GDM primarily aims to normalize hyperglycemia and mitigate the risk of unfavorable pregnancy outcomes. A crucial aspect of GDM management involves lifestyle interventions, such as dietary adjustments, physical activity, and weight control. If glycemic targets are not achieved through these interventions, it is necessary to introduce glucose-lowering pharmacologic therapy (68, 69). Although these treatments offer short-term benefits, their long-term effects on children exposed to antidiabetic medication during pregnancy remain uncertain. Hence, there is an urgent need for therapies that can improve both maternal and fetal glucose metabolism. BAs have emerged as vital signaling molecules that regulate glucose and lipid metabolism by interacting with FXR and TGR5 receptors (70–73). This suggests that therapeutic approaches targeting BAs could potentially be a powerful new strategy for GDM management.
The FXR agonist obeticholic acid (OCA) has been found to improve dyslipidemia and reduces the impact of pregnancy on insulin resistance in a mouse model of GDM, although it does not affect glucose tolerance (74). However, the limited effects of OCA in pregnant mice indicate that its agonistic action alone may not fully counteract the metabolic consequences of reduced FXR activity during pregnancy. Therefore, when considering FXR agonists for treating metabolic disorders during pregnancy, it is essential to consider the potential inhibition of FXR activity during gestation to ensure the safety of the pharmaceutical agent.
Studies have indicated that lower levels of GDCA are associated with increased risk of adverse pregnancy outcomes in GDM patients (63). Based on this, we hypothesize that GDCA supplementation may reduce these adverse outcomes, but further research is required to validate this hypothesis. Notably, UDCA has been shown to significantly lower fasting plasma glucose, hemoglobin A1c (HbA1c), and insulin concentrations, indicating a beneficial effect on glucose homeostasis (75). Preliminary data from studies involving UDCA treatment in women with ICP also suggest a reduction in insulin resistance (76). The study emphasizes that UDCA’s potential as an effective therapy for improving maternal glycemia in GDM. Although direct evidence supporting UDCA’s use in GDM treatment is lacking, some trial protocols have been designed (77), paving the way for future studies. Furthermore, animal studies have provided additional insights. For instance, mice fed a high-fat diet (HFD) exhibit elevated fasting glucose and a reduced BA pool size, but supplementation with CA improves insulin resistance (78). Another study found that secondary BAs exert a protective effect on pancreatic islet β-cells in diabetic rats (79).
BA sequestrants, which effectively disrupt the enterohepatic circulation of BAs and significantly reduce plasma cholesterol levels, provide evidence for a connection between BA and glucose metabolism (80). Numerous lipid-lowering studies have demonstrated that BA sequestrants, exemplified by colesevelam hydrochloride (81), cholestyramine (82) and colestilan (83), can also decrease plasma glucose and glycosylated hemoglobin levels. This suggests a potential role for these agents in the treatment of T2DM. Given the application of BAs in managing T2DM, it is reasonable to postulate that BAs may also hold promise in treating GDM. However, direct evidence supporting this hypothesis is currently lacking. Thus, further exploration into the therapeutic benefits of BA metabolites for GDM is crucial. While BA sequestrants demonstrate proven efficacy in T2DM management through TGR5/GLP-1 pathway (84, 85), their application in pregnancy warrants meticulous investigation. The placental transfer potential of BA sequestrants derivatives and their effects on fetal BA circulation remain undefined. The present study indicates that the use of BA sequestrants can impede the absorption of fat-soluble vitamins, such as vitamin K, potentially increasing the risk of neonatal cerebral bleeding (86), emphasizing the need for trimester-specific therapeutic development.
In summary, a novel approach to the treatment of GDM with BA has demonstrated significant potential. Evidently, future research should be directed towards three primary areas: first, conducting research on longitudinal BA profiling; second, performing randomized controlled trials (RCTs) of BA modulators; and third, investigating microbiome - BA interactions.
Author contributions
CXL: Conceptualization, Investigation, Writing – original draft. CYL: Validation, Writing – review & editing. XL: Writing – review & editing, Conceptualization.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
We would like to acknowledge all the friends and colleagues who have supported us in various ways.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. (2010) 33:676–82. doi: 10.2337/dc09-1848
2. Wang H, Li N, Chivese T, Werfalli M, Sun H, Yuen L, et al. Idf diabetes atlas: estimation of global and regional gestational diabetes mellitus prevalence for 2021 by international association of diabetes in pregnancy study group’s criteria. Diabetes Res Clin Pract. (2022) 183:109050. doi: 10.1016/j.diabres.2021.109050
3. Billionnet C, Mitanchez D, Weill A, Nizard J, Alla F, Hartemann A, et al. Gestational diabetes and adverse perinatal outcomes from 716,152 births in France in 2012. Diabetologia. (2017) 60:636–44. doi: 10.1007/s00125-017-4206-6
4. Vounzoulaki E, Khunti K, Abner SC, Tan BK, Davies MJ, and Gillies CL. Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis. Bmj. (2020) 369:m1361. doi: 10.1136/bmj.m1361
5. Daly B, Toulis KA, Thomas N, Gokhale K, Martin J, Webber J, et al. Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study. PloS Med. (2018) 15:e1002488. doi: 10.1371/journal.pmed.1002488
6. Gunderson EP, Chiang V, Pletcher MJ, Jacobs DR, Quesenberry CP, Sidney S, et al. History of gestational diabetes mellitus and future risk of atherosclerosis in mid-life: the coronary artery risk development in young adults study. J Am Heart Assoc. (2014) 3:e000490. doi: 10.1161/jaha.113.000490
7. Guan J, Qiu J, Li L, Fu M, Zhang M, Wu Y, et al. A meta-analysis of adverse offspring health outcomes in patients with gestational diabetes mellitus. Diabetes Obes Metab. (2025) 27:3555–67. doi: 10.1111/dom.16341
8. Ruth Gründahl F, Hammer K, Braun J, Oelmeier de Murcia K, Köster HA, Möllers M, et al. Fetal brain development in diabetic pregnancies and normal controls. J Perinat Med. (2018) 46:797–803. doi: 10.1515/jpm-2017-0341
9. Van Dam JM, Garrett AJ, Schneider LA, Hodyl NA, Goldsworthy MR, Coat S, et al. Reduced cortical excitability, neuroplasticity, and salivary cortisol in 11-13-year-old children born to women with gestational diabetes mellitus. EBioMedicine. (2018) 31:143–9. doi: 10.1016/j.ebiom.2018.04.011
10. Xuan DS, Zhao X, Liu YC, Xing QN, Shang HL, Zhu PY, et al. Brain development in infants of mothers with gestational diabetes mellitus: A diffusion tensor imaging study. J Comput Assist Tomogr. (2020) 44:947–52. doi: 10.1097/rct.0000000000001110
11. Liu T, Li J, Xu F, Wang M, Ding S, Xu H, et al. Comprehensive analysis of serum metabolites in gestational diabetes mellitus by uplc/Q-tof-ms. Anal Bioanal Chem. (2016) 408:1125–35. doi: 10.1007/s00216-015-9211-3
12. Dudzik D, Zorawski M, Skotnicki M, Zarzycki W, Kozlowska G, Bibik-Malinowska K, et al. Metabolic fingerprint of gestational diabetes mellitus. J Proteomics. (2014) 103:57–71. doi: 10.1016/j.jprot.2014.03.025
13. Kong M, Lu Z, Zhong C, Gao Q, Zhou X, Chen R, et al. A higher level of total bile acid in early mid-pregnancy is associated with an increased risk of gestational diabetes mellitus: A prospective cohort study in Wuhan, China. J Endocrinol Invest. (2020) 43:1097–103. doi: 10.1007/s40618-020-01196-7
14. Liu Y, Sun R, Li Y, Chen H, Wu L, Shen S, et al. Changes in serum total bile acid concentrations are associated with the risk of developing adverse maternal and perinatal outcomes in pregnant chinese women. Clin Chim Acta. (2021) 520:160–7. doi: 10.1016/j.cca.2021.05.036
15. Slijepcevic D and van de Graaf SF. Bile acid uptake transporters as targets for therapy. Digest Dis (Basel Switzerland). (2017) 35:251–8. doi: 10.1159/000450983
16. Xie C, Huang W, Young RL, Jones KL, Horowitz M, Rayner CK, et al. Role of bile acids in the regulation of food intake, and their dysregulation in metabolic disease. Nutrients. (2021) 13:1104. doi: 10.3390/nu13041104
17. Monte MJ, Marin JJ, Antelo A, and Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol. (2009) 15:804–16. doi: 10.3748/wjg.15.804
18. Sorrentino G, Perino A, Yildiz E, El Alam G, Bou Sleiman M, Gioiello A, et al. Bile acids signal via tgr5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology. (2020) 159:956–68.e8. doi: 10.1053/j.gastro.2020.05.067
19. Guillot A, Guerri L, Feng D, Kim S-J, Ahmed YA, Paloczi J, et al. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin Avβ6 upregulation following liver injury. J Clin Invest. (2021) 131:e132305. doi: 10.1172/JCI132305
20. Hylemon PB, Takabe K, Dozmorov M, Nagahashi M, and Zhou H. Bile acids as global regulators of hepatic nutrient metabolism. Liver Res. (2017) 1:10–6. doi: 10.1016/j.livres.2017.03.002
21. Jiao N, Baker SS, Chapa-Rodriguez A, Liu W, Nugent CA, Tsompana M, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in nafld. Gut. (2018) 67:1881–91. doi: 10.1136/gutjnl-2017-314307
22. Li T and Chiang JY. Bile acids as metabolic regulators. Curr Opin Gastroenterol. (2015) 31:159–65. doi: 10.1097/mog.0000000000000156
23. Staels B and Fonseca VA. Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care. (2009) 32 Suppl 2:S237–45. doi: 10.2337/dc09-S355
24. Pavlovic N, Stanimirov B, and Mikov M. Bile acids as novel pharmacological agents: the interplay between gene polymorphisms, epigenetic factors and drug response. Curr Pharm Des. (2017) 23:187–215. doi: 10.2174/1381612822666161006161409
25. Kim Y-C, Jung H, Seok S, Zhang Y, Ma J, Li T, et al. Microrna-210 promotes bile acid-induced cholestatic liver injury by targeting mixed-lineage leukemia-4 methyltransferase in mice. Hepatol (Baltimore Md). (2020) 71:2118–34. doi: 10.1002/hep.30966
26. Zimny S, Koob D, Li J, Wimmer R, Schiergens T, Nagel J, et al. Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through pi3k P110 alpha signaling. Cells. (2022) 11:2344. doi: 10.3390/cells11152344
27. Kumari A, Pal Pathak D, and Asthana S. Bile acids mediated potential functional interaction between fxr and fatp5 in the regulation of lipid metabolism. Int J Biol Sci. (2020) 16:2308–22. doi: 10.7150/ijbs.44774
28. McGlone ER and Bloom SR. Bile acids and the metabolic syndrome. Ann Clin Biochem. (2019) 56:326–37. doi: 10.1177/0004563218817798
29. Russell DW. Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res. (2009) 50 Suppl:S120–5. doi: 10.1194/jlr.R800026-JLR200
30. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. (2003) 72:137–74. doi: 10.1146/annurev.biochem.72.121801.161712
31. de Aguiar Vallim TQ, Tarling EJ, and Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab. (2013) 17:657–69. doi: 10.1016/j.cmet.2013.03.013
32. Chiang JYL and Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. (2018) 18:71–87. doi: 10.3727/105221618x15156018385515
33. Lund EG, Guileyardo JM, and Russell DW. Cdna cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci United States America. (1999) 96:7238–43. doi: 10.1073/pnas.96.13.7238
34. Yamagata K, Daitoku H, Shimamoto Y, Matsuzaki H, Hirota K, Ishida J, et al. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and foxo1. J Biol Chem. (2004) 279:23158–65. doi: 10.1074/jbc.M314322200
35. Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci (Landmark Ed). (2009) 14:2584–98. doi: 10.2741/3399
36. Ma K, Saha PK, Chan L, and Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. (2006) 116:1102–9. doi: 10.1172/JCI25604
37. Kumar DP, Rajagopal S, Mahavadi S, Mirshahi F, Grider JR, Murthy KS, et al. Activation of transmembrane bile acid receptor tgr5 stimulates insulin secretion in pancreatic B Cells. Biochem Biophys Res Commun. (2012) 427:600–5. doi: 10.1016/j.bbrc.2012.09.104
38. Kumar DP, Asgharpour A, Mirshahi F, Park SH, Liu S, Imai Y, et al. Activation of transmembrane bile acid receptor tgr5 modulates pancreatic islet A Cells to promote glucose homeostasis. J Biol Chem. (2016) 291:6626–40. doi: 10.1074/jbc.M115.699504
39. Chen MJ, Liu C, Wan Y, Yang L, Jiang S, Qian DW, et al. Enterohepatic circulation of bile acids and their emerging roles on glucolipid metabolism. Steroids. (2021) 165:108757. doi: 10.1016/j.steroids.2020.108757
40. Ticho AL, Malhotra P, Dudeja PK, Gill RK, and Alrefai WA. Intestinal absorption of bile acids in health and disease. Compr Physiol. (2019) 10:21–56. doi: 10.1002/cphy.c190007
41. Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. (2015) 6:7629. doi: 10.1038/ncomms8629
42. Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, et al. Fgf19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Sci (New York NY). (2011) 331:1621–4. doi: 10.1126/science.1198363
43. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. (2018) 27:740–56. doi: 10.1016/j.cmet.2018.03.001
44. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, et al. Intestinal Fxr Agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. (2015) 21:159–65. doi: 10.1038/nm.3760
45. Pathak P, Xie C, Nichols RG, Ferrell JM, Boehme S, Krausz KW, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology. (2018) 68:1574–88. doi: 10.1002/hep.29857
46. Potthoff MJ, Boney-Montoya J, Choi M, He T, Sunny NE, Satapati S, et al. Fgf15/19 regulates hepatic glucose metabolism by inhibiting the Creb-Pgc-1α pathway. Cell Metab. (2011) 13:729–38. doi: 10.1016/j.cmet.2011.03.019
47. Renga B, Mencarelli A, Vavassori P, Brancaleone V, and Fiorucci S. The bile acid sensor Fxr regulates insulin transcription and secretion. BBA Mol Basis Dis. (2010) 1802:363–72. doi: 10.1016/j.bbadis.2010.01.002
48. Cao H, Chen ZX, Wang K, Ning MM, Zou QA, Feng Y, et al. Intestinally-targeted Tgr5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect. Sci Rep. (2016) 6:28676. doi: 10.1038/srep28676
49. Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Møller E, Andersen DB, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. (2018) 11:84–95. doi: 10.1016/j.molmet.2018.03.007
50. Lasalle M, Hoguet V, Hennuyer N, Leroux F, Piveteau C, Belloy L, et al. Topical intestinal aminoimidazole agonists of G-protein-coupled bile acid receptor 1 promote glucagon like peptide-1 secretion and improve glucose tolerance. J Med Chem. (2017) 60:4185–211. doi: 10.1021/acs.jmedchem.6b01873
51. Lan T, Morgan DA, Rahmouni K, Sonoda J, Fu X, Burgess SC, et al. Fgf19, Fgf21, and an Fgfr1/Β-klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab. (2017) 26:709–18. doi: 10.1016/j.cmet.2017.09.005
52. Hou W, Meng X, Zhao W, Pan J, Tang J, Huang Y, et al. Elevated first-trimester total bile acid is associated with the risk of subsequent gestational diabetes. Sci Rep. (2016) 6:34070. doi: 10.1038/srep34070
53. Glantz A, Marschall HU, and Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatol (Baltimore Md). (2004) 40:467–74. doi: 10.1002/hep.20336
54. Gao J, Xu B, Zhang X, Cui Y, Deng L, Shi Z, et al. Association between serum bile acid profiles and gestational diabetes mellitus: A targeted metabolomics study. Clin Chim Acta. (2016) 459:63–72. doi: 10.1016/j.cca.2016.05.026
55. Parsaei M, Dashtkoohi M, Haddadi M, Rashidian P, Mansouri Z, and Hantoushzadeh S. The association of serum total bile acid levels with gestational diabetes mellitus: A systematic review and meta-analysis. BMC Pregnancy Childbirth. (2024) 24:744. doi: 10.1186/s12884-024-06954-6
56. Hou W, Meng X, Zhao A, Zhao W, Pan J, Tang J, et al. Development of multimarker diagnostic models from metabolomics analysis for gestational diabetes mellitus (Gdm). Mol Cell Proteom: MCP. (2018) 17:431–41. doi: 10.1074/mcp.RA117.000121
57. Arafa A and Dong JY. Association between intrahepatic cholestasis of pregnancy and risk of gestational diabetes and preeclampsia: A systematic review and meta-analysis. Hypertens Pregnancy. (2020) 39:354–60. doi: 10.1080/10641955.2020.1758939
58. Liu C, Gao J, Liu J, Wang X, He J, Sun J, et al. Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes and preeclampsia. Ann Trans Med. (2020) 8:1574. doi: 10.21037/atm-20-4879
59. Martinefski MR, Cocucci SE, Di Carlo MB, Vega HR, Lucangioli SE, Perazzi BE, et al. Fetal coenzyme Q10 deficiency in intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol. (2020) 44:368–74. doi: 10.1016/j.clinre.2019.07.006
60. O’Neill K, Alexander J, Azuma R, Xiao R, Snyder NW, Mesaros CA, et al. Gestational diabetes alters the metabolomic profile in 2nd trimester amniotic fluid in a sex-specific manner. Int J Mol Sci. (2018) 19:2696. doi: 10.3390/ijms19092696
61. Dalfrà MG, Burlina S, Del Vescovo GG, and Lapolla A. Genetics and epigenetics: new insight on gestational diabetes mellitus. Front Endocrinol. (2020) 11:602477. doi: 10.3389/fendo.2020.602477
62. Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, et al. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol. (2008) 4:214. doi: 10.1038/msb.2008.50
63. Zhu B, Ma Z, Zhu Y, Fang L, Zhang H, Kong H, et al. Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus. J Zhejiang Univ Sci B. (2021) 22:223–32. doi: 10.1631/jzus.B2000483
64. Wu Y, Wang Z, Zhao Z, Song X, Miao M, and Zhang X. Bile acid metabolites in early pregnancy and risk of gestational diabetes mellitus: results from a prospective cohort study. Diabetes Obes Metab. (2023) 25:2255–67. doi: 10.1111/dom.15104
65. Li J, Huo X, Cao YF, Li SN, Du Z, Shao P, et al. Bile acid metabolites in early pregnancy and risk of gestational diabetes in chinese women: A nested case-control study. EBioMedicine. (2018) 35:317–24. doi: 10.1016/j.ebiom.2018.08.015
66. van Nierop FS, Meessen ECE, Nelissen KGM, Achterbergh R, Lammers LA, Vaz FM, et al. Differential effects of a 40-hour fast and bile acid supplementation on human glp-1 and fgf19 responses. Am J Physiol Endocrinol Metab. (2019) 317:E494–e502. doi: 10.1152/ajpendo.00534.2018
67. Bellafante E, McIlvride S, Nikolova V, Fan HM, Manna LB, Chambers J, et al. Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis. Sci Rep. (2020) 10:11523. doi: 10.1038/s41598-020-67968-6
68. National Collaborating Centre for Ws and Children’s H. National institute for health and care excellence: clinical guidelines. In: Diabetes in Pregnancy: Management of Diabetes and Its Complications from Preconception to the Postnatal Period. National Institute for Health and Care Excellence (UK) Copyright © 2015 National Collaborating Centre for Women’s and Children’s Health, London (2015).
69. Keely E, Berger H, and Feig DS. New diabetes Canada clinical practice guidelines for diabetes and pregnancy - what’s changed? J Obstet Gynaecol Can. (2018) 40:1484–9. doi: 10.1016/j.jogc.2018.06.024
70. Shapiro H, Kolodziejczyk AA, Halstuch D, and Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med. (2018) 215:383–96. doi: 10.1084/jem.20171965
71. Jia ET, Liu ZY, Pan M, Lu JF, and Ge QY. Regulation of bile acid metabolism-related signaling pathways by gut microbiota in diseases. J Zhejiang Univ Sci B. (2019) 20:781–92. doi: 10.1631/jzus.B1900073
72. Jin LH, Fang ZP, Fan MJ, and Huang WD. Bile-ology: from bench to bedside. J Zhejiang Univ Sci B. (2019) 20:414–27. doi: 10.1631/jzus.B1900158
73. Chávez-Talavera O, Wargny M, Pichelin M, Descat A, Vallez E, Kouach M, et al. Bile acids associate with glucose metabolism, but do not predict conversion from impaired fasting glucose to diabetes. Metabol: Clin Exp. (2020) 103:154042. doi: 10.1016/j.metabol.2019.154042
74. McIlvride S, Nikolova V, Fan HM, McDonald JAK, Wahlström A, Bellafante E, et al. Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes. Am J Physiol Endocrinol Metab. (2019) 317:E399–410. doi: 10.1152/ajpendo.00407.2018
75. Sánchez-García A, Sahebkar A, Simental-Mendía M, and Simental-Mendía LE. Effect of ursodeoxycholic acid on glycemic markers: A systematic review and meta-analysis of clinical trials. Pharmacol Res. (2018) 135:144–9. doi: 10.1016/j.phrs.2018.08.008
76. Borges Manna L, Papacleovoulou G, Flaviani F, Pataia V, Qadri A, Abu-Hayyeh S, et al. Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy. Sci Rep. (2020) 10:10361. doi: 10.1038/s41598-020-67301-1
77. Lovell H, Mitchell A, Ovadia C, Pitrelli N, Briley A, Singh C, et al. A multi-centered trial investigating gestational treatment with ursodeoxycholic acid compared to metformin to reduce effects of diabetes mellitus (Guard): A randomized controlled trial protocol. Trials. (2022) 23:571. doi: 10.1186/s13063-022-06462-y
78. Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, et al. Lowering bile acid pool size with a synthetic farnesoid X receptor (Fxr) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem. (2011) 286:26913–20. doi: 10.1074/jbc.M111.248203
79. Lukivskaya O, Lis R, Egorov A, Naruta E, Tauschel HD, and Buko VU. The protective effect of ursodeoxycholic acid in alloxan-induced diabetes. Cell Biochem Funct. (2004) 22:97–103. doi: 10.1002/cbf.1063
80. Staels B and Kuipers F. Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs. (2007) 67:1383–92. doi: 10.2165/00003495-200767100-00001
81. Zieve FJ, Kalin MF, Schwartz SL, Jones MR, and Bailey WL. Results of the glucose-lowering effect of welchol study (Glows): A randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther. (2007) 29:74–83. doi: 10.1016/j.clinthera.2007.01.003
82. Park S, Zhang T, Yue Y, and Wu X. Effects of bile acid modulation by dietary fat, cholecystectomy, and bile acid sequestrant on energy, glucose, and lipid metabolism and gut microbiota in mice. Int J Mol Sci. (2022) 23:5935. doi: 10.3390/ijms23115935
83. Kondo K and Kadowaki T. Colestilan monotherapy significantly improves glycaemic control and ldl cholesterol levels in patients with type 2 diabetes: A randomized double-blind placebo-controlled study. Diabetes Obes Metab. (2010) 12:246–51. doi: 10.1111/j.1463-1326.2009.01159.x
84. Suzuki T, Oba K, Igari Y, Matsumura N, Watanabe K, Futami-Suda S, et al. Colestimide lowers plasma glucose levels and increases plasma glucagon-like peptide-1 (7-36) levels in patients with type 2 diabetes mellitus complicated by hypercholesterolemia. J Nippon Med Sch. (2007) 74:338–43. doi: 10.1272/jnms.74.338
85. Hansen M, Sonne DP, and Knop FK. Bile acid sequestrants: glucose-lowering mechanisms and efficacy in type 2 diabetes. Curr Diabetes Rep. (2014) 14:482. doi: 10.1007/s11892-014-0482-4
86. International Weight Management in Pregnancy (i-WIP) Collaborative Group. Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. Bmj. (2017) 358:j3119. doi: 10.1136/bmj.j3119
Keywords: gestational diabetes mellitus, bile acids, glucose homeostasis, offspring, therapeutic applications
Citation: Lu C, Li C and Lei X (2025) Bile acids and gestational diabetes mellitus: exploring the link and implications - a review. Front. Endocrinol. 16:1574228. doi: 10.3389/fendo.2025.1574228
Received: 10 February 2025; Accepted: 23 June 2025;
Published: 10 July 2025.
Edited by:
John Punnose, St. Stephen’s Hospital, IndiaReviewed by:
Emanuel Vamanu, University of Agricultural Sciences and Veterinary Medicine, RomaniaCassandra Henderson, Rockwood Partners, LLC, United States
Copyright © 2025 Lu, Li and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaoping Lei, bGVpeGlhb3BpbmcyMDIwQHN3bXUuZWR1LmNu