1.Department of Clinical Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
2.Department of Clinical Nutrition, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3.School of Pediatrics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
4.College of Clinical Medicine, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
5.Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
The global incidence of gestational diabetes mellitus (GDM) continues to rise in recent years. Research has shown that GDM can increase the risk of adverse pregnancy outcomes in pregnant women and lead to malignant intergenerational circulation. The etiology of GDM is complex and the pathogenesis has not been fully elucidated. Maternal dietary assessment and guidance is the first-line method for managing GDM in clinical practice. Reasonable diet plays an important role in gut microbia and its metabolites during pregnancy, and the dysfunction of gut microbia is closely related to the occurrence of metabolic diseases. It has been shown that gut microbial metabolites such as short-chain fatty acids (SCFAs), trimethylamine oxide (TMAO) and bile acids are strongly influenced by diet and play an important role in metabolic disorders related to insulin resistance (such as GDM). Progress has been made in the prevention and treatment of metabolic diseases by improving gut microbia through medical nutrition therapy, which provides a new direction for the control of GDM. The status quo of GDM, the characteristics and alteration of gut microbia in pregnant women with GDM, the GDM-related gut microbial metabolites, and the feasible prevention and treatment of GDM by targeting gut microbia and its metabolites are reviewed.
Keywords：gestational diabetes mellitus (GDM)
;
gut microbia
;
gut microbia metabolite
;
dietary estimation
LIU Qianruo, FANG Zichen, WU Yuhan, ZHONG Xianxin, GUO Muhe, JIA Jie. Research progress in the relationship between gut microbia and its metabolites and gestational diabetes mellitus. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(5): 641-647 doi:10.3969/j.issn.1674-8115.2023.05.016
妊娠期糖尿病（gestational diabetes mellitus，GDM）与母婴健康密切相关。临床上，GDM可增加妊娠不良结局的发生风险，并影响母婴未来患代谢相关疾病的风险。研究［1］表明，肠道菌群在增强宿主免疫力、调节代谢、影响肠道细胞内分泌等方面发挥着重要作用，且其代谢产物可在胰岛素相关代谢紊乱［如肥胖、2型糖尿病（diabetes mellitus type 2，T2DM）等］中发挥促进或抑制疾病的作用。与健康孕妇相比，GDM患者的肠道菌群α多样性较低、有益菌和有害菌群丰度失衡，这些变化均可能导致GDM孕妇的代谢发生紊乱；同时，肠道菌群又可受到食物成分、营养素和益生菌的影响，因此通过饮食调节肠道菌群及其代谢产物可能成为防治GDM的有效方式。本文就GDM与肠道菌群及其代谢产物的关联进行综述，并针对饮食、运动、益生元（菌）等对GDM的防治作用进行分析。
胆汁酸包括初级胆汁酸和次级胆汁酸，可参与体内的脂肪消化，是细胞和肠道菌群的能量来源。初级胆汁酸的合成在肝脏中进行，包括经典途径和替代途径，均需要胆固醇的参与。经典途径中，在胆固醇羟化酶细胞色素P450家族成员7A1（cytochrome P450 family 7 subfamily A member 1，CYP7A1）、CYP 8B1和CYP 27A1的作用下，胆固醇可转变为7-羟基胆固醇，进一步被催化为初级胆汁酸，包括胆酸（cholic acid，CA）和鹅去氧胆酸（chenodeoxycholic acid，CDCA）。旁路途径中，胆固醇的羟基化需要依赖肠道梭菌（Fusobacterium）和真杆菌属的羟化酶来进行［28］。经典途径和旁路途径均需辅酶A合成酶、胆汁酸辅酶A将游离态的初级胆汁酸结合到甘氨酸中，形成结合型初级胆汁酸，随后其被分泌入胆汁［29］。待结合型初级胆汁酸进入肠腔后，由拟杆菌门、真杆菌属和大肠埃希菌属（Escherichia coli）等肠道菌群将其分解为游离型次级胆汁酸，如熊脱氧胆酸（ursodeoxycholic acid，UDCA）以及脱氧胆酸（deoxycholic acid，DCA）。在完成食物中的脂肪代谢后，游离型胆汁酸会被重吸收入血液循环，在肝细胞中重新合成为结合型胆汁酸，以此完成胆汁酸的肠肝循环［28］。
The topic design and writing guidance were performed by JIA Jie. The manuscript was drafted and revised by LIU Qianruo, FANG Zichen, WU Yuhan, ZHONG Xianxin and GUO Muhe. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
All authors disclose no relevant conflict of interests.
DENG K, SHUAI M, ZHANG Z, et al. Temporal relationship among adiposity, gut microbiota, and insulin resistance in a longitudinal human cohort[J]. BMC Med, 2022, 20(1): 171.
JOHNS E C, DENISON F C, NORMAN J E, et al. Gestational diabetes mellitus: mechanisms, treatment, and complications[J]. Trends Endocrinol Metab, 2018, 29(11): 743-754.
DE GENNARO G, PALLA G, BATTINI L, et al. The role of adipokines in the pathogenesis of gestational diabetes mellitus[J]. Gynecol Endocrinol, 2019, 35(9): 737-751.
GAO C H, SUN X, LU L, et al. Prevalence of gestational diabetes mellitus in mainland China: a systematic review and meta-analysis[J]. J Diabetes Investig, 2019, 10(1): 154-162.
HAN R Y, JIANG Z S, GAO C Y, et al. Research progress of intestinal flora metabolites as indicators for disease diagnosis [J]. Microbiology China, 2021, 48(11): 4261-4274.
KOREN O, GOODRICH J K, CULLENDER T C, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy[J]. Cell, 2012, 150(3): 470-480.
MA S J, YOU Y P, HUANG L T, et al. Alterations in gut microbiota of gestational diabetes patients during the first trimester of pregnancy[J]. Front Cell Infect Microbiol, 2020, 10: 58.
CRUSELL M K W, HANSEN T H, NIELSEN T, et al. Gestational diabetes is associated with change in the gut microbiota composition in third trimester of pregnancy and postpartum[J]. Microbiome, 2018, 6(1): 89.
SU M L, NIE Y Y, SHAO R C, et al. Diversified gut microbiota in newborns of mothers with gestational diabetes mellitus[J]. PLoS One, 2018, 13(10): e0205695.
GHOLIZADEH P, MAHALLEI M, PORMOHAMMAD A, et al. Microbial balance in the intestinal microbiota and its association with diabetes, obesity and allergic disease[J]. Microb Pathog, 2019, 127: 48-55.
KUMBHARE S V, PATANGIA D V V, PATIL R H, et al. Factors influencing the gut microbiome in children: from infancy to childhood[J]. J Biosci, 2019, 44(2): 49.
KIMURA I, MIYAMOTO J, OHUE-KITANO R, et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice[J]. Science, 2020, 367(6481): eaaw8429.
LIU X N, LI X, XIA B, et al. High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis[J]. Cell Metab, 2021, 33(5): 923-938.e6.
CHITTIM C L, MARTÍNEZ DEL CAMPO A, BALSKUS E P. Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline[J]. Nat Microbiol, 2019, 4(1): 155-163.
CHO C E, TAESUWAN S, MALYSHEVA O V, et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial[J]. Mol Nutr Food Res, 2017, 61(1). doi: 10.1002/mnfr.201600324.
WANG Z N, BERGERON N, LEVISON B S, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women[J]. Eur Heart J, 2019, 40(7): 583-594.
HUO X X, LI J, CAO Y F, et al. Trimethylamine N-oxide metabolites in early pregnancy and risk of gestational diabetes: a nested case-control study[J]. J Clin Endocrinol Metab, 2019, 104(11): 5529-5539.
LI P Y, ZHONG C R, LI S Z, et al. Plasma concentration of trimethylamine-N-oxide and risk of gestational diabetes mellitus[J]. Am J Clin Nutr, 2018, 108(3): 603-610.
LIN X J, ZHANG Y Q, HE X L, et al. The choline metabolite TMAO inhibits NETosis and promotes placental development in GDM of humans and mice[J]. Diabetes, 2021, 70(10): 2250-2263.
LIU J N, LI J, YANG K, et al. Ceramides and their interactive effects with trimethylamine-N-oxide metabolites on risk of gestational diabetes: a nested case-control study[J]. Diabetes Res Clin Pract, 2021, 171: 108606.
JIA W, XIE G X, JIA W P. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(2): 111-128.
MCINTYRE H D, SACKS D A, BARBOUR L A, et al. Issues with the diagnosis and classification of hyperglycemia in early pregnancy[J]. Diabetes Care, 2016, 39(1): 53-54.
LIU Y, SUN R, LI Y, 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[J]. Clin Chim Acta, 2021, 520: 160-167.
KONG M, LU Z, ZHONG C, 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]. J Endocrinol Invest, 2020, 43(8): 1097-1103.
HE J, JIANG D M, CUI X W, et al. Vitamin B12 status and folic acid/vitamin B12 related to the risk of gestational diabetes mellitus in pregnancy: a systematic review and meta-analysis of observational studies[J]. BMC Pregnancy Childbirth, 2022, 22(1): 587.
KANWAL A, BASHIR A. Vitamin B12 in pregnancy and its relationship with maternal BMI and gestational diabetes mellitus: a study from Pakistan[J]. Pak J Med Sci, 2022, 38(4Part-II): 807-810.
CHEN X T, ZHANG Y, CHEN H Y, et al. Association of maternal folate and vitamin B12 in early pregnancy with gestational diabetes mellitus: a prospective cohort study[J]. Diabetes Care, 2021, 44(1): 217-223.
SARAVANAN P, SUKUMAR N, ADAIKALAKOTESWARI A, et al. Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study)[J]. Diabetologia, 2021, 64(10): 2170-2182.
JACOBSON A N, CHOUDHURY B P, FISCHBACH M A. The biosynthesis of lipooligosaccharide from Bacteroides thetaiotaomicron[J]. mBio, 2018, 9(2): e02289-e02217.
FERROCINO I, PONZO V, GAMBINO R, et al. Changes in the gut microbiota composition during pregnancy in patients with gestational diabetes mellitus (GDM)[J]. Sci Rep, 2018, 8(1): 12216.
MAHIZIR D, BRIFFA J F, WOOD J L, et al. Exercise improves metabolic function and alters the microbiome in rats with gestational diabetes[J]. FASEB J, 2020, 34(1): 1728-1744.
WU N, ZHOU J W, MO H, et al. The gut microbial signature of gestational diabetes mellitus and the association with diet intervention[J]. Front Cell Infect Microbiol, 2021, 11: 800865.
MAGNE F, GOTTELAND M, GAUTHIER L, et al. The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients?[J]. Nutrients, 2020, 12(5): 1474.
LI G L, XIE C, LU S Y, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota[J]. Cell Metab, 2017, 26(5): 801.
MOTIANI K K, COLLADO M C, ESKELINEN J J, et al. Exercise training modulates gut microbiota profile and improves endotoxemia[J]. Med Sci Sports Exerc, 2020, 52(1): 94-104.
TURNBAUGH P J, LEY R E, MAHOWALD M A, et al. An obesity-associated gut microbiome with increased capacity for energy harvest[J]. Nature, 2006, 444(7122): 1027-1031.
RAJILIĆ-STOJANOVIĆ M, DE VOS W M. The first 1000 cultured species of the human gastrointestinal microbiota[J]. FEMS Microbiol Rev, 2014, 38(5): 996-1047.
TONUCCI L B, OLBRICH DOS SANTOS K M, LICURSI DE OLIVEIRA L, et al. Clinical application of probiotics in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study[J]. Clin Nutr, 2017, 36(1): 85-92.
ZHENG Q X, JIANG X M, WANG H W, et al. Probiotic supplements alleviate gestational diabetes mellitus by restoring the diversity of gut microbiota: a study based on 16S rRNA sequencing[J]. J Microbiol, 2021, 59(9): 827-839.
CHEN Y T, LU J, WICKENS K, et al. Effect of Lactobacillus rhamnosus probiotic in early pregnancy on plasma conjugated bile acids in a randomised controlled trial[J]. Nutrients, 2021, 13(1): 209.
HASAIN Z, CHE ROOS N A, RAHMAT F, et al. Diet and pre-intervention washout modifies the effects of probiotics on gestational diabetes mellitus: a comprehensive systematic review and meta-analysis of randomized controlled trials[J]. Nutrients, 2021, 13(9): 3045.
SHAHRIARI A, KARIMI E, SHAHRIARI M, et al. The effect of probiotic supplementation on the risk of gestational diabetes mellitus among high-risk pregnant women: a parallel double-blind, randomized, placebo-controlled clinical trial[J]. Biomedecine Pharmacother, 2021, 141: 111915.
GIBSON G R, HUTKINS R, SANDERS M E, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(8): 491-502.
AHMADI S, JAMILIAN M, TAJABADI-EBRAHIMI M, et al. The effects of synbiotic supplementation on markers of insulin metabolism and lipid profiles in gestational diabetes: a randomised, double-blind, placebo-controlled trial-Expression of concern[J]. Br J Nutr, 2022, 127(1): 153.
VITALI B, NDAGIJIMANA M, CRUCIANI F, et al. Impact of a synbiotic food on the gut microbial ecology and metabolic profiles[J]. BMC Microbiol, 2010, 10: 4.
NABHANI Z, HEZAVEH S J G, RAZMPOOSH E, et al. The effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile and total antioxidant capacity in women with gestational diabetes mellitus: a randomized double blind placebo controlled clinical trial[J]. Diabetes Res Clin Pract, 2018, 138: 149-157.
