Infertility is a disease of the reproductive system which is defined as the inability to conceive after more than 12 months of unprotected intercourse. It affects millions of people and has far-reaching impacts on quality of life, sexual dysfunction, marital impact, and societal implications. Despite advancements in understanding infertility, the cause of infertility in around 28% of cases remains unclear. This review addresses the pivotal relation between Gut microbiota (GM) and infertility. GM is now believed to interplay with the human body at different levels and is essential for our well-being. The abnormal translocation of GM to the systemic circulation, known as dysbiosis triggers an over-stimulated immune response associated with a marked increase in pro-inflammatory cytokines. This inflammatory situation may disrupt the hypothalamic-pituitary-gonadal axis and lead to disseminated inflammation ending in adhesions and obstructive lesions of the reproductive tract. Dysbiosis can also predispose individuals to obesity and insulin resistance, where both are risk factors for diabetes, hypertension, polycystic ovary syndrome (PCOS), impaired spermatogenesis, erectile dysfunction, and infertility. GM has an inevitable role in the pharmacokinetics of many drugs and can regulate the expression of many cytochrome P450 enzymes and several transporters. Further research is needed to validate the possible implication of GM in the pathophysiology of infertility, the efficacy of infertility medications, and the potential of GM-based therapies to treat infertile couples.
MatzukMMLambDJ. The biology of infertility: research advances and clinical challenges. Nat Med2008; 14(11): 1197–1213.
2.
BabakhanzadehENazariMGhasemifarS, et al. Some of the factors involved in male infertility: a prospective review. Int J Gen Med2020; 13: 29–41.
3.
SekirovIRussellSLAntunesLC, et al. Gut microbiota in health and disease. Physiol Rev2010; 90: 859–904.
4.
HolmesELiJVMarchesiJR, et al. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab2012; 16(5): 559–564.
5.
De la FuenteM. The role of the microbiota-gut-brain axis in the health and illness condition: a focus on Alzheimer’s disease. J Alzheimers Dis2021; 81(4): 1345–1360.
6.
LaydenBTAngueiraARBrodskyM, et al. Short chain fatty acids and their receptors: new metabolic targets. Transl Res2013; 161(3): 131–140.
7.
VojinovicDRadjabzadehDKurilshikovA, et al. Relationship between gut microbiota and circulating metabolites in population-based cohorts. Nat Commun2019; 10(1): 5813.
8.
NicholsonJKHolmesEKinrossJ, et al. Host-gut microbiota metabolic interactions. Science2012; 336(6086): 1262–1267.
9.
MorrisonDJPrestonT. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes2016; 7(3): 189–200.
10.
PriyadarshiniMNavarroGLaydenBT. Gut microbiota: FFAR reaching effects on islets. Endocrinology2018; 159(6): 2495–2505.
11.
WangHBWangPYWangX, et al. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci2012; 57: 3126–3135.
12.
GeirnaertACalatayudMGrootaertC, et al. Butyrate-producing bacteria supplemented in vitro to Crohn’s disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity. Sci Rep2017; 7(1): 11450.
13.
TangJXuLZengY, et al. Effect of gut microbiota on LPS-induced acute lung injury by regulating the TLR4/NF-kB signaling pathway. Int Immunopharmacol2021; 91: 107272.
14.
TanJMcKenzieCPotamitisM, et al. The role of short-chain fatty acids in health and disease. Adv Immunol2014; 121: 91–119.
15.
MaleszaIJMaleszaMWalkowiakJ, et al. High-fat, western-style diet, systemic inflammation, and gut microbiota: a narrative review. Cells2021; 10(11): 3164.
16.
LuuMWeigandKWediF, et al. Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate. Sci Rep2018; 8(1): 14430.
17.
XuHLiuMCaoJ, et al. The dynamic interplay between the gut microbiota and autoimmune diseases. J Immunol Res2019; 2019: 7546047.
18.
YuYRakaFAdeliK. The role of the gut microbiota in lipid and lipoprotein metabolism. J Clin Med2019; 8(12): 2227.
19.
SunLPangYWangX, et al. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters. Acta Pharm Sin B2019; 9(4): 702–710.
20.
Martinez-GurynKHubertNFrazierK, et al. Small intestine Microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe2018; 23(4): 458–469.e5.
21.
EverardABelzerCGeurtsL, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA2013; 110(22): 9066–9071.
22.
LeoneVGibbonsSMMartinezK, et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe2015; 17(5): 681–689.
23.
ReaKDinanTGCryanJF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress2016; 4: 23–33.
24.
NamHS. Gut microbiota and ischemic stroke: the role of trimethylamine N-oxide. J Stroke2019; 21(2): 151–159.
25.
WallDJReinholdCAkinEA, et al. ACR appropriateness criteria® female infertility. J Am Coll Radiol2020; 17(5S): S113–S124.
26.
CarsonSAKallenAN. Diagnosis and management of infertility: a review. JAMA2021; 326(1): 65–76.
27.
WangYXieZ. Exploring the role of gut microbiome in male reproduction. Andrology2022; 10(3): 441–450.
28.
BusterJE. Gestational changes in steroid hormone biosynthesis, secretion, metabolism, and action. Clin Perinatol1983; 10(3): 527–552.
29.
HuangZ. Reproductive physiology of the human spermatozoon and oocyte. In: SinghK, editor. Integrated Approach to Obstetrics and Gynaecology. Singapore: World Scientific Publishing; 2016. p. 177.
30.
QiXYunCPangY, et al. The impact of the gut microbiota on the reproductive and metabolic endocrine system. Gut Microbes2021; 13(1): 1–21.
31.
Mayneris-PerxachsJArnoriaga-RodríguezMLuque-CórdobaD, et al. Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status. Microbiome2020; 8(1): 136–145.
32.
SallissMEFarlandLVMahnertND, et al. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Hum Reprod Update2021; 28(1): 92–131.
SovijitWNSovijitWEPuS, et al. Ovarian progesterone suppresses depression and anxiety-like behaviors by increasing the Lactobacillus population of gut microbiota in ovariectomized mice. Neurosci Res2021; 168: 76–82.
35.
CoombesZYadavVMcCoubreyLE, et al. Progestogens are metabolized by the gut microbiota: implications for colonic drug delivery. Pharmaceutics2020; 12(8): 760.
36.
LiYShenLHuangC, et al. Altered nitric oxide induced by gut microbiota reveals the connection between central precocious puberty and obesity. Clin Transl Med2021; 11(2): e299.
37.
LiuYLiJYanZ, et al. Improvement of insulin sensitivity increases pregnancy rate in infertile PCOS women: a systemic review. Front Endocrinol2021; 12: 657889.
38.
PitteloudNHardinMDwyerAA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab2005; 90(5): 2636–2641.
39.
SakumotoTTokunagaYTanakaH, et al. Insulin resistance/hyperinsulinemia and reproductive disorders in infertile women. Reprod Med Biol2010; 9: 185–190.
40.
HeFFLiYM. Role of gut microbiota in the development of insulin resistance and the mechanism underlying polycystic ovary syndrome: a review. J Ovarian Res2020; 13(1): 1–3.
41.
MasharaniUBMadduxBALiX, et al. Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle. PLoS One2011; 6(5): e19878.
42.
BäckhedFDingHWangT, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci2004; 101(44): 15718–15723.
43.
VriezeAVan NoodEHollemanFSalojärviJKootteRSBartelsmanJFDallinga–ThieGMAckermansMTSerlieMJOozeerRDerrienM. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012; 143(4): 913–6.
44.
DaoMCEverardAAron-WisnewskyJ, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut2016; 65(3): 426–436.
45.
ZhangJNiYQianL, et al. Decreased abundance of Akkermansia muciniphila leads to the impairment of insulin secretion and glucose homeostasis in lean type 2 diabetes. Adv Sci2021; 8(16): 2100536.
46.
GaneshBPKlopfleischRLohG, et al. Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella typhimurium-infected gnotobiotic mice. PLoS One2013; 8(9): e74963.
47.
GaoZYinJZhangJ, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes2009; 58(7): 1509–1517.
48.
GlintborgDAndersenM. An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome. Gynecol Endocrinol2010; 26(4): 281–296.
49.
RoesslerJLeistnerDMLandmesserU, et al. Modulatory role of gut microbiota in cholesterol and glucose metabolism: potential implications for atherosclerotic cardiovascular disease. Atherosclerosis2022; 359: 1–12.
50.
TorresPJSiakowskaMBanaszewskaB, et al. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endocrinol Metab2018; 103(4): 1502–1511.
51.
GuoJShaoJYangY, et al. Gut microbiota in patients with polycystic ovary syndrome: a systematic review. Reprod Sci2022; 29: 69–83.
52.
DuanLAnXZhangY, et al. Gut microbiota as the critical correlation of polycystic ovary syndrome and type 2 diabetes mellitus. Biomed Pharmacother2021; 142: 112094.
53.
GuoYQiYYangX, et al. Association between polycystic ovary syndrome and gut microbiota. PLoS One2016; 11(4): e0153196.
54.
QiXYunCSunL, et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med2019; 25(8): 1225–1233.
55.
JamilianMMansurySBahmaniF, et al. The effects of probiotic and selenium co-supplementation on parameters of mental health, hormonal profiles, and biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome. J Ovarian Res2018; 11(1): 7.
56.
MenshaweyEMenshaweyRNabehOA. Shedding light on vitamin D: the shared mechanistic and pathophysiological role between hypovitaminosis D and COVID-19 risk factors and complications. Inflammopharmacology2021; 29(4): 1017–1031.
57.
CaniPDAmarJIglesiasMA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes2007; 56(7): 1761–1772.
58.
ZengYLuoMPanL, et al. Vitamin D signaling maintains intestinal innate immunity and gut microbiota: Potential intervention for metabolic syndrome and NAFLD. Am J Physiol Gastrointest Liver Physiol2020; 318(3): G542–G553.
59.
ChenJThomsenMVitettaL. Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics. J Cell Biochem2019; 120(3): 2713–2720.
60.
WahlströmASayinSIMarschallHU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab2016; 24(1): 41–50.
61.
GozukaraIDokuyucuRÖzgürT, et al. Histopathologic and metabolic effect of ursodeoxycholic acid treatment on PCOS rat model. Gynecol Endocrinol2016; 32(6): 492–497.
62.
HeYWangQLiX, et al. Lactic acid bacteria alleviate polycystic ovarian syndrome by regulating sex hormone related gut microbiota. Food Funct2020; 11(6): 5192–5204.
63.
Montanino OlivaMBuonomoGCalcagnoM, et al. Effects of myo-inositol plus alpha-lactalbumin in myo-inositol-resistant PCOS women. J Ovarian Res2018; 11(1): 38–47.
64.
QuarantaGSanguinettiMMasucciL. Fecal microbiota transplantation: a potential tool for treatment of human female reproductive tract diseases. Front Immunol2019; 10: 2653.
65.
SinghRKChangHWYanD, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med2017; 15(1): 73–77.
66.
LeePCLeeKCLuHS, et al. Vitamin D deficiency associates with gut dysbiosis, endotoxemia and the risk of infectious complications in patients with liver cirrhosis. J Hepatol2023; 78: S252.
67.
IlangavanKKaluE. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril2010; 93(3): e10.
68.
BonavinaGTaylorHS. Endometriosis-associated infertility: from pathophysiology to tailored treatment. Front Endocrinol2022; 13: 2671.
69.
PluchinoNWengerJMPetignatP, et al. Sexual function in endometriosis patients and their partners: effect of the disease and consequences of treatment. Hum Reprod Update2016; 22(6): 762–774.
70.
KhanKNFujishitaAKitajimaM, et al. Intra-uterine microbial colonization and occurrence of endometritis in women with endometriosis. Hum Reprod2014; 29(11): 2446–2456.
71.
ZhangQShenQCelestinoJ, et al. Enhanced estrogen-induced proliferation in obese rat endometrium. Am J Obstet Gynecol2009; 200(2): 186.e1–186.e8.
72.
AtaBYildizSTurkgeldiE, et al. The endobiota study: comparison of vaginal, cervical and gut microbiota between women with stage 3/4 endometriosis and healthy controls. Sci Rep2019; 9(1): 2204.
73.
SvenssonABrunkwallLRothB, et al. Associations between endometriosis and gut microbiota. Reprod Sci2021; 28: 2367–2377.
ZhengWZhangSChenX, et al. Case report: dendritic cells and macrophages capture sperm in chronically inflamed human epididymis. Front Immunol2021; 12: 629680.
76.
DingNZhangXZhangXD, et al. Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes. Gut2020; 69(9): 1608–1619.
77.
RoubalováRProcházkováPPapežováH, et al. Anorexia nervosa: gut microbiota-immune-brain interactions. Clin Nutr2020; 39(3): 676–684.
78.
BaderM. Inhibition of serotonin synthesis: A novel therapeutic paradigm. Pharmacol Ther2020; 205: 107423.
79.
GonçalvesWSGhermanBRAbdoCHN, et al. Prevalence of sexual dysfunction in depressive and persistent depressive disorders: a systematic review and meta-analysis. Int J Impot Res2023; 35(4): 340–349.
80.
ChenSWuRHuangY, et al. Insulin resistance is an independent determinate of ED in young adult men. PLoS One2013; 8(12): e83951.
81.
Azmy NabehOAhmed El-BatrawyFAnwar KhorshidO, et al. The potential effect of ambrisentan as monotherapy and combined with tadalafil on diabetic erectile dysfunction in rats. Urol J2024; 91: 159–169.
82.
GengQChenSSunY, et al. Correlation between gut microbiota diversity and psychogenic erectile dysfunction. Transl Androl Urol2021; 10(12): 4412–4421.
83.
CraigJRJenkinsTGCarrellDT, et al. Obesity, male infertility, and the sperm epigenome. Fertil Steril2017; 107: 848–859.
84.
Cornejo-ParejaIMuñoz-GarachAClemente-PostigoM, et al. Importance of gut microbiota in obesity. Eur J Clin Nutr2019; 72: 26–37.
85.
ZhaoL. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol2013; 11: 639–647.
86.
GengJNiQSunW, et al. The links between gut microbiota and obesity and obesity related diseases. Biomed Pharmacother2022; 147: 112678.
87.
AbenavoliLScarpelliniEColicaC, et al. Gut microbiota and obesity: a role for probiotics. Nutr2019; 11: 2690.
88.
TemidayoSStefanSP. Diabetes mellitus and male infertility. Asian Pac J Reprod2018; 7: 6.
89.
LivshitsASeidmanDS. Fertility issues in women with diabetes. Womens Health2009; 5: 701–707.
90.
CaniPDDelzenneNM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des2009; 15: 1546–1558.
91.
LiW-ZStirlingKYangJ-J, et al. Gut microbiota and diabetes: from correlation to causality and mechanism. World J Diabetes2020; 11: 293–308.
92.
LiJZhaoFWangY, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome2017; 5: 14.
93.
MaJLiH. The role of gut microbiota in atherosclerosis and hypertension. Front Pharmacol2018; 9: 1082.
94.
JosePARajD. Gut microbiota in hypertension. Curr Opin Nephrol Hypertens2015; 24: 403–409.
95.
KhalesiSSunJBuysN, et al. Effect of probiotics on blood pressure. Hypertension2014; 64: 897–903.
96.
GuoDLiSBehrB, et al. Hypertension and male fertility. World J Mens Health2017; 35: 59.
97.
NilssonPMViigimaaMGiwercmanA, et al. Hypertension and reproduction. Curr Hypertens Rep2020; 22: 29.
98.
BasheerLKeremZ. Interactions between CYP3A4 and dietary polyphenols. Oxid Med Cell Longev2015; 2015: 854015.
99.
FeltrinCFariasIVSandjoLP, et al. Effects of standardized medicinal plant extracts on drug metabolism mediated by CYP3A4 and CYP2D6 enzymes. Chem Res Toxicol2020; 33(9): 2408–2419.
100.
LynchTPriceA. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician2007; 76(3): 391–396.
101.
NabehOA. Gut microbiota and cardiac arrhythmia: a pharmacokinetic scope. Egypt Heart J2022; 74(1): 1–9.
102.
GaoXJLiTWeiB, et al. [Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis]. Act Pharm Sin2017; 52(1): 34–43.
103.
TogaoMKawakamiKOtsukaJ, et al. Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: midazolam. Biopharm Drug Dispos2020; 41(7): 275–282.
104.
HuNLiuXMuQ, et al. The gut microbiota contributes to the modulation of intestinal CYP3A1 and P-gp in streptozotocin-induced type 1 diabetic rats. Eur J Pharm Sci2021; 162: 105833.
105.
WilsonIDNicholsonJK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res2017; 179: 204–222.
106.
GuengerichFPRendicS. Update information on drug metabolism systems–2009, part I. Curr Drug Metab2010; 11(1): 1–3.
107.
SewerMBKoopDRMorganET. Differential inductive and suppressive effects of endotoxin and particulate irritants on hepatic and renal cytochrome P-450 expression. J Pharmacol Exp Ther1997; 280(3): 1445–1454.
108.
MissoMLCostelloMFGarrubbaM, et al. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update2013; 19(1): 2–11.
109.
KahyaoğluSYılmazBIşıkAZ. Pharmacokinetic, pharmacodynamic, and clinical aspects of ovulation induction agents: a review of the literature. J Turk Ger Gynecol Assoc2017; 18(1): 48–55.
PotmešilPSzotkowskáR. Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes. Ther Adv Chronic Dis2020; 11: 2040622320964152.
112.
AnttilaMValavaaraRKivinenS, et al. Pharmacokinetics of toremifene. J Steroid Biochem1990; 36(3): 249–252.
113.
D’AmelioPIsaiaGC. The use of raloxifene in osteoporosis treatment. Expert Opin Pharmacother2013; 14(7): 949–956.
114.
HaynesBPDowsettMMillerWR, et al. The pharmacology of letrozole. J Steroid Biochem Mol Biol2003; 87(1): 35–45.
115.
RaymondLRayaniNPolsonG, et al. Determining the IC 50 values for vorozole and letrozole, on a series of human liver cytochrome p450s, to help determine the binding site of vorozole in the liver. Enzyme Res2015; 2015: 321820.
116.
LønningPEGeislerJDowsettM. Pharmacological and clinical profile of anastrozole. Breast Cancer Res Treat1998; 49: S53–S57.
117.
Del DottoPBonuccelliU. Clinical pharmacokinetics of cabergoline. Clin Pharmacokinet2003; 42: 633–645.
RobertsOKinvigHOwenA, et al. In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel. HIV Med2021; 22(10): 898–906.
120.
OuranidisATsiaxerliAVardakaE, et al. Sildenafil 4.0-Integrated synthetic chemistry, formulation and analytical strategies effecting immense therapeutic and societal impact in the fourth industrial era. Pharmaceuticals2021; 14(4): 365.
121.
ForgueSTPattersonBEBeddingAW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol2006; 61(3): 280–288.
122.
KimJKChoiMSKimJY, et al. Ginkgo biloba leaf extract suppresses intestinal human breast cancer resistance protein expression in mice: correlation with gut microbiota. Biomed Pharmacother2021; 140: 111712.
123.
JiHYLeeHWKimHH, et al. Role of human cytochrome P450 3A4 in the metabolism of DA–8159, a new erectogenic. Xenobiotica2004; 34(11-12): 973–982.
124.
KimDH. Gut microbiota-mediated drug-antibiotic interactions. Drug Metab Dispos2015; 43(10): 1581–1589.
125.
GuptaMCKhannaJ. Clomiphene citrate: the changing landscape. Int J Basic Clin Pharmacol2018; 7(8): 1437–1443.
126.
HammondMGRadwanskaETalbertLM. Effect of clomiphene citrate on corticosteroid-binding globulin and serum progesterone levels during ovulation induction. Fertil Steril1980; 33(4): 383–386.
127.
LiXLiuLCaoZ, et al. Gut microbiota as an “invisible organ” that modulates the function of drugs. Biomed Pharmacother2020; 121: 109653.
128.
Vich VilaACollijVSannaS, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun2020; 11(1): 362.
129.
XueLHeJGaoN, et al. Probiotics may delay the progression of nonalcoholic fatty liver disease by restoring the gut microbiota structure and improving intestinal endotoxemia. Sci Rep2017; 7(1): 45176.
130.
CorbettGACrosbyDAMcAuliffeFM. Probiotic therapy in couples with infertility: a systematic review. Eur J Obstet Gynecol Reprod Biol2021; 256: 95–100.
131.
BizzarriFPCampetellaMRagoneseM, et al. The role of alternative medicine and complimentary therapies in urologic disease: new horizons. Urol J2024; 91(4): 641–646.
