Causal Link between Gut Microbiota and Infertility: A Two-sample Bidirectional Mendelian Randomization Study

Abstract

Objective

To investigate the associations of the gut microbiota with reproductive system diseases, including female infertility, male infertility, polycystic ovary syndrome (PCOS), primary ovarian failure, endometriosis, uterine fibroids, uterine polyps, sexual dysfunction, orchitis, and epididymitis.

Methods

A two-sample bidirectional Mendelian randomization (MR) analysis was performed to evaluate the potential causal relationship between the composition of gut microbiota and infertility, along with associated diseases.

Results

Sixteen strong causal associations between gut microbes and reproductive system diseases were identified. Sixty-one causal associations between gut microbes and reproductive system diseases were determined. The genus Eubacterium hallii was a protective factor against premature ovarian failure and a pathogenic factor of endometriosis. The genus Erysipelatoclostridium was the pathogenic factor of many diseases, such as PCOS, endometriosis, epididymitis, and orchitis. The genus Intestinibacter is a pathogenic factor of male infertility and sexual dysfunction. The family Clostridiaceae 1 was a protective factor against uterine polyps and a pathogenic factor of orchitis and epididymitis. The results of reverse causal association analysis revealed that endometriosis, orchitis, and epididymitis all led to a decrease in the abundance of bifidobacteria and that female infertility-related diseases had a greater impact on gut microbes than male infertility-related diseases did.

Conclusions

The findings from the MR analysis indicate that there is a bidirectional causal relationship between the gut microbiota and infertility as well as associated ailments. Compared with ovarian diseases, uterine diseases are more likely to lead to changes in women’s gut microbiota. The findings of this research offer valuable perspectives on the mechanism and clinical investigation of reproductive system diseases caused by microorganisms.

Keywords

gut microbiota / infertility / Mendelian randomization / ovarian / uterine / sexual dysfunction / orchitis / epididymitis

References

[1] Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, stability and resilience of the human gut microbiota. Nature, 2012, 489(7415): 220-230

[2] Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiotagut-brain axis. Physiol Rev, 2019, 99(4): 1877-2013

[3] Heijtza RD, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A, 2011, 108(7): 3047-3052

[4] Hsiao EY, McBride SW, Hsien S, et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell, 2013, 155(7): 1451-1463

[5] Morais LH, Schreiber HL, Mazmanian SK. The gut microbiotabrain axis in behaviour and brain disorders. Nat Rev Microbiol, 2021, 19(4): 241-255

[6] Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe, 2022, 30(3): 289-300

[7] Erttmann SF, Swacha P, Aung KM, et al. The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity, 2022, 55(5): 847-861

[8] Federici S, Kredo-Russo S, Valdes-Mas R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell, 2022, 185(16): 2879-2898

[9] Park EM, Chelvanambi M, Bhutiani N, et al. Targeting the gut and tumor microbiota in cancer. Nat Med, 2022, 28(4): 690-703

[10] Parker A, Romano S, Ansorge R, et al. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 2022, 10(1): 68

[11] Schluter J, Peled JU, Taylor BP, et al. The gut microbiota is associated with immune cell dynamics in humans. Nature, 2020, 588(7837): 303-307

[12] Boulund U, Bastos DM, Ferwerda B, et al. Gut microbiome associations with host genotype vary across ethnicities and potentially influence cardiometabolic traits. Cell Host Microbe, 2022, 30(10): 1464-1480

[13] Kalantar-Zadeh K, Lockwood MB, Rhee CM, et al. Patient-centred approaches for the management of unpleasant symptoms in kidney disease. Nat Rev Nephrol, 2022, 18(3): 185-198

[14] Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study. BMC Med, 2023, 21(1): 66

[15] Zhuang Z, Yang R, Wang W, et al. Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia. J Neuroinflammation, 2020, 17(1): 288

[16] Garcia-Penarrubia P, Ruiz-Alcaraz AJ, Martinez-Esparza M, et al. Hypothetical roadmap towards endometriosis: prenatal endocrine-disrupting chemical pollutant exposure, anogenital distance, gut-genital microbiota and subclinical infections. Hum Reprod Update, 2020, 26(2): 214-246

[17] Qi X, Yun C, Sun L, et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med, 2019, 25(8): 1225-1233

[18] Salliss ME, Farland LV, Mahnert ND, et al. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain. Hum Reprod Update, 2022, 28(1): 92-131

[19] Qi X, Yun C, Pang Y, et al. The impact of the gut microbiota on the reproductive and metabolic endocrine system. Gut Microbes, 2021, 13(1): 1-21

[20] Chadchan SB, Naik SK, Popli P, et al. Gut microbiota and microbiota-derived metabolites promotes endometriosis. Cell Death Discov, 2023, 9(1): 28

[21] Wang Y, Xie Z. Exploring the role of gut microbiome in male reproduction. Andrology, 2022, 10(3): 441-450

[22] Zhang T, Sun P, Geng Q, et al. Disrupted spermatogenesis in a metabolic syndrome model: the role of vitamin A metabolism in the gut-testis axis. Gut, 2022, 71(1): 78-87

[23] Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-98

[24] Zhang Z, Huang B, Wang Y, et al. Dynamic alterations in the donkey fecal bacteria community and metabolome characteristics during gestation. Front Microbiol, 2022, 13: 927561

[25] Tariq EF, Irshad Y, Khalil HB, et al. Urinary Tract Infection Caused by the Novel Pathogen, Lactococcus Garvieae: A Case Report. Cureus, 2020, 12(7): e9462

[26] Xi Y, Zhang C, Feng Y, et al. Genetically predicted the causal relationship between gut microbiota and infertility: bidirectional Mendelian randomization analysis in the framework of predictive, preventive, and personalized medicine. EPMA J, 2023, 14(3): 405-416

[27] Ding N, Zhang X, Zhang XD, et al. Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes. Gut, 2020, 69(9): 1608-1619

[28] Annunziata G, Ciampaglia R, Capo X, et al. Polycystic ovary syndrome and cardiovascular risk. Could trimethylamine N-oxide (TMAO) be a major player? A potential upgrade forward in the DOGMA theory. Biomed Pharmacother, 2021, 143: 112171

[29] Chen F, Chen Z, Chen M, et al. Reduced stress-associated FKBP5 DNA methylation together with gut microbiota dysbiosis is linked with the progression of obese PCOS patients. NPJ Biofilms Microbiomes, 2021, 7(1): 60

[30] Crunkhorn S. Role of the gut microbiota in PCOS. Nat Rev Drug Discov, 2019, 18(9): 668

[31] Han Q, Wang J, Li W, et al. Androgen-induced gut dysbiosis disrupts glucolipid metabolism and endocrinal functions in polycystic ovary syndrome. Microbiome, 2021, 9(1): 101

[32] Li Y, Tan Y, Xia G, et al. Effects of probiotics, prebiotics, and synbiotics on polycystic ovary syndrome: a systematic review and meta-analysis. Crit Rev Food Sci Nutr, 2023, 63(4): 522-538

[33] Chen G, Peng Y, Huang Y, et al. Fluoride induced leaky gut and bloom of Erysipelatoclostridium ramosum mediate the exacerbation of obesity in high-fat-diet fed mice. J Adv Res, 2023, 50: 35-54

[34] Aranaz P, Ramos-Lopez O, Cuevas-Sierra A, et al. A predictive regression model of the obesity-related inflammatory status based on gut microbiota composition. Int J Obes (Lond), 2021, 45(10): 2261-2268

[35] Wise-Oringer BK, Burghard AC, Park H, et al. Salivary microbiome differences in prepubertal children with and without adrenal androgen excess. Pediatr Res, 2022, 91(7): 1797-1803

[36] Cao LB, Leung CK, Law P-N, et al. Systemic changes in a mouse model of VCD-induced premature ovarian failure. Life Sci, 2020, 262: 118543

[37] Geng Z, Nie X, Ling L, et al. Electroacupuncture May Inhibit Oxidative Stress of Premature Ovarian Failure Mice by Regulating Intestinal Microbiota. Oxid Med Cell Longev, 2022, 2022: 4362317

[38] Wu J, Zhuo Y, Liu Y, et al. Association between premature ovarian insufficiency and gut microbiota. BMC Pregnancy Childbirth, 2021, 21(1): 418

[39] Jiang L, Fei H, Tong J, et al. Hormone Replacement Therapy Reverses Gut Microbiome and Serum Metabolome Alterations in Premature Ovarian Insufficiency. Front Endocrinol (Lausanne), 2021, 12: 794496

[40] Wang J, Luo R, Zhao X, et al. Association between gut microbiota and primary ovarian insufficiency: a bidirectional two-sample Mendelian randomization study. Front Endocrinol (Lausanne), 2023, 14: 1183219

[41] Kovacs Z, Glover L, Reidy F, et al. Novel diagnostic options for endometriosis - Based on the glycome and microbiome. J Adv Res, 2021, 33: 167-181

[42] Yuan M, Li D, Zhang Z, et al. Endometriosis induces gut microbiota alterations in mice. Hum Reprod, 2018, 33(4): 607-616

[43] Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen gut microbiome axis: Physiological and clinical implications. Maturitas, 2017, 103: 45-53

[44] Enck P, Aziz Q, Barbara G, et al. Irritable bowel syndrome. Nat Rev Dis Primers, 2016, 2: 16014

[45] Ducarmon QR, Zwittink RD, Hornung BVH, et al. Gut Microbiota and Colonization Resistance against Bacterial Enteric Infection. Microbiol Mol Biol Rev, 2019, 83(3): e00007-e00019

[46] Giel KE, Bulik CM, Fernandez-Aranda F, et al. Binge eating disorder. Nat Rev Dis Primers, 2022, 8(1): 16

[47] Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest, 2015, 125(3): 926-938

[48] Romano S, Savva GM, Bedarf JR, et al. Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis, 2021, 7(1): 27

[49] Sarkar A, Lehto SM, Harty S, et al. Psychobiotics and the Manipulation of Bacteria-Gut-Brain Signals. Trends Neurosci, 2016, 39(11): 763-781

[50] Socala K, Doboszewska U, Szopa A, et al. The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res, 2021, 172: 105840

[51] Bayrer JR, Castro J, Venkataraman A, et al. Gut enterochromaffin cells drive visceral pain and anxiety. Nature, 2023, 616(7955): 137-142

[52] Korczynska L, Zeber-Lubecka N, Zgliczynska M, et al. The role of microbiota in the pathophysiology of uterine fibroids - a systematic review. Front Cell Infect Microbiol, 2023, 13: 1177366

[53] Mao X, Peng X, Pan Q, et al. Uterine Fibroid Patients Reveal Alterations in the Gut Microbiome. Front Cell Infect Microbiol, 2022, 12: 863594

[54] Vineetha KK, Bhat RG, Rao BK, et al. The Gut Microbiota: a Novel Player in the Pathogenesis of Uterine Fibroids. Reprod Sci, 2023, 30(12): 3443-3455

[55] Choi S, Hwang YJ, Shin MJ, et al. Difference in the Gut Microbiome between Ovariectomy-Induced Obesity and Diet-Induced Obesity. J Microbiol Biotechnol, 2017, 27(12): 2228-2236

[56] Chen C, Song X, Wei W, et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun, 2017, 8(1): 875

[57] Russo GI, Bongiorno D, Bonomo C, et al. The relationship between the gut microbiota, benign prostatic hyperplasia, and erectile dysfunction. Int J Impot Res, 2023, 35(4): 350-355

[58] Che L, Hu Q, Wang R, et al. Inter-correlated gut microbiota and SCFAs changes upon antibiotics exposure links with rapid body-mass gain in weaned piglet model. J Nutr Biochem, 2019, 74: 108246

[59] Whon TW, Kim HS, Shin NR, et al. Male castration increases adiposity via small intestinal microbial alterations. EMBO Rep, 2021, 22(1): e50663

[60] Zhang C, Chen F, Shen Y, et al. Sleep apnea is associated with the increase of certain genera of Ruminococcaceae and Lachnospiraceae in the gut microbiome of hypertensive patients. Expert Rev Respir Med, 2022, 16(11–12): 1247-1256

[61] Zhang Q, Fan XY, Cao YJ, et al. The beneficial effects of Lactobacillus brevis FZU0713-fermented Laminaria japonica on lipid metabolism and intestinal microbiota in hyperlipidemic rats fed with a high-fat diet. Food Funct, 2021, 12(16): 7145-7160

[62] Tirandaz H, Ebrahim-Habibi M-B, Moradveisi B, et al. Microbiota potential for the treatment of sexual dysfunction. Med Hypotheses, 2018, 115: 46-49

[63] Mueller S, Saunier K, Hanisch C, et al. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: A cross-sectional study. Appl Environ Microbiol, 2006, 72(2): 1027-1033

[64] Tian X, Yu Z, Feng P, et al. Lactobacillus plantarum TW1-1 Alleviates Diethylhexylphthalate-Induced Testicular Damage in Mice by Modulating Gut Microbiota and Decreasing Inflammation. Front Cell Infect Microbiol, 2019, 9: 221

[65] Sheng W, Xu W, Ding J, et al. Guijiajiao (Colla Carapacis et Plastri, CCP) prevents male infertility via gut microbiota modulation. Chin J Nat Med, 2023, 21(6): 403-410

[66] He N, Wang S, Lv Z, et al. Low molecular weight chitosan oligosaccharides (LMW-COSs) prevent obesity-related metabolic abnormalities in association with the modification of gut microbiota in high-fat diet (HFD)-fed mice. Food Funct, 2020, 11(11): 9947-9959

[67] Zhao L, Zhang Q, Ma W, et al. A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. Food Funct, 2017, 8(12): 4644-4656

[68] Schulthess J, Pandey S, Capitani M, et al. The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity, 2019, 50(2): 432-445

[69] Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med, 2014, 20(2): 159-166

[70] Zuo Z, Zhao F. Gut microbiota-targeted interventions: from conventional approaches to genetic engineering. Sci Bull (Beijing), 2023, 68(12): 1231-1234

[71] Chen XL, Gong LZ, Xu JX. Antioxidative activity and protective effect of probiotics against high-fat diet-induced sperm damage in rats. Animal, 2013, 7(2): 287-292

[72] Abbasi B, Abbasi H, Niroumand H. Synbiotic (FamiLact) administration in idiopathic male infertility enhances sperm quality, DNA integrity, and chromatin status: A triple-blinded randomized clinical trial. Int J Reprod Biomed, 2021, 19(3): 235-244

[73] Valcarce DG, Genoves S, Riesco MF, et al. Probiotic administration improves sperm quality in asthenozoospermic human donors. Benef Microbes, 2017, 8(2): 193-206

[74] Hao Y, Feng Y, Yan X, et al. Gut Microbiota-Testis Axis: FMT Mitigates High-Fat Diet-Diminished Male Fertility via Improving Systemic and Testicular Metabolome. Microbiol Spectr, 2022, 10(3): e0002822

[75] Zhang C, Xiong B, Chen L, et al. Rescue of male fertility following faecal microbiota transplantation from alginate oligosaccharide-dosed mice. Gut, 2021, 70(11): 2213-2215

[76] Dai Z, Wu Z, Hang S, et al. Amino acid metabolism in intestinal bacteria and its potential implications for mammalian reproduction. Mol Hum Reprod, 2015, 21(5): 389-409

[77] Zhou L, Ni Z, Yu J, et al. Correlation Between Fecal Metabolomics and Gut Microbiota in Obesity and Polycystic Ovary Syndrome. Front Endocrinol (Lausanne), 2020, 11: 628