The influence of the gut microbiome on ovarian aging

Figures & data

Figure 1. The physiologic succession of gut microbiota across natural ovarian aging.

Figure 2. FMT alter the gut microbiota and slow the progression of ovarian aging related diseases.

Table 1. Association among antiaging drugs, ovarian function and intestinal microbes.

Drug	Animal	Gut microbiota alterations induced by antiaging drugs	Effect on ovarian function
Resveratrol	Hen^Citation71 Mouse^Citation72–75 Rat^Citation76 Annual fish N. guentheri^Citation77	Firmicutes, Rikenellaceae, Lactobacillus, Lactobacillales, Firmicutes/Bacteroidetes ratio, Blautia, Bacteroides, Lachnospiraceae_NK4A136_group, Lachnoclostridium, Parabacteroides, Ruminiclostridium_9↑ Clostridiales_bacterium_CHKC1001, Lactobacillus_mucosae, Desulfovibrio, Lachnospiraceae_NK4A136_group↓	Egg-laying rate reduction, atretic follicles↓ E2, FSH, AMH, ovarian relative weight, primary and growing follicles, oocyte quantity and quality, litter size, oocyte primary growth, cortical alveolus and vitellogenesis stage↑
Melatonin	Mouse^Citation78–80 Hen^Citation81	Alpha diversity, Bacteroides, Alistipes, Firmicutes, Firmicutes/Bacteroidetes ratio↓ Lactobacillales, Lactobacillus, Bacteroidetes↑	E2, LH, growing follicles, pool of follicles, litter size, oocyte quantity and quality↑
NMN	Mouse^Citation82–84	Firmicutes, Firmicutes/Bacteroidetes ratio↓ Bacteroidetes↑	Oocyte quality, number of follicles at different stages, corpora luteum, estrus cycle↑ FSH↓
Rapamycin	Mouse^Citation85–88 Drosophila ^Citation89	Segmented filamentous bacteria (Candidatus arthromitus sp.) ↑ Bacterial load, Alphaproteobacteria↓	Ovarian reserve, oocyte quality↑ Disturbed estrous cycle but recovered after 2 months
CoQ10	Rat^Citation90 Mouse^Citation91–93 Human^Citation94,Citation95 Hen^Citation96 Sow^Citation97 Red tilapia^Citation98	Ruminococcus, Lachnospiraceae AC 2044, Lactobacillus, Bifidobacterium↑ Helicobacter, Proteobacteria↓	Primordial, preantral, antral follicles, ovarian response to stimulation, numbers of zygotes retrieved, embryological parameters, pregnancy↑
NAC	Mouse^Citation99–101	Akkermansia, Bifidobacterium, Lactobacillus, Allobaculum↑ Desulfovibrio, Blautia↓	Oocyte quality, total blastocyst cell number, litter size↑

(↑, increase; ↓, decrease).

E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; AMH, anti-Müllerian hormone; CoQ10, coenzyme Q10; NAC, N-acetyl-L-cysteine.

Table 2. Caloric restriction modulates ovarian function.

Dietary regimen	Animal	Effect on ovarian function
10-week 45% CR	Rat^Citation118,Citation119	Ovarian reserve, total follicles, surviving follicles↑ LH, FSH, E2, atretic follicles ↓ Irregular estrous cycles↑
26-week 30% CR	Mouse^Citation120	Ovarian reserve, surviving follicles↑ Atretic follicles↓ Irregular estrous cycles↑
9-month CR (Alternate-day feeding)	Mouse^Citation121	ER/AR↑
93-day 30% CR	Mouse^Citation85	Ovarian reserve↑
2-month 25% and 45% CR	Rat^Citation122	Ovarian reserve, healthy follicles↑
24-week 10% CR	Mouse^Citation123	Ovarian reserve, pregnancy rate↑ Respond to superovulation↓

(↑, increase; ↓, decrease).

CR, caloric restriction; E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; AMH, anti-Müllerian hormone; ER, estrogen receptor; AR, androgen receptor.

Table 3. Gut microbiota alterations induced by caloric restriction.

Dietary regimen	Animal	Gut microbiota alterations
4-week VLCD	Human^Citation124	Anaerostipes hadrus, Blautia sp., Ruminococcus faecis, Bifidobacterium sp.↑ Agathobacter rectalis↓
30-day 40% CR	Mouse^Citation125	Lactobacillaceae, Erysipelotichaceae, Bacteroidaceae, Verrucomicrobiaceae↑ Firmicutes↓
28-month 30% CR	Mouse^Citation126	Firmicutes, Peptostreptococcaceae, Clostridium sensu stricto 1, Turicibacter↓ Actinobacteria, Verrucomicrobia, Bifidobacterium, Lactobacillus↑
2-week 30% CR	Mouse^Citation127,Citation128	Lactobacillus↑
3-month 34% CR	Human^Citation129	Subdoligranulum, Collinsella, ↓ Parabacteroides, Alistipes, Bacteroides↑
8-week VLCD	Human^Citation130	Bacteria capable of foraging on host glycans (Akkermansia) ↑ Bacteria specialized for the metabolism of plant polysaccharides (Roseburia, Ruminococcus, Eubacterium) ↓
4-day, 70% protein-restricted, 30% CR	Human^Citation131	Butyrate producers (Faecalibacterium prausnitzii, Roseburia intestinalis) ↓
8-week 30% CR	Rat^Citation132	Lactobacillus↑
62-week 30% CR	Mouse^Citation133	Lactobacillus↑
Lifelong 30% CR	Mouse^Citation134	Lactococcus↓ Lactobacillus, Bifidobacterium↑
8-week 30% CR	Mouse^Citation135	Helicobacter pylori↓ Lactobacillus, Bifidobacterium↑
2-month 30% CR	Mouse^Citation136	Clostridia, Clostridiales, Firmicutes↓
45-day 25% CR	Mouse^Citation137	Firmicutes/Bacteroidetes↓ Bacteroidetes↑
1-year 30% CR	Human^Citation138	Firmicutes/Bacteroidetes↓ Bacteroides, Roseburia, Faecalibacterium, Clostridium↑
12-week VLCD	Human^Citation139	Bacteroides↓ Firmicutes, butyrate-producing bacteria↑

(↑, increase; ↓, decrease) CR, caloric restriction; VLCD, very-low-calorie diet.

Hao EY, Chen H, Wang DH, Huang CX, Tong YG, Chen YF, Zhou R-Y, Huang R-L. Melatonin regulates the ovarian function and enhances follicle growth in aging laying hens via activating the mammalian target of rapamycin pathway. Poult Sci. 2020;99(4):2185–95. doi:10.1016/j.psj.2019.11.040.

 PubMed Web of Science ®Google Scholar

Tamura H, Jozaki M, Tanabe M, Shirafuta Y, Mihara Y, Shinagawa M, Tamura I, Maekawa R, Sato S, Taketani T, et al. Importance of Melatonin in assisted reproductive technology and ovarian aging. Int J Mol Sci. 2020;21(3):21. doi:10.3390/ijms21031135.

 Web of Science ®Google Scholar

Ivanova AY, Shirokov IV, Toshchakov SV, Kozlova AD, Obolenskaya ON, Mariasina SS, Ivlev VA, Gartseev IB, Medvedev OS. Effects of coenzyme Q10 on the biomarkers (hydrogen, methane, SCFA and TMA) and composition of the gut microbiome in rats. Pharmaceuticals (Basel, Switzerland). 2023;16(5):686. doi:10.3390/ph16050686.

 PubMedGoogle Scholar

Bertoldo MJ, Listijono DR, Ho WJ, Riepsamen AH, Goss DM, Richani D, Jin XL, Mahbub S, Campbell JM, Habibalahi A, et al. NAD(+) repletion rescues female fertility during reproductive aging. Cell Rep. 2020;30(6):1670–81.e7. doi:10.1016/j.celrep.2020.01.058.

 PubMed Web of Science ®Google Scholar

Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016;5:e16351. doi:10.7554/eLife.16351.

 PubMed Web of Science ®Google Scholar

Duan H, Pan J, Guo M, Li J, Yu L, Fan L. Dietary strategies with anti-aging potential: dietary patterns and supplements. Food Res Int. 2022;158:111501. doi:10.1016/j.foodres.2022.111501.

 PubMed Web of Science ®Google Scholar

Raghu G, Berk M, Campochiaro PA, Jaeschke H, Marenzi G, Richeldi L, Wen F-Q, Nicoletti F, Calverley PMA. The multifaceted therapeutic role of N-Acetylcysteine (NAC) in disorders characterized by oxidative stress. Curr Neuropharmacol. 2021;19(8):1202–24. doi:10.2174/1570159X19666201230144109.

 PubMed Web of Science ®Google Scholar

Lee MB, Hill CM, Bitto A, Kaeberlein M. Antiaging diets: separating fact from fiction. Sci. 2021;374(6570):eabe7365. doi:10.1126/science.abe7365.

 PubMed Web of Science ®Google Scholar

Liu J, Liu M, Ye X, Liu K, Huang J, Wang L, Ji G, Liu N, Tang X, Baltz JM, et al. Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum Reprod. 2012;27(5):1411–20. doi:10.1093/humrep/des019.

 PubMed Web of Science ®Google Scholar

Zheng J, Yuan X, Zhang C, Jia P, Jiao S, Zhao X, Yin H, Du Y, Liu H. N-Acetylcysteine alleviates gut dysbiosis and glucose metabolic disorder in high-fat diet-fed mice. J Diabetes. 2019;11(1):32–45. doi:10.1111/1753-0407.12795.

 PubMed Web of Science ®Google Scholar

Ding Q, Guo R, Pei L, Lai S, Li J, Yin Y, Xu T, Yang W, Song Q, Han Q, et al. N-Acetylcysteine alleviates high fat diet-induced hepatic steatosis and liver injury via regulating the intestinal microecology in mice. Food Funct. 2022;13(6):3368–3380. doi:10.1039/D1FO03952K.

 PubMed Web of Science ®Google Scholar

Isola JVV, Zanini BM, Hense JD, Alvarado-Rincon JA, Garcia DN, Pereira GC, Vieira AD, Oliveira TL, Collares T, Gasperin BG, et al. Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice. Exp Gerontol. 2022;159:111669. doi:10.1016/j.exger.2021.111669.

 PubMed Web of Science ®Google Scholar

Słuczanowska-Głąbowska S, Laszczyńska M, Piotrowska K, Grabowska M, Grymuła K, Ratajczak MZ. Caloric restriction increases ratio of estrogen to androgen receptors expression in murine ovaries–potential therapeutic implications. J Ovarian Res. 2015;8(1):57. doi:10.1186/s13048-015-0185-8.

 PubMedGoogle Scholar

Li L, Fu YC, Xu JJ, Lin XH, Chen XC, Zhang XM, Luo L-L. Caloric restriction promotes the reserve of follicle pool in adult female rats by inhibiting the activation of mammalian target of rapamycin signaling. Reprod Sci. 2015;22(1):60–7. doi:10.1177/1933719114542016.

 PubMed Web of Science ®Google Scholar

Cox LM, Schafer MJ, Sohn J, Vincentini J, Weiner HL, Ginsberg SD, Blaser MJ. Calorie restriction slows age-related microbiota changes in an Alzheimer’s disease model in female mice. Sci Rep. 2019;9(1):17904. doi:10.1038/s41598-019-54187-x.

 PubMedGoogle Scholar

Zhang Y, Zhang J, Wang S. The role of rapamycin in healthspan extension via the delay of Organ aging. Ageing Res Rev. 2021;70:101376. doi:10.1016/j.arr.2021.101376.

 PubMed Web of Science ®Google Scholar

Li L, Fu YC, Xu JJ, Chen XC, Lin XH, Luo LL. Caloric restriction promotes the reproductive capacity of female rats via modulating the level of insulin-like growth factor-1 (IGF-1). Gen Comp Endocr. 2011;174(2):232–237. doi:10.1016/j.ygcen.2011.09.005.

 PubMed Web of Science ®Google Scholar

Luo LL, Chen XC, Fu YC, Xu JJ, Li L, Lin XH, Xiang Y-F, Zhang X-M. The effects of caloric restriction and a high-fat diet on ovarian lifespan and the expression of SIRT1 and SIRT6 proteins in rats. Aging Clin Exp Res. 2012;24(2):125–33. doi:10.1007/BF03654792.

 PubMed Web of Science ®Google Scholar

Tang D, Zeng T, Wang Y, Cui H, Wu J, Zou B, Tao Z, Zhang L, Garside GB, Tao S, et al. Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity. Gut Microbes. 2020;12(1):1714401. doi:10.1080/19490976.2020.1714401.

 PubMed Web of Science ®Google Scholar

Sbierski-Kind J, Grenkowitz S, Schlickeiser S, Sandforth A, Friedrich M, Kunkel D, Glauben R, Brachs S, Mai K, Thürmer A, et al. Effects of caloric restriction on the gut microbiome are linked with immune senescence. Microbiome. 2022;10(1):57. doi:10.1186/s40168-022-01249-4.

 PubMed Web of Science ®Google Scholar

Pan F, Zhang L, Li M, Hu Y, Zeng B, Yuan H, Zhao L, Zhang C. Predominant gut Lactobacillus murinus strain mediates anti-inflammaging effects in calorie-restricted mice. Microbiome. 2018;6(1):54. doi:10.1186/s40168-018-0440-5.

 PubMed Web of Science ®Google Scholar

Krautkramer KA, Fan J, Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol. 2021;19(2):77–94. doi:10.1038/s41579-020-0438-4.

 PubMed Web of Science ®Google Scholar

Kok DEG, Rusli F, van der Lugt B, Lute C, Laghi L, Salvioli S, Picone G, Franceschi C, Smidt H, Vervoort J, et al. Lifelong calorie restriction affects indicators of colonic health in aging C57Bl/6J mice. J Nutr Biochem. 2018;56:152–164. doi:10.1016/j.jnutbio.2018.01.001.

 PubMed Web of Science ®Google Scholar

Fabbiano S, Suarez-Zamorano N, Chevalier C, Lazarevic V, Kieser S, Rigo D, Leo S, Veyrat-Durebex C, Gaïa N, Maresca M, et al. Functional gut microbiota remodeling contributes to the caloric restriction-induced metabolic Improvements. Cell Metab. 2018;28(6):907–921.e7. doi:10.1016/j.cmet.2018.08.005.

 PubMed Web of Science ®Google Scholar

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–278. doi:10.1016/j.cell.2022.11.001.

 PubMed Web of Science ®Google Scholar

Finamore A, Roselli M, Donini L, Brasili DE, Rami R, Carnevali P, Mistura L, Pinto A, Giusti A, Mengheri E, et al. Supplementation with Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 mixture improves immunity in elderly humans (over 75 years) and aged mice. Nutrition (Burbank, Los Angeles County, Calif). 2019;63-64:184–192. doi:10.1016/j.nut.2019.02.005.

 PubMed Web of Science ®Google Scholar

Dardmeh F, Alipour H, Gazerani P, van der Horst G, Brandsborg E, Nielsen HI, Fam B. Lactobacillus rhamnosus PB01 (DSM 14870) supplementation affects markers of sperm kinematic parameters in a diet-induced obesity mice model. Plos One. 2017;12(10):e0185964. doi:10.1371/journal.pone.0185964.

 PubMed Web of Science ®Google Scholar

Barbonetti A, Cinque B, Vassallo MR, Mineo S, Francavilla S, Cifone MG, Francavilla F. Effect of vaginal probiotic lactobacilli on in vitro–induced sperm lipid peroxidation and its impact on sperm motility and viability. Fertil Steril. 2011;95(8):2485–8. doi:10.1016/j.fertnstert.2011.03.066.

 PubMed Web of Science ®Google Scholar

Valcarce DG, Genovés S, Riesco MF, Martorell P, Herráez MP, Ramón D, Robles V. Probiotic administration improves sperm quality in asthenozoospermic human donors. Benef Microbes. 2017;8(2):193–206. doi:10.3920/BM2016.0122.

 PubMed Web of Science ®Google Scholar

Poutahidis T, Springer A, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE, et al. Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice. Plos One. 2014;9(1):e84877. doi:10.1371/journal.pone.0084877.

 PubMed Web of Science ®Google Scholar

Song C, Peng W, Yin S, Zhao J, Fu B, Zhang J, Mao T, Wu H, Zhang Y. Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Sci Rep. 2016;6(1):35165. doi:10.1038/srep35165.

 PubMedGoogle Scholar

Wang P, Gao J, Ke W, Wang J, Li D, Liu R, Jia Y, Wang X, Chen X, Chen F, et al. Resveratrol reduces obesity in high-fat diet-fed mice via modulating the composition and metabolic function of the gut microbiota. Free Radic Biol Med. 2020;156:83–98. doi:10.1016/j.freeradbiomed.2020.04.013.

 PubMed Web of Science ®Google Scholar

Anderson EM, Rozowsky JM, Fazzone BJ, Schmidt EA, Stevens BR, O’Malley KA, Scali ST, Berceli SA. Temporal dynamics of the intestinal microbiome following short-term dietary restriction. Nutrients. 2022;14(14):14. doi:10.3390/nu14142785.

 Web of Science ®Google Scholar

Fraumene C, Manghina V, Cadoni E, Marongiu F, Abbondio M, Serra M, Palomba A, Tanca A, Laconi E, Uzzau S, et al. Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. Gut Microbes. 2018;9(2):104–114. doi:10.1080/19490976.2017.1371894.

 PubMed Web of Science ®Google Scholar