From gut to gamete: how the microbiome influences fertility and preconception health

The time is now to integrate microbiome science into reproductive medicine. We propose three immediate priorities for the field: First, establish rigorous standards for causality using our proposed framework to move beyond correlative studies. Second, develop longitudinal cohort studies that monitor microbiome-reproduction interactions, with a focus on key developmental periods. Third, establish interdisciplinary research networks that integrate expertise in microbiology, reproductive biology, nutrition, immunology, and clinical medicine to accelerate the translation of findings. As evidence accumulates, several practical steps can help bridge the gap between research and clinical care. Fertility specialists can collect more detailed dietary and antibiotic histories during consultations, with a particular focus on fiber intake and other nutritional factors known to influence the microbiota. Clinicians may also advise patients planning to conceive to adopt microbiota-directed complementary diets several months in advance, with the caveat that while such strategies are biologically plausible and low-risk, they have not yet been validated through clinical trials to improve fertility outcomes. To advance from current knowledge to validated interventions, we recommend focusing on (1) prospective cohort studies tracking individuals from preconception through pregnancy; (2) randomized controlled trials testing microbiome-targeted dietary interventions on reproductive outcomes; and (3) development of validated biomarkers linking microbial function to oocyte quality and fertility potential. Achieving these goals will require strong interdisciplinary collaboration among reproductive endocrinologists, microbiome scientists, nutrition researchers, immunologists, and systems biologists to translate emerging insights into actionable clinical protocols.

Researchers first discovered a link between gut microbiota and reproduction when they observed that germ-free mice had smaller litter sizes [ 86 ]. This phenotype was reversed by accidental bacterial contamination of the isolators, where germ-free mice are typically maintained under axenic conditions [ 86 , 87 ]. Subsequent studies in multiple species, including flies, mosquitoes, nematodes, and honeybees, have shown that the loss of commensal intestinal bacteria prevents the onset of sexual maturity [ 88 – 95 ]. These processes are reversible with the reintroduction of commensal bacteria. Almost half a century after the initial observation in germ-free mice, our group discovered that germ-free female mice also exhibit hallmarks of accelerated reproductive aging, including depletion of the primordial follicle pool, which constitutes the ovarian reserve, excessive collagen buildup, and a shortened reproductive lifespan, ultimately leading to secondary infertility [ 64 ]. Although germ-free mice are born with normal numbers of primordial follicles, primordial follicle loss begins to occur rapidly during the weaning transition, a conserved period of maturation during which the microbiota shifts from milk-associated to solid food-associated communities [ 96 ]. This weaning transition represents a crucial window of rapid expansion in the diversity of microbiota and microbial genes, which are necessary for producing metabolites that have lasting consequences for epigenetic programming, immunity, metabolism, and health outcomes [ 97 – 101 ]. Together with reports on microbiota functions in other developmental processes, such as sexual maturity and aging [ 102 – 104 ], these findings suggest that microbiota play previously underexplored roles in regulating the timing of key life stages in their hosts, with significant implications for ovarian biology and reproductive medicine. They also raise an important question: how do environmental factors influence the crosstalk between the intestinal microbiota and ovarian tissue? One key example is Western dietary patterns, which disrupt the gut microbiota by altering microbial composition and reducing the production of key metabolites, including SCFAs. These microbial changes occur before obesity-induced ovarian dysfunction, including oocyte lipid accumulation, mitochondrial impairment, oxidative stress, disrupted meiosis, decreased fertilization rates, subfertility, poorer embryo quality, and weaker responses to superovulation during in vitro fertilization [ 105 , 106 ]. Diet-induced changes in the microbiota can occur even without obvious obesity or insulin resistance [ 45 , 49 , 107 , 108 ]. This work further highlights the limitations of body mass index, which is widely used to determine eligibility for fertility treatment and to guide clinical decisions [ 109 , 110 ], as a marker of reproductive health. For instance, metabolically healthy individuals with obesity (as defined by BMI) might have normal reproductive function, while those with a normal BMI may experience metabolic dysfunction that affects fertility [ 111 , 112 ]. It also suggests that dietary modifications that affect the microbiota and its metabolites, rather than just lowering calorie intake, may be crucial for improving oocyte quality and fertility. Intriguingly, colonizing germ-free mice with intestinal microbiota during the weaning transition is sufficient to rescue the premature ovarian aging phenotype we have observed [ 64 ], as is treatment with microbial-derived SCFAs alone [ 64 ], pointing to a direct, metabolite-mediated pathway through which the intestinal microbiota can influence ovarian longevity, independent of systemic metabolic status. Antibiotic exposure is another significant disruptor of the microbiota with effects on reproductive health outcomes. Broad-spectrum antibiotics have a potent impact on gut microbiota, resulting in decreased microbial diversity, reduced SCFA availability, and dysbiosis with damaging effects on host immune and metabolic processes [ 113 ]. Some human studies have linked preconception exposure to antibiotics with increased interaction effects with oral contraceptives, risk of infertility, miscarriage, and congenital anomalies [ 113 – 115 ]. However, some caution is necessary when interpreting these results, as (chronic) antibiotic use may be indicated for unrelated comorbid health conditions that can have unintended reproductive consequences.

Despite significant technological progress in reproductive medicine over recent decades, fecundity rates continue to decline worldwide [ 1 – 7 ]. We can now manipulate reproduction at the cellular and molecular levels in ways that were previously impossible, including freezing oocytes for decades [ 8 , 9 ], genetically screening embryos for chromosomal abnormalities [ 10 , 11 ], and even editing disease-causing variants using CRISPR technology [ 12 – 14 ]. These innovations have transformed the available menu of fertility treatments for patients, but they have not addressed the primary determinant of female fertility: the ovarian reserve [ 15 , 16 ]. This finite pool of primordial follicles is established before birth and represents a woman’s total reproductive potential [ 17 – 19 ]. Throughout life, primordial follicles are continuously recruited, activated, and depleted, a process that is inevitable but varies significantly between individuals [ 20 , 21 ]. Environmental factors, such as diet, toxicant exposure, antibiotics, and stress, can influence the rate of follicle depletion, but our understanding of which factors are essential and how they exert their effects remains limited [ 22 – 25 ]. The consequences of this incomplete understanding are clear in clinical trials focusing on obesity-related fertility complications, which show a puzzling paradox: weight-loss interventions improve cardiovascular and metabolic health but, in most cases, fail to improve fertility outcomes and may even increase the risk of adverse pregnancy outcomes [ 26 – 30 ]. This gap between systemic and reproductive health suggests that we are still missing key factors that connect environmental influences on ovarian biology. We propose that the microbiome is one such missing link. The microbiota—referring to the trillions of microorganisms living in and on our bodies—produces tens of thousands of bioactive metabolites that regulate essential aspects of host physiology, effectively representing the critical link between diet, metabolism, immunity, and health outcomes [ 31 – 37 ]. While these microbial communities are influenced by age, genetics, environment, and lifestyle factors, diet stands out as the most direct and modifiable factor shaping their composition, function, and activity [ 38 – 43 ]. Within days, dietary changes can alter microbial community structure and metabolite production, particularly short-chain fatty acids (SCFAs) [ 41 , 42 , 44 ]. This rapid responsiveness has profound implications: Western nutritional patterns that are high in fat and ultra-processed foods but low in fiber disrupt the intestinal microbiota, reducing SCFA production and triggering intestinal permeability and low-grade inflammation even before weight gain occurs [ 43 , 45 – 49 ]. These microbiome-mediated effects may help explain why lifestyle interventions focused on caloric restriction, rather than diet composition and quality, often fail to improve fertility outcomes despite improving metabolic health [ 28 , 29 , 50 , 51 ]. Given its sensitivity to external inputs and its systemic reach, the gut microbiome is uniquely positioned to influence reproductive physiology. Distinct gut microbial signatures characterize women with reproductive disorders, including primary ovarian insufficiency (POI) [ 52 ], polycystic ovarian syndrome (PCOS) [ 53 , 54 ], decreased ovarian reserve [ 55 ], endometriosis [ 56 ], and early menopause [ 57 , 58 ], who exhibit alterations in gut microbiota composition and function. Such gut microbial imbalances (dysbiosis) are also associated with infertility [ 59 , 60 ], poor responses to assisted reproductive technologies [ 55 ], recurrent implantation failure [ 59 ], and adverse pregnancy outcomes [ 61 ]. Animal studies have demonstrated that the gut microbiota and its metabolites influence both the quantity and quality of oocytes [ 62 – 65 ], as well as the modulation of cisplatin-induced POI to help preserve fertility [ 66 ]. While cervicovaginal and endometrial microbiota undoubtedly influence reproductive outcomes and have been extensively reviewed elsewhere [ 67 – 71 ], this commentary focuses on the gut microbiome, which has received less attention despite its potential for systemic effects through dietary and nutritional strategies [ 35 , 39 , 41 , 72 – 74 ]. This expanding body of evidence suggests that the gut microbiome represents a mechanistic link connecting environmental influences on reproductive health. Thus, in this commentary, we review existing evidence linking gut microbial communities to reproductive outcomes, propose mechanisms of microbial dependence, and set standards for establishing causality in this emerging field. We also emphasize the importance of timing, context, and model selection in evaluating host-microbiota interactions during the preconception period and their impact on fertility, as well as how to apply basic research to translate these findings into clinical practice. We propose that integrating microbiome science into reproductive medicine presents a unique opportunity to reconceptualize fertility not just as an isolated endocrine process but as one intricately embedded within a broader ecological system. As the field advances, a unified framework for research will be crucial to unlock these possibilities and bridge the gap between systemic and reproductive health. The same experimental challenges and conceptual questions arise in other fields of microbiome research, including metabolism [ 75 ], immunity [ 42 , 76 ], neuroscience and neuropsychiatry [ 77 – 81 ], and oncology [ 82 – 85 ]. By framing sufficiency, necessity, specificity, and timing within the context of reproductive biology, we aim to provide a transferable blueprint that can guide discovery across different organ systems.

As interest in the role of the microbiota in reproductive outcomes continues to grow, this emerging field must develop the criteria needed to establish microbial causation. These standards are already in place in many other fields [ 177 – 183 ], and we draw inspiration from them to create a framework specifically designed for reproductive biology (sufficiency, necessity, specificity, timing, and mechanism). This framework is particularly crucial as clinical tests used in infertility care without proper validation can lead to misdiagnosis, unnecessary interventions, and increased emotional and financial burden for patients. First, model selection influences interpretations. Germ-free mice are a powerful model for demonstrating the effects of microbiota; however, they exhibit inherent reproductive deficits, including accelerated follicle loss and a shorter reproductive lifespan [ 38 ]. Using these models without proper controls risks circular reasoning. For example, transplanting microbiota from patients with reproductive pathologies like POI or PCOS into germ-free mice may produce disease-like traits. We might interpret this as evidence that the microbiota causes the reproductive disorder. However, this reasoning is circular, as reproductive phenotypes in germ-free mice could arise from two sources: (1) the baseline reproductive deficits inherent to the germ-free state itself, or (2) the specific effects of the transplanted microbiota. Without proper controls, we cannot distinguish between these possibilities. For instance, if both the microbiota of healthy donors and PCOS patients exhibit similar reproductive deficits when transplanted into germ-free mice, this would suggest that the issue lies with the germ-free model rather than the disease-associated microbiota. This distinction is key: showing microbiota influences a particular endpoint or phenotype is different from proving they cause disease. Rigorous experimental design includes multiple controls, such as conventionally raised mice and gnotobiotic mice that are colonized with known, defined microbial communities, as well as detailed baseline phenotyping to differentiate host susceptibility from microbial causation. Second, timing is crucial in depletion and reconstitution experiments. Microbial signals May have different effects before versus after conception or during critical windows of reproductive, immune, or endocrine development. Antibiotic-based depletion studies, which investigate the role of the microbiome by disrupting or reducing microbial populations with broad-spectrum antibiotics, can help determine microbial necessity and sufficiency. Recolonization methods help establish sufficiency, but both must consider the unique timing of female reproductive transitions and microbial signaling. For example, mouse strains exhibit differences in the rate of follicle depletion, which is further compounded by age; pubertal mice Maintain a larger ovarian reserve than 6-month-old mice that have undergone repeated ovulations and significant follicle loss. Initiating antibiotic depletion in older mice thus involves assessing the effects of microbes on an already diminished reserve, potentially missing critical preservation mechanisms that operate earlier in life (e.g., developmental programming of follicle survival pathways, early immune-ovarian crosstalk). Defined consortia, such as the altered Schaedler flora [ 184 ] or Oligo-Mouse Microbiota [ 185 ], provide tractable systems. These simplified, well-characterized microbial communities enable researchers to manipulate microbial composition with precision, reduce biological variability, and more easily link specific microbial signals to host outcomes. This approach could be beneficial for teasing out complex interactions in reproductive biology, where both host physiology and microbial ecology undergo changes over time. Regardless of the approach used—whether germ-free, antibiotic-depleted, or gnotobiotic models—reproductive outcomes must be measured explicitly and rigorously. Variables such as estrous cyclicity, hormone levels, follicle counts, ovulation patterns, and oocyte quality provide critical context for interpreting the effects of the microbiome on fertility. Without directly assessing these endpoints, studies risk overgeneralizing or missing reproductive-specific phenotypes, limiting both mechanistic insight and translational potential. Third, human studies must focus on timing and context as important a priori factors. Most microbiome research involving humans is retrospective or cross-sectional and usually includes patients who are already diagnosed. These approaches limit the ability to draw causal conclusions and make it hard to determine whether changes are causes or effects. We advise against overinterpreting fecal microbiota transplantation (FMT) from clinical donors into germ-free mice as evidence of causality. While FMT can reveal whether a disease-associated microbiota can transfer specific phenotypes to a recipient, it cannot disentangle the contributions of underlying host factors, comorbidities, or environmental exposures that may have shaped the donor microbiome in the first place. Moreover, germ-free mice are not immunologically or hormonally identical to humans, and their responses to human-derived microbiota may reflect exaggerated or artificial effects. Without appropriate controls and contextual understanding, these models risk reinforcing associations rather than revealing actual mechanisms. To advance the field, we advocate for longitudinal, prospective studies that track microbiome changes in individuals before the onset of reproductive dysfunction. Populations at elevated risk, such as daughters of women with reproductive disorders, adolescent girls with menstrual irregularities, or patients pursuing fertility preservation for non-infertility indications, offer unique windows for observing how microbial shifts might precede or predict reproductive decline. These designs are better positioned to identify early microbial signatures of disease, uncover modifiable risk factors, and lay the groundwork for preventive interventions. Crucially, embedding microbiome assessments into fertility care pathways and life course studies may help reframe reproductive aging as not only hormonally driven but also ecologically shaped. Fourth, studies must link microbial signatures to functional outputs and their target cells in reproductive tissues. Relying solely on microbial relative abundance offers a limited understanding of the mechanisms involved. Instead, functional outputs of the microbiota are more likely to mediate direct effects on reproductive physiology. Integrated multi-omic methods, including transcriptomics, metabolomics, and in vitro assays, can connect microbial signals to specific cellular responses. Stable isotope tracing provides an additional layer by directly tracking microbial metabolites in ovarian tissues and mapping their incorporation into host metabolic or epigenetic pathways. We propose that novel insights into mechanisms will arise when specific microbial products are associated with changes in inflammation, endocrine signaling, mitochondrial function, or fibrosis within relevant ovarian cell types, such as oocytes, granulosa cells, stromal cells, or immune populations. Such granularity is necessary for identifying which microbial signals interact with specific host targets to influence reproductive outcomes.

Having established that microbiota influences female reproductive outcomes, the mechanistic pathways that may link intestinal microbiota to ovarian function warrant examination. The influence of microbes on immune populations in tissues, such as the intestinal tract, is well-documented, and the microbiota and its metabolites may also shape the ovarian tissue immune compartment. Once touted as an immune-privileged site [ 116 ], recent single-cell analyses revealed that the ovary maintains a dynamic immune environment that includes infiltrating and tissue-resident macrophages, monocytes, neutrophils, dendritic cells, CD4⁺ and CD8⁺ T cells, γδ T cells, mucosal-associated invariant T cells (MAIT), innate lymphoid cells (ILCs), natural killer (NK) cells, and B cells [ 117 – 126 ]. These populations are part of a somatic cellular network that includes granulosa and stromal cells, which control follicle development, ovulation, and luteal remodeling [ 127 – 132 ]. This immune landscape also changes with age, as the number of inflammatory cells accumulates in the ovaries and the surrounding adipose tissue [ 117 , 133 , 134 ]. These changes are thought to contribute to follicular dysfunction and eventual age-related ovarian fibrosis. It is important to note that work in other tissues has shown that the microbiota influences these immune populations in some capacity, including IL-17-producing effector T cells and regulatory T cells [ 135 – 138 ], as well as ILCs, NK cells, and MAIT cells [ 139 – 141 ]. However, whether the ovarian immune compartment similarly depends on microbial signals remains unexplored, representing a fundamental gap in our understanding of ovarian-microbiome crosstalk. Germ-free mice show disrupted follicle quiescence gene expression before significant follicle loss occurs [ 64 ], suggesting that microbial signals influence transcriptional networks that regulate follicle quiescence, activation, and atresia [ 64 ]. Transcriptomic analyses reveal that genes related to SCFA transporter activity are altered in germ-free ovaries [ 38 ]. This suggests that the ovary may directly sense and respond to SCFAs, but further validation is required. SCFAs act as key mediators of host-microbe communication [ 40 , 142 ], primarily influencing gene expression through two mechanisms: (1) binding to G protein-coupled receptors (GPR41, GPR43, GPR109A) to initiate signaling pathways that regulate cellular metabolism, inflammation, and hormone secretion, and (2) inhibition of class I and IIa histone deacetylases (HDACs), which increases chromatin accessibility [ 143 – 146 ]. Stable isotope tracing has confirmed that microbe-derived substrates are incorporated into histone tails, demonstrating direct epigenetic modification [ 147 – 153 ]. In immune contexts, microbial-derived SCFAs promote the growth and activity of regulatory T cells through similar mechanisms [ 113 – 115 ]. While SCFAs promote cell cycle arrest and quiescence through histone deacetylase inhibition in other tissues [ 102 – 104 ], whether this specific pathway operates in the ovary to maintain follicle quiescence remains to be determined. This represents a critical knowledge gap in understanding how microbial metabolites contribute to preserving ovarian reserve. While transcriptional and immune mechanisms await confirmation in ovarian tissue, the microbial regulation of reproductive hormones offers more established links. One of the best-known roles of the intestinal microbiota is the recycling and recirculation of estrogens. Specific bacterial species, such as Bacteroides thetaiotaomicron , Phocaeicola vulgatus , and Clostridium perfringens , produce β-glucuronidase enzymes that deconjugate estrogens in the gut, allowing for their reabsorption and subsequent return to the systemic circulation [ 154 , 155 ]. This “estrobolome” influences circulating estrogen levels and has been linked to conditions like PCOS, endometriosis, and early menopause [ 156 , 157 ]. Elevated fecal β-glucuronidase activity correlates with higher serum estradiol and testosterone levels in women with PCOS [ 158 ]. Commensal microbes also impact neuroactive steroid levels, including the synthesis and metabolism of progesterone derivatives, such as allopregnanolone [ 159 , 160 ]. Recent research has identified Eggerthella lenta and Gordonibacter pamelaeae as microbial producers of allopregnanolone from glucocorticoids via a hydrogen-dependent 21-dehydroxylation pathway, demonstrating that commensal bacteria can produce bioactive progestins in vivo [ 159 , 160 ]. Stable isotope tracing and infusion studies demonstrate that microbial-derived SCFAs build up in regions of the hypothalamus responsible for regulating fertility, reproduction, and pregnancy [ 161 ]. Whether these metabolites play a causal role in regulating the hypothalamic circuits that control fertility and reproduction remains to be investigated [ 162 ]. While we have focused on the intestinal microbiota and its impact on ovarian function, it is essential to recognize that other microbial niches also play crucial roles in reproductive health. The cervicovaginal and endometrial microbiota have a significant impact on fertility and pregnancy outcomes [ 163 – 165 ]. Reproductive niches dominated by Lactobacillus , particularly L. crispatus , have been associated with higher rates of embryo implantation and live births after in vitro fertilization. In contrast, women with Lactobacillus -depleted or anaerobe-rich communities have increased rates of poor IVF response, failed embryo transfer, and miscarriage [ 67 , 166 – 170 ]. A systematic review and meta-analysis of 25 studies confirmed this pattern, showing an 18% lower pregnancy rate and a 50% higher risk of early pregnancy loss in women harboring a non-optimal cervicovaginal microbiota [ 171 ]. However, results on live births were inconsistent [ 171 ]. In the first multicenter randomized placebo-controlled IVF trial, women with non-optimal cervicovaginal microbiota dominated by Gardnerella and Fannyhessea received 7 days of oral clindamycin followed by intravaginal L. crispatus  CTV 05 (LACTIN V), clindamycin alone, or double placebo [ 172 ]. None of the treatment arms showed improvement in any IVF endpoint compared with the placebo, including hormone levels, implantation rates, pregnancy rates, live birth rates, perinatal outcomes, or safety indices [ 172 ]. The investigators noted that approximately one-quarter of participants had already shifted to Lactobacillus dominance before randomization, and more than one-third of the placebo group exhibited a spontaneous transition toward Lactobacillus dominance by the time of embryo transfer [ 172 ]. Thus, the authors recommend that future trials enroll women with persistent non-optimal communities at the time of transfer and analyze both vaginal and endometrial niches to test mechanism-based therapies [ 172 ]. Emerging evidence also suggests that the paternal microbiome may influence fertility and offspring health by affecting sperm quality and epigenetic programming [ 173 – 176 ], highlighting another critical area for future research. These diverse microbial influences underscore the need for comprehensive approaches to understanding microbiome–reproduction interactions.

Dietary interventions hold great promise For improving fertility and reproductive outcomes. Recent work has shown that a plant-based diet, which involves doubling fiber intake and eliminating ultra-processed Foods, leads to significant changes in gut microbiota within 4 days, characterized by fewer pro-inflammatory taxa and increased SCFA production compared to a calorie-matched control diet [ 186 ]. These shifts are accompanied by clinical improvements, including weight loss, a 17% reduction in LDL cholesterol, a 14% decrease in inflammatory markers, and improved glucose control [ 186 ]. These effects are eliminated within weeks of participants returning to their pre-intervention dietary habits [ 186 ], suggesting that continued compliance is likely required to sustain microbiota-driven improvements in reproductive and metabolic health. In contrast, although calorie-restricted diets can improve weight and metabolic markers, patients often start by reducing their intake of carbohydrate-rich foods. This inadvertently reduces dietary fiber because it eliminates sources of microbiota-accessible carbohydrates, which in turn decreases the production of beneficial microbial metabolites [ 187 – 189 ]. Food processing, regardless of caloric content, promotes metabolic dysfunction, with ultra-processed diets leading to weight gain compared to unprocessed diets, even when the calorie content is matched [ 190 ]. Emphasizing high-protein intake during caloric restriction can also cause colonic fermentation to shift from saccharolytic to proteolytic processes, resulting in the overproduction of metabolites that are detrimental to colonic health, such as phenolic compounds and N-nitroso compounds [ 191 ]. Relying on ultra-processed “diet” foods and artificial sweeteners during calorie restriction may further disrupt the microbiome [ 192 , 193 ]. These findings reinforce an important concept that “a calorie is not a calorie” when it comes to its biological effects [ 50 , 194 ], suggesting that food quality and processing may influence reproductive outcomes through microbiome-mediated mechanisms. Additionally, the impact of dietary approaches may vary depending on the reproductive outcome being targeted, the timing of the intervention, and the specific population studied. Indeed, it is essential to distinguish between interventions that aim to preserve oocyte quantity (i.e., the ovarian reserve) and those designed to improve or maintain oocyte quality, as these rely on distinct biological processes and require different timing strategies. Animal studies have identified early-life windows, such as the weaning period and the onset of puberty, as critical periods when the pool of primordial follicles appears to be especially sensitive to microbial and dietary cues. While the exact timing may differ in humans, analogous critical windows likely include early childhood dietary transitions (ages 2–5) [ 96 , 97 , 195 – 197 ], the pubertal period [ 198 , 199 ], and adolescence [ 200 ], representing periods when both the microbiome and reproductive system undergo significant developmental changes. Since this follicle pool is non-renewable once depleted, early interventions may be key for preserving long-term ovarian reserve. In contrast, oocyte quality may remain modifiable beyond these early developmental windows. Folliculogenesis and the maturation of high-quality oocytes require sustained metabolic and hormonal support, which occurs over several months [ 201 ]. In contrast, the microbiome can shift within days in response to nutritional changes. Therefore, interventions with microbiota-directed complementary foods might need to be sustained over extended periods to support the full duration of the follicular maturation process. Filling critical knowledge gaps—such as identifying the key microbial metabolites and their mechanisms of action—will be essential to optimizing the design, timing, and personalization of these interventions.

Ultimately, the microbiome offers a powerful, systems-level lens through which to understand and improve reproductive health by linking diet, immunity, metabolism, and hormonal signaling. Going forward, targeted investment in basic and translational research, the development of standardized tools and protocols, and the training of a new generation of interdisciplinary scientists will be essential to realizing this potential. We anticipate that the rigor and mechanistic focus advocated in this commentary will accelerate the transition from correlation to causation, not only in reproductive medicine but also in cardiovascular disease, metabolic disorders, neurologic conditions, cancer, and other fields exploring how microbial communities and their metabolites impact health and disease.