Microbiota-Host Interactions in Perimenopausal Syndrome: Mechanisms and Therapeutic Strategies (Review).

As individuals develop and age, the dominant microbial communities in the human gut undergo dynamic shifts. Cross-sectional studies have shown that the composition of the gut microbiota evolves in distinct stages with age, characterized by a significant post-weaning decline in Actinobacteria abundance that persists throughout life and a marked increase in Bacteroidetes and Proteobacteria in old age. 31 Interestingly, these age-related microbial changes in women are closely linked to menopausal status. Compared to premenopausal women, postmenopausal women generally exhibit reduced alpha diversity in their gut microbiota, with increased abundance of Odoribacter and Bilophila at the genus level, and a relative decrease in Lachnospira . 22 , 32 , 33 Additionally, postmenopausal women show a reduction in Firmicutes and Roseburia spp., while Bacteroidetes and the toluene-producing genus Tolumonas are excessively elevated. 22 Furthermore, research by Peters et al identified more specific species-level changes: Prevotella marshii and Sutterella wadsworthensis are enriched in postmenopausal women. 23 However, this pattern has not been consistently observed across studies. A systematic review and meta-analysis found that menopause-related changes in alpha diversity and the relative abundance of major phyla varied across cohorts, likely reflecting differences in population characteristics, dietary patterns, the regions sequenced, reference databases, and statistical methods. 32 In the large multiethnic HELIUS cohort, microbiome-based models showed only modest ability to classify menopausal status, and several microbial associations were attenuated after adjustment for age, cardiometabolic factors, and diet. 26 A Brazilian cohort study likewise found that hormonal and metabolic changes during the menopausal transition were accompanied by significant alterations in the fecal microbiome, particularly in the abundance of Clostridium . 34 Collectively, these findings substantiate a correlation between the progression of reproductive aging and alterations in the gut microbiota. More importantly, the difference in intestinal microbiome structure is closely related to the specific disease state, especially in PMS, which shows significant characteristics ( Table 1 ). During this period, estrogen levels fluctuate substantially, while FSH levels generally increase. 35 Direct studies in symptomatic perimenopausal women remain limited and should be distinguished from broader comparisons of premenopausal and postmenopausal populations. In a Chinese cross-sectional study of 77 women with menopausal syndrome and 24 menopausal women without the syndrome, median FSH was 68.46 versus 7.91 IU/L, luteinizing hormone was 37.33 versus 5.45 IU/L, and estradiol (E 2 ) was 51.65 versus 216.50 pmol/L, respectively. 24 LEfSe analysis identified 14 differentially abundant species (linear discriminant analysis threshold >2). Aggregatibacter segnis, Bifidobacterium animalis , and Acinetobacter guillouiae were depleted in symptomatic women and correlated with sex-hormone indices. Acinetobacter guillouiae showed the strongest reported positive correlation with E 2 (r=0.253, p=0.018), whereas Bifidobacterium animalis showed the strongest negative correlations with FSH (r=−0.302, p=0.004) and luteinizing hormone (r=−0.276, p=0.009). 24 This suggests that the onset and progression of PMS may be significantly associated with specific alterations in the gut microbiota. A separate study of 44 perimenopausal women stratified by FSH above or below 40 IU/L found no significant alpha- or beta-diversity difference but reported lower Faecalibacterium, Subdoligranulum, Agathobacter , and unclassified Lachnospiraceae in the high-FSH group. 25 This suggests that the onset and progression of PMS may be significantly associated with specific alterations in the gut microbiota. Table 1 Changes in Gut Microbiota of Perimenopausal Syndrome Sample Source Sequencing Methods Elevated Microbiota Decreased Microbiota References Human 16S RNA gene sequencing – Aggregatibacter segnis, Bifidobacterium animalis and Acinetobacter guillouiae [ 24 ] Human 16S RNA gene sequencing Faecalibacterium, Subdoligranulum, Agathobacter, and unclassified Lachnospiraceae [ 25 ] Virgin Wistar rats 16S RNA gene sequencing The ratio of phyla Firmicutes and Bacteroidetes – [ 36 ] Sprague-Dawley rats 16S RNA gene sequencing - Community diversity [ 37 ] C57BL/6 mice Quantitative real-time PCR assays Bacteroides spp. Akkermansia muciniphila and Clostridium spp [ 38 ] C57BL/6J mice 16S rRNA gene sequencing Bacteroidota and Desulfobacterota Verrucomicrobiota, Proteobacteria, Actinobacteria, Cyanobacteria, Acidobacteia, Actinobacteria, Nitrospirota , and Fusobacteria [ 39 ] C57BL/6J mice 16S rRNA gene sequencing Lactobacillus and Eubacterium ruminantium - [ 40 ] C57BL/6J mice 16S rDNA Sequencing Muribaculaceae, Escherichia-Shigella, Allobaculum, Alloprevptella, Alistipes , and Akkermansia Lactobacillus [ 41 ] C57BL/6N mice 16S rDNA Sequencing The radio of Firmicutes and Bacteroidetes Alpha diversity in fecal samples [ 42 ] C57BL/6 mice 16S rDNA Sequencing - Beneficial lactic acid producing bacteria [ 43 ] C57BL/6 mice 16S rDNA Sequencing - Verrucomicrobia and Tenericutes populations [ 44 ] Sprague Dawley rats 16S rDNA Sequencing The ratio of Firmicutes and Bacteroidetes - [ 45 , 46 ] C57BL/6 mice 16S rRNA analysis of mice feces Phylum- Bacteroidetes , Class- Bacilli , Order- Lactobacillales , Order- Turicibacterales Genus-Coprococcus [ 47 ] Sprague Dawley rats 16S rDNA Sequencing Actinobacteriota, Chloroflexi, Gemmatimonadota , and Streptococcus Coprococcus, Phascolarctobacterium, Turicibacter, Bacteroides and Blautia [ 48 ] Human Determination of Intestinal Flora Blautia obeum, Roseburia faecis, Ruminococcus, Prevotella copri, and Fusicatenibacter saccharivorans Aecalibacterium prausnitzii, Bacteroides , and fecal Bacteroidetes [ 49 ] Sprague Dawley rats 16S rRNA analysis of mice feces Bacteroidetes, Elusimicrobia and Gemmatimonadetes Firmicutes and Verrucomicrobia [ 50 ] C57BL/6J mice 16S rRNA gene Deferribacteres, Proteobacteria and Bacteroidetes Firmicutes [ 51 ] C57BL/6J mice 16S rRNA gene Lactobacillus Desulfovibrionaceae [ 52 ] Changes in Gut Microbiota of Perimenopausal Syndrome Although clinical research evidence remains limited, a small number of preclinical studies have revealed a connection between PMS and the gut microbiota. Studies using rodent models have provided valuable insights into the potential mechanisms of PMS and the development of new therapeutic approaches. To explore the relationship between estrogen deficiency and microbial changes, ovariectomized (OVX) and natural aging models are widely used in preclinical studies of PMS. 53 , 54 In OVX rats, the levels of SCFAs and microbial diversity were reduced, whereas colonic epithelial permeability was increased. 36 , 55 In OVX mouse models, the relative abundances of Actinobacteriota, Clostridium, Dubosiella , and Akkermansia muciniphila were decreased, whereas those of Lactobacillus, Eubacterium ruminantium, Bacteroidia , unclassified Muribaculaceae, Alistipes, Alloprevotella , and unclassified Clostridia were increased. 38–40 Similarly, a rat model of menopause-related aging established by combining OVX with D-galactose injections exhibited increased intestinal epithelial permeability as well as reduced microbial richness and diversity. The model also showed decreased relative abundances of Akkermansia and Bifidobacterium , accompanied by increased relative abundances of Helicobacter, Enterococcus , and Escherichia-Shigella . 37 Collectively, these preclinical findings support a potential association between gut microbial alterations and menopause-related phenotypes and provide a rationale for further investigating microbiota-targeted strategies for PMS prevention and treatment. Notably, a 2026 study using naturally estropausal mice found that transplantation of estropausal microbiota unexpectedly improved several ovarian outcomes in young recipients. 56 This counterintuitive finding argues against assuming that all microbiota associated with reproductive aging are uniformly detrimental. Overall, these findings highlight the close relationship between the gut microbiota and PMS, suggesting that microbiota-targeted interventions may offer promising new strategies for PMS prevention and treatment. Similarly, changes in gut microbiota observed in PMS during preclinical studies are detailed in Table 1 .

Perimenopausal syndrome (PMS) refers to a special period in women around menopause (about 40–55 years old), due to the decline of ovarian function and abnormal fluctuations in estrogen, causing neuro-endocrine dysfunction, leading to a series of syndromes mainly including autonomic nervous system dysfunction and endocrine metabolic disorders. 1 , 2 The main clinical manifestations include menstrual irregularities and vasomotor symptoms, such as hot flashes and night sweats. They also include symptoms of autonomic dysfunction, such as palpitations, insomnia, dizziness, and tinnitus, as well as genitourinary symptoms, including vaginal dryness, dyspareunia, and recurrent vaginal infections. 3 , 4 PMS not only seriously affects the psychological health and quality of life of women in the postmenopausal period, but also increases the risk of diseases such as cardiovascular disease, type 2 diabetes mellitus, and osteoporosis. 5 , 6 Perimenopause encompasses the menopausal transition and extends through approximately the first 12 months after the final menstrual period. 7 Driven by global population aging, the number of women affected by PMS continues to increase. The global population of women aged 50 years or older is projected to reach 1.65 billion by 2050. 8 Epidemiological data indicate that over 80% of women in Europe and North America experience menopausal symptoms, and more than 70% of Chinese women report varying degrees of perimenopausal discomfort. 9 Therefore, how to choose a reasonable and effective interventional treatment for PMS has become the focus of current clinical research. In PMS, ovarian functional decline is the primary factor triggering metabolic changes and clinical symptoms. Excessively low estrogen levels cause imbalances in neurotransmitters, hormones, and cytokines due to dysfunction of the hypothalamic-pituitary-ovarian axis or adrenal glands, representing the most significant cause of symptoms and signs during the perimenopausal period. 10 Currently, hormone replacement therapy is the internationally recognized primary method for alleviating the symptoms of PMS. 11 Although hormone replacement therapy can effectively alleviate symptoms associated with perimenopausal syndrome, its use may increase the risk of breast cancer and venous thromboembolism in some women. 12–14 Therefore, it is crucial to find appropriate intervention methods for clinical PMS. Gut microbiota refers to the collection of microorganisms living in the human intestine, the number of genes it carries is 150 times that of the entire human genome, and it is known as “the second human genome”. 15 , 16 The gut microbiota is composed predominantly of bacteria but also includes fungi, protozoa, and viruses. 17 It is worth noting that the gut microbiota is highly dynamic, and age, gender, and dietary habits can all affect its composition. 18 It is still mainly composed of Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. 19 As a key factor in maintaining the physiological stability of the body, the gut microbiota is widely involved in the host’s digestion and absorption, energy metabolism, immune regulation, and neurotransmitter synthesis. 20 , 21 However, when the intestinal microorganism group is disrupted, the effects of various bacterial populations on the host may change and exhibit different effects in different host environments. Recent advances in microbiome sequencing and multi-omics technologies have broadened understanding of PMS beyond models centered primarily on ovarian hormones. Early metagenomic studies identified compositional and functional differences in the gut microbiota between premenopausal and postmenopausal women. 22 Subsequent population-based studies linked menopause-related microbial alterations, particularly changes in the estrobolome, to sex hormone metabolism and cardiometabolic risk. 23 A case–control study further identified bacterial taxa associated with hormone levels and symptoms in women with menopausal syndrome, although no consistent differences in overall microbial diversity were observed. 24 More recent multi-omics studies have implicated microbial metabolites in estrogen metabolism, immune and inflammatory responses, and gut–brain communication. 25 However, findings from a large, multiethnic cohort study indicated that many menopause-associated differences in the gut microbiota were attenuated after adjustment for age, diet, metabolic factors, and medication use. 26 Preliminary studies suggest that probiotic interventions may modulate gut microbial function; however, the available clinical evidence remains limited. 27 Collectively, these findings support a shift from viewing gut dysbiosis as a simple consequence of estrogen deficiency toward a bidirectional and context-dependent microbiota–host interaction model. Building on the population-based and multi-omics evidence described above, research priorities have gradually shifted. Rather than focusing solely on perimenopause-associated differences in microbial composition, recent studies have increasingly investigated potential bidirectional interactions between the gut microbiota and the host endocrine, immune, and nervous systems. 22–24 , 26 , 28 The estrobolome represents a key functional link between the gut microbiota and host hormonal homeostasis. It comprises a collection of gut microbial genes encoding estrogen-metabolizing enzymes, including β-glucuronidase and β-glucosidase. 23 , 29 Thus, declining ovarian function and fluctuations in sex hormone levels may reshape the gut microbial ecosystem. In turn, changes in the composition and function of the gut microbiota may alter host estrogen metabolism, thereby contributing to a putative bidirectional estrogen–gut microbiota axis. Microbially derived metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, may also influence mood and somatic symptoms in perimenopausal women by modulating intestinal barrier integrity, immune and inflammatory responses, the kynurenine pathway of tryptophan metabolism, and neurotransmitter signaling. 25 , 30 Probiotics, dietary fiber, and other microbiota-targeted interventions may modulate these pathways. 27 , 30 However, clinical studies of these interventions in women with PMS remain limited. Further rigorously designed longitudinal studies and randomized controlled trials are needed to determine their efficacy, identify the populations most likely to benefit, and clarify the underlying microbiota-mediated mechanisms.

Although the gut microbiota holds considerable promise as a therapeutic target, the field continues to face several challenges, including substantial interindividual variability in microbial composition, limited clinical evidence, and a lack of standardized intervention protocols. Systematic synthesis and critical appraisal of the available evidence are therefore essential for identifying future research priorities. Accordingly, this review aims to characterize alterations in the gut microbiota associated with PMS, elucidate the mechanisms through which the gut microbiota may contribute to PMS, critically evaluate the current evidence for microbiota-targeted interventions, and summarize available therapeutic strategies and their limitations. Finally, we outline future research directions to inform the development of gut microbiota–targeted interventions and personalized management strategies for women with PMS.

The gut microbiota may contribute to PMS through interconnected estrogen metabolism, ovarian function, immune–inflammatory, and gut–brain pathways. Although experimental studies support individual links within this network, mechanistic evidence is derived predominantly from OVX and aging animal models and other preclinical systems, whereas human evidence remains largely cross-sectional. Accordingly, the integrated microbiota–estrogen–ovary–immune–brain network has not yet been causally established in women with PMS ( Figure 1 ). Figure 1 Potential mechanisms linking the gut microbiota to perimenopausal syndrome. The schematic integrates four interconnected domains: estrogen metabolism, ovarian function, gut–brain signaling, and immune-inflammatory regulation. Solid arrows indicate mechanistic relationships supported by experimental evidence in the cited studies, whereas dashed arrows indicate proposed links between these domains and PMS that remain predominantly preclinical, associative, or incompletely validated in humans. NLRP3, NOD-, LRR- and pyrin domain-containing protein 3. The schematic illustrates potential mechanisms linking the gut microbiota to perimenopausal syndrome through four interconnected domains: estrogen metabolism, ovarian function, gut–brain signaling, and immune–inflammatory regulation. In the estrogen-metabolism domain, Firmicutes and Prevotellaceae are linked to estrogen recycling and production. In the ovarian-function domain, dietary fiber and high-fat diets are associated with ovarian support and dysfunction, respectively. The gut–brain-signaling domain includes short-chain fatty acids and neurotransmitters, including serotonin and dopamine. The immune–inflammatory-regulation domain depicts relationships among microbial metabolites, the regulatory T-cell/T-helper-17-cell balance, cytokine levels, and NLRP3. Solid arrows indicate mechanistic relationships supported by experimental evidence in the cited studies, whereas dashed arrows indicate proposed links between these domains and perimenopausal syndrome that remain predominantly preclinical, associative, or incompletely validated in humans. Together, these interconnected pathways illustrate the complex potential relationships between the gut microbiota and perimenopausal syndrome. NLRP3, NOD-, LRR- and pyrin domain-containing protein 3. Schematic of potential mechanisms linking the gut microbiota to perimenopausal syndrome. Potential mechanisms linking the gut microbiota to perimenopausal syndrome. The schematic integrates four interconnected domains: estrogen metabolism, ovarian function, gut–brain signaling, and immune-inflammatory regulation. Solid arrows indicate mechanistic relationships supported by experimental evidence in the cited studies, whereas dashed arrows indicate proposed links between these domains and PMS that remain predominantly preclinical, associative, or incompletely validated in humans. NLRP3, NOD-, LRR- and pyrin domain-containing protein 3. The gut–brain axis mediates bidirectional communication between the gastrointestinal tract and the central nervous system and plays an essential role in regulating physiological processes and influencing disease progression. This complex signaling network operates through neural, immune, and endocrine pathways, integrating gut-derived signals with central regulatory mechanisms to modulate brain function, behavior, and physical and mental health. 57 Findings from the Flemish Gut Flora Project in Belgium and an independent cohort showed that several butyrate-producing taxa and the neuroactive potential of the gut microbiota were associated with quality of life and depression, although potential confounding by medication use and host-related factors must be considered. 58 The Rotterdam Study and the HELIUS cohort likewise identified associations between depressive symptoms and specific gut microbial features, and these associations were validated across cohorts. 59 Collectively, these observations highlight potential links between the gut–brain axis, mental health, and quality of life. However, alterations in gut microbial community composition may disrupt this complex bidirectional communication system. 60 Gut microbial dysbiosis has also been implicated in the pathogenesis of several gynecological conditions, including polycystic ovary syndrome, endometriosis, and PMS. 61 During the menopausal transition, ovarian dysfunction and fluctuations in sex hormones may disturb hypothalamic–pituitary–gonadal regulation and alter monoaminergic, γ-aminobutyric acid, and neuropeptide signaling, thereby contributing to hot flashes, sleep disturbance, anxiety, depressive symptoms, and cognitive complaints. 62–64 In a cross-sectional study of 566 perimenopausal women, the mean serum concentrations of serotonin and tryptophan were 151.59 ± 104.01 ng/mL and 13.14 ± 5.58 μg/mL, respectively. Serum serotonin showed a weak but statistically significant inverse correlation with climacteric symptom severity (r = −0.09, p = 0.022), and multivariable analysis further demonstrated an inverse association between serum serotonin levels and symptom severity (β = −0.604, p = 0.005). In contrast, serum tryptophan was not significantly associated with climacteric symptom severity (r = 0.019, p = 0.657). 64 Although peripheral serotonin concentrations do not directly reflect central serotonergic activity, these findings provide quantitative clinical evidence of an association between circulating serotonin levels and perimenopausal symptoms. The gut microbiota may modulate serotonergic signaling through SCFAs, bile acids, tryptophan-derived metabolites, regulation of intestinal barrier integrity, immune–inflammatory signaling, and vagal pathways. Evidence relevant to microbiota-mediated gut–brain interactions in PMS is derived predominantly from preclinical studies. In OVX mice, administration of melatonin at 0.2 mg/mL for 28 days suppressed the expansion of Alistipes inops , restored systemic tryptophan–serotonin metabolism, and reversed depressive-like behavior, supporting a taxon-specific association between microbial tryptophan utilization and neurobehavioral outcomes. 41 Lactobacillus intestinalis YT2 similarly altered gut microbial composition and alleviated depressive-like behavior and cognitive impairment in OVX rats. 65 Quantitatively, supplementation with Limosilactobacillus reuteri JCM 1112 reduced forced swim test immobility time from approximately 214 to 169s, representing a decrease of approximately 21% (p < 0.05), and increased hippocampal brain-derived neurotrophic factor mRNA expression from a normalized value of 1.0 to approximately 2.4 (p < 0.05) in OVX mice. 66 Collectively, these findings support a potential role of microbiota-mediated gut–brain communication in neurobehavioral symptoms associated with perimenopause. However, current evidence is derived predominantly from preclinical studies, and whether these mechanisms contribute to psychiatric symptoms in women with PMS remains to be established. The estrobolome refers to the collection of gut microbial genes involved in estrogen metabolism, particularly those encoding enzymes such as β-glucuronidase and β-glucosidase. 67 , 68 Following hepatic conjugation and biliary excretion of estrogens, microbial β-glucuronidase can deconjugate estrogen conjugates in the intestine, facilitating their reabsorption and thereby contributing to the enterohepatic recycling of biologically active estrogens. 69 , 70 This represents a plausible functional pathway through which microbial activity may influence systemic estrogen exposure. Clinical observations also support an association between menopausal hormonal status and microbial function, although findings regarding microbial composition have not been entirely consistent. Small studies conducted in the United States reported associations between fecal microbial diversity and estrogen metabolites measured in urine or feces. 71 Among postmenopausal women in Ghana, serum estrone and certain hydroxylated or methoxylated estrogens were associated with the Shannon index of the fecal microbiota; however, the direction of these associations varied among metabolites, and overall fecal microbial β-diversity was not significantly associated with most estrogen measures. 72 In addition, a larger US study of 164 healthy postmenopausal women subsequently found that gut microbial diversity was associated with several urinary estrogen metabolism ratios, whereas the Firmicutes / Bacteroidetes ratio was not associated with the estrogen measures. 73 Human studies have identified associations of microbial diversity and estrobolome-related functions with estrogen metabolites, although the direction and magnitude of these associations vary across populations and individual metabolites. 23 Animal studies have also reported compartment-specific alterations in β-glucuronidase activity following ovariectomy. 74 The gut microbiota can influence female sex steroid hormone levels by producing SCFAs, including the abundant metabolites acetate, propionate, and butyrate. Notably, butyric acid has been shown to upregulate E 2 levels in porcine granulosa cells via the cAMP signaling pathway. Interestingly, low concentrations of butyric acid can stimulate progesterone secretion, whereas high concentrations inhibit its secretion. 75 These in vitro findings support a biologically plausible pathway but do not demonstrate that butyrate derived from the diet or gut microbiota reaches concentrations in human ovarian tissue comparable to those used in vitro. Conversely, the gut microbiota is also affected by estrogen levels. Studies have shown that during late menopause, estrogen levels decline rapidly, accompanied by a marked increase in Prevotellaceae , which is negatively correlated with estrogen, although this has not yet been clinically validated. 32 Overall, current evidence supports an association between the gut microbiota and estrogen metabolism, but the directionality and clinical significance of this relationship during the menopausal transition remain uncertain. The ovary is the central reproductive organ in women. During the perimenopausal period, declining ovarian function leads to a reduction in follicle count and a decrease in oocyte quality. Preclinical studies suggest that microbial composition and microbial metabolites can influence follicular development and ovarian reserve. 76 For example, the opportunistic gut pathogen Clostridium innocuum can cause follicular development arrest in female mice. 77 In contrast, Limosilactobacillus reuteri and its metabolite β-resorcylic acid can inhibit granulosa cell apoptosis, protect oocyte function, and enhance ovarian reserve capacity. 78 Similarly, SCFAs, which are metabolic products of the gut microbiota, are critical regulators of female reproductive function and host microbial balance. Research has found a positive correlation between the concentration of SCFAs and follicle development in gilts; SCFAs supplementation can not only improve gut microbiota composition and alpha diversity but also promote follicle maturation. 79 Furthermore, fecal microbiota transplantation (FMT) from young mice can induce a “younger-like phenotype” in aged mice, increasing commensal bacteria and enhancing ovarian cell proliferation. 80 In addition, dietary factors can indirectly affect ovarian function by disrupting intestinal microbiota. Diet plays an important role in the composition, function, and diversity of intestinal microbiota, and various diets have a profound effect on the stability and diversity of intestinal microbiota. 81 Among them, a high-protein diet reduces the beneficial bacteria Lactobacillus and Roseburia , although the direction and magnitude of these changes vary across dietary patterns. 82 Dietary effects on the ovary may therefore be mediated, at least in part, by microbial and metabolic alterations. In mice fed a high-fat diet, an increased abundance of Gram-negative bacteria was associated with elevated circulating endotoxin levels, ovarian infiltration of M1 macrophages, and activation of STAT3 signaling in oocytes, thereby accelerating primordial follicle activation and depletion. 83 Similarly, dietary fiber supplementation increased SCFAs concentrations and melatonin levels in serum and follicular fluid and attenuated high-fat diet-associated follicular atresia. 84 Collectively, these experiments indicate that gut microbes and their metabolites can influence ovarian phenotypes. However, evidence for a microbiota-mediated effect on ovarian function during human perimenopause remains limited, and the relevance of these preclinical findings to PMS requires further investigation. Perimenopause is accompanied by changes in immune tone, but PMS is not itself an autoimmune disease. Declining and fluctuating estrogen levels may affect both innate and adaptive immune function, creating a host environment in which microbial signals and metabolites may modulate inflammatory responses. 85–87 The gut microbiota, as a key regulator of immunity, produces metabolites such as SCFAs, tryptophan, and bile acids that promote the differentiation of regulatory T cells. Among these, bile acids enhance Tregs differentiation while suppressing T-helper17 cell generation, thereby regulating immune homeostasis. 88 Similarly, clinical studies have confirmed that in women with postmenopausal osteoporosis, the number of Proteobacteria and Campylobacterota increases, while the number of Butyricicoccus and Faecalibacterium decreases, the level of Treg cells decreases, and the level of T-helper17 cell increases. 89 Clinical studies have reported associations between inflammatory markers and the menopausal transition or vasomotor symptoms but have not established a causal role for the gut microbiota in these relationships. Mechanistic support has come primarily from animal models. Some clinical studies have reported alterations in circulating cytokine levels in women with PMS, including interleukin-6, interleukin-8, interleukin-4, interleukin-2, and tumor necrosis factor-α (TNF-α). However, these cytokines have distinct immunological functions, and findings have varied across cohorts. 90 , 91 For example, konjac oligosaccharides increased the abundance of Bifidobacterium and restored the Treg/Th17 cell balance in OVX rats. 92 Intestinal microbiota and its metabolites are also involved as important inflammatory regulators. Evidence from polycystic ovary syndrome (PCOS) suggests that Bifidobacterium longum subsp. longum BL21 may reduce the levels of interleukin-6 and TNF-α while increasing interleukin-10. 93 In addition, SCFAs produced by intestinal bacteria decomposing carbohydrates can exhibit anti-inflammatory effects by downregulating pro-inflammatory factors and promoting the production of anti-inflammatory cytokines. 94 Specifically, SCFAs can effectively reduce the levels of proinflammatory factors such as interferon-gamma, interleukin-1β, and TNF-α, while upregulating the levels of anti-inflammatory interleukin-10 and transforming growth factor-β. 95 In addition, indole-3-propionic acid, another anti-inflammatory metabolite, can inhibit the production of pro-inflammatory cytokines. In a PCOS mouse model, indole-3-propionic acid reduced ovarian oxidative stress and inflammatory responses through regulation of the AhR–NLRP3 axis. 96 In aged mice, FMT from young donors increased interleukin-4 levels and reduced interferon-γ levels, 80 providing experimental evidence that manipulation of the gut microbiota can alter inflammatory phenotypes. These findings support the biological plausibility of microbiota–immune interactions in PMS, although their relevance to human symptoms requires confirmation in clinical studies. By contrast, another experimental study found that age-related bone loss occurred to a similar extent in germ-free and colonized mice, regardless of microbiota donor age. 97 This finding indicates that not all menopause-associated phenotypes are necessarily dependent on the microbiota. The relationship between the gut microbiota and PMS may involve a bidirectional microbiota–estrogen–ovary–immune–brain axis. 98–100 Ovarian aging and fluctuations in estrogen levels can alter the composition and metabolic activity of the gut microbiota. 23 , 32 , 101 In turn, microbial β-glucuronidase activity may affect estrogen deconjugation, enterohepatic circulation, and the availability of biologically active estrogens. 102 Microbial metabolites, including SCFAs, bile acids, tryptophan metabolites, and indole derivatives, may also influence immune responses and ovarian function by regulating the Treg/Th17 balance, cytokine production, granulosa cell survival, follicular development, and ovarian reserve. 83 , 103 , 104 These changes may further affect neurotransmitter metabolism and neuroendocrine signaling through the gut–brain axis, thereby contributing to PMS. These processes are unlikely to occur in a simple linear sequence. Declining ovarian function and altered estrogen levels may promote microbial, immune, and neuroendocrine changes, whereas inflammation and abnormal microbial metabolism may further impair ovarian and nervous system function. Diet, psychological stress, reduced physical activity, and medication use may also affect the gut microbiota during the menopausal transition. Gut dysbiosis should therefore not be regarded as the sole cause of PMS but rather as one factor that may link hormonal changes to ovarian dysfunction, inflammation, and altered gut–brain signaling. However, this model has not yet been confirmed in humans. Most mechanistic evidence is derived from animal and in vitro studies, whereas human studies remain predominantly cross-sectional. Future longitudinal and interventional studies should integrate repeated hormone measurements with functional microbiome analyses, metabolomics, and immune profiling to clarify the temporal sequence and directionality of these relationships.

The most clinically actionable recommendations continue to include healthy dietary patterns, regular physical activity, individualized management of menopausal symptoms. Selected strain-specific probiotics are supported by preliminary evidence from randomized trials, but replication is needed in PMS and across ethnically diverse populations. Prebiotics, synbiotics, acupuncture, and standardized traditional formulations are supported by preliminary evidence, whereas FMT and most strategies involving botanical products or metabolites remain at the preclinical or investigational stage. Translating microbiome findings into PMS care presents several challenges. Human studies are often geographically concentrated, small in scale, and limited to assessments conducted at a single time point, whereas animal studies rely heavily on OVX models that do not recapitulate the gradual and fluctuating endocrine transition characteristic of PMS. Reverse causation is also difficult to exclude because diet, sleep, stress, physical activity, medication use, and body composition may change in association with PMS and can themselves reshape the microbiota. Substantial interindividual variability further complicates the identification of stable microbial biomarkers. Future studies should therefore apply standardized menopausal staging and symptom phenotyping, recruit larger and more diverse cohorts, collect longitudinal samples, and prespecify adjustment for diet, body mass index, medication use, antibiotic exposure, and hormone therapy. In preclinical research, several complementary approaches can help determine whether the gut microbiota or its metabolites are necessary for the observed effects. These approaches include depletion of the gut microbiota with antibiotics, the use of animals lacking a microbiota or harboring defined microbial communities, standardized microbiota transfer, and metabolite rescue experiments. In human studies, repeated sampling and adequately powered randomized controlled trials are needed to determine whether microbiome changes precede, mediate, or merely accompany symptom improvement.

Interest in the relationship between the gut microbiota and PMS has grown in recent years, but research has largely focused on individual mechanisms or interventions. Consequently, a systematic understanding of microbiota changes associated with PMS and their clinical significance remains limited. Available evidence suggests that gut microbial composition and function may change with reproductive aging, although findings remain inconsistent. The gut microbiota–estrogen–ovary–immune–brain axis may mediate the progression of PMS. Within this framework, reproductive aging may reshape the gut microbiota, whereas the microbiota or its metabolites may influence hormone levels, immune function, ovarian biology, and neural signaling. Support for this framework comes mainly from clinical associations and preclinical findings. Diet and exercise have a relatively strong evidence base, and selected probiotic strains have shown preliminary clinical promise. Evidence for TCM and acupuncture comes mainly from small clinical trials and preclinical studies, whereas prebiotics, synbiotics, and FMT remain exploratory. Accordingly, the routine use of microbiome data to guide diagnosis or treatment remains premature. Future multicenter studies should use standardized protocols, incorporate integrative omics analyses, and recruit diverse populations to clarify the underlying mechanisms and identify clinically meaningful microbial targets.

A targeted literature search of PubMed and Web of Science was conducted for articles published through July 15, 2026. The following search terms and related terms were used in various combinations: “perimenopause”, “menopausal transition”, “climacteric syndrome”, “gut microbiota”, “gut microbiome”, “estrobolome”, “β-glucuronidase”, “gut–brain axis”, “ovary”, “inflammation”, “probiotics”, “prebiotics”, “synbiotics”, “fecal microbiota transplantation”, “acupuncture”, and “traditional Chinese medicine”. The reference lists of relevant reviews and original studies were also screened. Priority was given to human observational studies and clinical trials; when clinical evidence was limited, high-quality animal and mechanistic studies were included as supplementary evidence.

A range of interventions capable of modifying the gut microbiota have been investigated in relation to menopausal symptoms, including lifestyle interventions, probiotics, prebiotics, synbiotics, FMT, Traditional Chinese Medicine (TCM), and acupuncture. However, evidence that their clinical effects are mediated specifically through the gut microbiota remains limited. The following sections therefore evaluate each intervention with particular attention to the source and strength of the available evidence, its proposed microbiota-related mechanisms, and its current translational limitations. Figure 2 and Table 2 summarize the major interventions and the evidence supporting them. Figure 2 Evidence-stratified overview of microbiota-modulating strategies discussed for perimenopausal syndrome. Level 1 includes lifestyle measures with the broadest supportive clinical evidence, although microbiota mediation of their clinical benefits remains unproven. Level 2 includes probiotics and Traditional Chinese Medicine, for which clinical evidence is emerging but is generally strain-, formulation-, or study-specific and often based on relatively small samples. Level 3 includes prebiotics, synbiotics, fecal microbiota transplantation, and other approaches supported predominantly by preclinical or investigational evidence. The levels represent a narrative summary of evidence maturity rather than a formal grading system, and the schematic is illustrative rather than exhaustive. The figure presents, from left to right, microbiota-modulating interventions, potentially relevant intestinal factors, and potential outcomes in perimenopausal syndrome (PMS). On the left, the interventions are divided into three evidence levels. Level 1 includes exercise and dietary habits. Level 2 includes traditional Chinese medicine and probiotics. Level 3 includes fecal microbiota transplantation, prebiotics, synbiotics, and other approaches. In the center, the figure shows the intestine and a magnified view of the intestinal environment. The labeled factors include intestinal mucosal proteins, short-chain fatty acids, immune cells, gut microbiota, and cytokines. On the right, an arrow points to a female figure representing a woman with PMS. The arrow indicates potential improvement in PMS-related symptoms. Evidence-stratified schematic of microbiota-modulating strategies for perimenopausal syndrome. Abbreviation : PMS, Perimenopausal syndrome. Table 2 Strategies for Targeting Gut Microbiota to Treat Perimenopausal Syndrome Therapy Medication Experimental Subject Major Finding References Lifestyle intervention Cheonggukjang Human Decrease the Kupperman index scores. [ 105 , 106 ] Blackcurrant Human Increase the abundance of Ruminococcus 2 , Decrease bone loss and osteoclastogenic cytokines. [ 107 ] A healthy diet based on seed-rich vegetables Human Improve the brain function of perimenopausal women. [ 108 ] A high-intensity interval training and resistance training Human Modify intestinal microbiota composition. [ 109 ] Fish Oil with Heat Treatment C57BL/6 mice Improve metabolic and insulin sensitivity, Modulate the gut microbiota and inflammation. [ 110 ] Probiotic A probiotic formula containing KABP052 Human Modulate estrogen. [ 27 ] Probiotics and soy isoflavones (SIFs) could C57BL/6N mice Regulate the the intestinal microbiota and serum lipid levels, Enhance SCFAs production and estrogen circulation. [ 42 ] Lactiplantibacillus plantarum ATCC8014 ApoE-deficient mice Elevate the abundances of Allobaculum and Olsenella , Correct BA abnormalities and lipid dysregulation. [ 111 ] Lactobacillus intestinalis YT2 Sprague Dawley rats Alleviate menopausal symptoms, Increase the Firmicutes / Bacteroides ratio and the mRNA levels of tight junction-related markers; Promote gut barrier integrity. [ 65 ] Probiotic therapy Wistar rats Improve a reduction in alveolar bone destruction and intestinal permeability, Increase estradiol levels. [ 112 ] Bacillus coagulans C57BL/6 mice Improve the bone mineral density, bone strength, and bone microarchitecture. [ 43 ] Probiotic Lactococcus lactis P32 and Bifidobacterium bifidum P45 C57BL/6 mice Alleviate postmenopausal symptoms and vaginal/gut microbiota dysbiosis, Suppress RANK/RANKL-mediated NF-κB activation. [ 44 ] Prebiotic Konjac Oligosaccharides Sprague Dawley rats Promote the growth of Bifidobacterium longum , restore Treg/Th17 balance in bone marrow. [ 92 ] Probiotic (Lactobacillus fermentum) and Cauliflower Mushroom β-Glucan Symbiotic Blend Sprague Dawley rats Improve energy, glucose, lipid, and bone metabolism. [ 45 ] Fecal microbiota transplantation Fecal microbiota transplantation C57BL/6 mice Enhance regeneration in vagina and the expression of ESR1 in vaginal cells. [ 47 ] Traditional Chinese Medicine (TCM) treatment Yangyin-ningshen formula C57BL/6 mice Improve serum E 2 level, brain neuronal function and depressive behavior. [ 39 ] Guizhi and Erxian Decoction Sprague Dawley rats Affect hypothalamic preoptic area levels of endothelial nitric oxide synthase and heat shock protein 70, Improve gut microbiota composition and menopausal hot flashes. [ 48 ] Tianwang Buxin Granules Human Regulate the disordered intestinal flora. [ 49 ] Jiangu granule Sprague Dawley rats Restore the abundance of gut microbiota, Increase bone strength and the proportion of Treg cells and the content of SCFAs. [ 55 ] Curcumin Virgin Wistar rats Decrease the abundance of the genera Anaerotruncus and Helicobacter. [ 36 ] Hypericum perforatum L. Sprague Dawley rats Increase the bile acid secretion and the levels of CYP7A1, GPR43, and GPR41. [ 50 ] Traditional Chinese Medicine (TCM) treatment The Effect of Hops (Humulus lupulus L). Extract C57BL/6 mice Protecte against increased visceral adiposity and liver triglyceride accumulation. [ 113 ] Agastache rugosa ethanol extract C57BL/6J mice Increase the expression of RUNX2 and β-catenin, Elevate calcium deposits. [ 51 ] Cinnamic acid C57BL/6J mice Improve bone indices and bone loss, Activate BMP/TGFβ/Smad signaling and osteoblast differentiation. [ 52 ] Hop Extract Standardized in 8-Prenylnaringenin Human Increase the abundance of the genera Turicibacter and Shigella . Improve the bone health of postmenopausal women with osteopenia. [ 114 ] Electroacupuncture Combined with Diet Treatment Human Increase species diversity and the proportions of Klebsiella and Kosakonia , Decease waist circumference, WHtR, WHR, TG, and LDL levels. [ 115 ] Acupoint catgut embedding Human Weight loss, Increase the proportions of Klebsiella and Kosakonia . [ 116 ] Others Low-dose brain estrogen Sprague Dawley rats Improve serum FSH levels and menopausal symptoms. [ 117 ] Isoflavone C57BL/6J mice Increase microbiota diversity and muscle strength Decease gene sets related to TNF-α signaling via NF-κB and the unfolded protein response. [ 118 ] Grape-seed extract C57BL/6J mice Improve intestinal microbiota and obesity. [ 46 ] Trifolium pratense ethanolic extract Sprague Dawley rats Reduce the Firmicutes to Bacteroidetes ratio, Improve serum lipid and cholesterol levels. [ 119 ] Rice Bran C57BL/6 mice Reduce the neuroinflammation in the brain, Increase the number of SCFAs-producing Clostridia. [ 120 ] Abbreviations : RUNX2, Runt-related transcription factor 2; SCFAs, Short-chain fatty acids; FSH, Follicle-stimulating hormone; E 2 , Estradiol; TNF-α, Tumor necrosis factor α; CYP7A1, cholesterol 7α-hydroxylase; GPR43, G protein-coupled receptors; GPR41, G protein-coupled receptors; WHtR, waist-height ratio; WHR, waist to hip ratio; TG, total cholesterol; LDL, low-density lipoprotein; Th17 cell, T-helper17; ESR1, Estrogen Receptor 1; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor -κB ligand; NF-κB, Nuclear factor of κ-light chain of enhancer-activated B cells. Evidence-stratified overview of microbiota-modulating strategies discussed for perimenopausal syndrome. Level 1 includes lifestyle measures with the broadest supportive clinical evidence, although microbiota mediation of their clinical benefits remains unproven. Level 2 includes probiotics and Traditional Chinese Medicine, for which clinical evidence is emerging but is generally strain-, formulation-, or study-specific and often based on relatively small samples. Level 3 includes prebiotics, synbiotics, fecal microbiota transplantation, and other approaches supported predominantly by preclinical or investigational evidence. The levels represent a narrative summary of evidence maturity rather than a formal grading system, and the schematic is illustrative rather than exhaustive. Strategies for Targeting Gut Microbiota to Treat Perimenopausal Syndrome Abbreviations : RUNX2, Runt-related transcription factor 2; SCFAs, Short-chain fatty acids; FSH, Follicle-stimulating hormone; E 2 , Estradiol; TNF-α, Tumor necrosis factor α; CYP7A1, cholesterol 7α-hydroxylase; GPR43, G protein-coupled receptors; GPR41, G protein-coupled receptors; WHtR, waist-height ratio; WHR, waist to hip ratio; TG, total cholesterol; LDL, low-density lipoprotein; Th17 cell, T-helper17; ESR1, Estrogen Receptor 1; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor -κB ligand; NF-κB, Nuclear factor of κ-light chain of enhancer-activated B cells. A reasonable dietary pattern and the use of nutritional supplements can help regulate the homeostasis of the intestinal microbiota and promote the production of beneficial metabolites, 121 laying the foundation for alleviating menopausal symptoms. 122 Studies have found that fermented foods can change the intestinal microbiota and promote positive changes in the intestinal environment, 123 especially in the prevention and treatment of PMS. In a clinical study, the Korean fermented soybean product (Cheonggukjang) can increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and significantly reduce the Kupperman index score. 105 Traditional soybean paste (Korean soybean paste) is more effective than commercial soybean paste. 106 Plant-based diets can also effectively improve the symptoms of PMS. 107 In an aging rat model, tea polyphenols ameliorated memory decline while modulating gut microbiota dysbiosis and brain TLR4/NF-κB inflammatory signaling. 37 Furthermore, a plant-based diet (a seed-rich vegetable diet) has been shown to improve cognitive function during perimenopause by increasing the abundance of the intestinal phyla Synergistetes and Verrucomicrobia , which are positively correlated with autonomic neural activity, and enhancing visual-spatial or executive function. 108 Dietary modification may serve as a low-risk adjunctive strategy. However, no menopause-specific, microbiota-targeted diet has been established, and microbial mediation of symptom improvement remains unproven. Regular exercise can enhance the growth of beneficial bacteria and the production of SCFAs, which are essential for metabolic and immune health. 124 In postmenopausal women, high-intensity interval training and resistance training did not significantly change the α diversity of fecal microbiota, but it regulated β diversity, while reducing visceral fat and increasing muscle mass, effectively alleviating obesity. 109 However, the small sample size of this trial and the high inter-individual variability in fecal microbiota composition make it difficult to determine the potential crosstalk between intestinal microbiota and adipose tissue after the training program. Subsequent large-sample, multi-center, standardized clinical trials are needed for verification. However, given the absence of large-scale trials, the potential of exercise as an economical microbiota-targeted strategy for PMS remains to be validated. Probiotics are beneficial active microorganisms that can change the composition of the microbiota in specific parts of the host and are closely related to estrogen levels. 125 , 126 In an exploratory randomized, double-blind, placebo-controlled trial, participants received a three-strain formulation containing Levilactobacillus brevis KABP052, Lactiplantibacillus plantarum KABP051, and Pediococcus acidilactici KABP021 in a 2:1:1 colony-forming unit ratio. Each daily capsule provided at least 1 × 10 9 colony-forming units for 12 weeks. 27 KABP052 was selected for its β-glucuronidase activity. At week 12, the mean serum E 2 concentration was 31.62 ± 7.97 pg/mL in the probiotic group compared with 25.12 ± 8.17 pg/mL in the placebo group, whereas the corresponding estrone concentrations were 21.38 ± 8.57 and 13.18 ± 8.77 pg/mL, respectively. 27 However, this exploratory study included healthy Japanese women with relatively mild symptoms, did not assess microbiome composition, and did not establish whether the magnitude of symptomatic improvement was proportional to the observed hormonal changes. In addition, a 2026 randomized trial involving 100 infertile women with leuprorelin-induced perimenopausal symptoms evaluated Limosilactobacillus reuteri NCU-37, with 50 healthy women serving as an additional comparison group. Compared with placebo, probiotic supplementation reduced the median Modified Kupperman Index score from 15.00 to 8.00, Hamilton Anxiety Scale score from 11.50 to 7.00, Hamilton Depression Scale score from 9.00 to 7.00, and Athens Insomnia Scale score from 7.50 to 5.00. These changes were accompanied by an increase in Blautia and a decrease in Bacteroides . 127 Although this trial provides clinically relevant quantitative evidence, the participants experienced medication-induced symptoms during infertility treatment; therefore, the generalizability of these findings to PMS remains uncertain. Other animal studies suggest that Bifidobacterium longum 15M1 may improve lipid profiles and menopause-associated obesity, 42 whereas Lacticaseibacillus casei 01, Bacillus coagulans, Lactococcus lactis , and Bifidobacterium bifidum have been investigated for their effects on intestinal barrier integrity, bone health, metabolism, or behavior. 43 , 44 , 111 , 112 Overall, the available evidence suggests that probiotic effects are strain specific rather than representative of a class effect. Existing clinical trials are small or involve selected populations, and findings from animal studies cannot be extrapolated across strains or formulations. Larger-scale, multicenter trials enrolling women with PMS are warranted to establish its efficacy, potential mechanisms, and safety. Prebiotics are substrates that are selectively utilized by host microorganisms and confer health benefits, 128 , 129 with oligosaccharides among the most extensively studied prebiotic substrates. 130 In OVX rats, konjac oligosaccharides promoted the growth of Bifidobacterium longum , reduced proinflammatory cytokine levels, restored the Treg/Th17 balance in bone marrow, and attenuated bone loss. 92 Synbiotics combine probiotics with complementary substrates and may exert combined effects on microbial composition and host metabolism. In estrogen-deficient rats, a formulation containing Lactobacillus fermentum and β-glucan derived from cauliflower mushroom altered the gut microbiota and improved glucose and lipid metabolism and bone-related outcomes. 45 , 131 However, evidence supporting the use of prebiotics and synbiotics in PMS remains predominantly preclinical, and their clinical efficacy has not been established. Future clinical studies should clearly characterize product composition and dosage, report viable microorganism counts for probiotic-containing synbiotics, assess adherence and gastrointestinal adverse events, and determine whether any observed benefits persist after discontinuation. Safety assessments should also be tailored to the specific product and target population. 132 FMT aims to restore microbial community function by transferring processed donor stool to a recipient. 133 Although FMT has established use in selected gastrointestinal indications, its application to PMS remains investigational. In an OVX mouse study, transplantation from ovary-intact donors increased Proteobacteria and Verrucomicrobia , enhanced vaginal epithelial proliferation, and significantly alleviated vaginal epithelial atrophy. 47 These findings support biological plausibility in a model of estrogen deficiency but do not establish the efficacy of FMT in women with naturally occurring PMS. To date, no robust clinical evidence supports its use in this population. Safety is a major translational constraint. In 2019, transmission of pathogenic Escherichia coli through FMT caused severe bacteremia in two patients, including one death. 134 Accordingly, FMT should remain an experimental approach for PMS and should not be used outside ethically approved clinical trials with rigorous donor screening, pathogen and antimicrobial-resistance testing, and long-term safety monitoring. TCM, with a history of over 2000 years in China, is grounded in a unique theoretical framework 135 and has shown potential in treating PMS by modulating the gut microbiota. Clinical research further demonstrates that the TCM formula Tianwang Buxin Granules can elevate the abundance of Bacteroidetes and Faecalibacterium prausnitzii in feces, reduce scores on the Pittsburgh Sleep Quality Index in PMS patients with insomnia, and improve sleep quality. 49 Studies have found that certain herbal formulations can enhance microbial diversity, increase the abundance of Blautia , thereby increasing l(+)-ornithine levels, and modulate the levels of vascular endothelial nitric oxide synthase and heat shock protein 70 in the hypothalamus. This effectively improves neuropsychiatric symptoms such as depression and hot flashes associated with PMS. 39 , 48 Additionally, TCM formulations can raise the levels of SCFAs, reduce colonic epithelial permeability, and increase the proportion of Treg cells in the spleen—effectively preventing bone loss and enhancing bone strength, thereby contributing to the regulation of bone metabolism in postmenopausal osteoporosis. 55 These observations are clinically relevant; however, cross-study comparisons are constrained by heterogeneity in herbal formulations, quality-control procedures, sequencing methods, sample sizes, and outcome definitions. Evidence regarding isolated herbal extracts and bioactive compounds is derived predominantly from preclinical studies, with limited clinical data. In OVX models, herbal extracts or bioactive compounds have been associated with alterations in bile acid metabolism, a reduced abundance of Anaerotruncus , and lower visceral fat accumulation or hepatic triglyceride levels. 36 , 50 , 113 Other preclinical studies suggest that certain extracts and compounds may increase gut microbial diversity and promote osteoblast differentiation. For example, Agastache rugosa ethanol extract has been linked to Wnt signaling, whereas cinnamic acid has been linked to BMP/TGF-β/Smad signaling in models of postmenopausal osteoporosis. 51 , 52 Clinical studies further reveal that hop extract standardized in 8-prenylnaringenin, when combined with vitamin D3 and calcium, can enhance SF-36 physical function scores in postmenopausal women and increase the abundance of genera Turicibacter and Shigella , both closely associated with bone mineral density. 114 In addition, acupuncture has a long history dating back at least 2000 years in promoting internal balance, regulating hormonal disorders, and treating female reproductive system diseases, especially as a classical therapy for PMS. 136 Today, acupuncture has been innovatively combined with modern technology to develop electroacupuncture and acupoint catgut embedding. Both therapies have been reported to alter gut microbiota composition and improve obesity-related outcomes in PMS. 115 , 116 Among these, electroacupuncture combined with dietary intervention was associated with increased abundances of Kosakonia and Klebsiella alongside reductions in body weight and waist circumference. 115 However, an Australian sham-controlled trial found no superiority of acupuncture over sham acupuncture for menopausal hot flashes. 137 Overall, evidence for acupuncture and related therapies in PMS remains inconsistent, and rigorous, independently replicated studies are needed to determine whether their reported clinical benefits are mediated by changes in the gut microbiota. Hormonal medications are among the commonly used treatments for PMS. They not only supplement the endogenous hormones lacking in postmenopausal women and slow the pathological progression of PMS, but also enhance the diversity of the gut microbiota. 117 , 138 For example, supplementation with exogenous E 2 benzoate can reduce fat accumulation in OVX mice while increasing the abundance of Lactobacillus and Bifidobacterium . 40 In OVX mice, isoflavone supplementation altered gut microbiota composition and attenuated muscle atrophy. 118 Additionally, ovarian progesterone can increase Lactobacillus levels and upregulate the expression of the Brain-derived Neurotrophic Factor gene in the hippocampus, effectively alleviating anxiety and depression symptoms. 66 Similarly, melatonin supplements, known for their antioxidant properties, can inhibit the growth of Alistipes inops , regulate tryptophan metabolism, and thereby improve depressive behaviors in OVX mice. 41 These observations indicate that hormone-related or neuroendocrine interventions can themselves reshape the gut microbiota, but do not establish that such microbiota changes mediate the established or potential clinical effects of these interventions. Fish oil supplementation and therapeutic hyperthermia have also been investigated as adjunctive interventions for PMS. Fish oil supplements are rich in n-3 polyunsaturated fatty acids and have beneficial effects on anti-inflammatory and lipid metabolism regulation, 139 and hyperthermia treatment has metabolic benefits. 140 Studies have shown that the combination of the two can increase alpha-diversity and enrich beneficial microbial groups, including Eubacterium coprostanoligenes and Bacteroides , and can reduce inflammation, significantly reduce body weight, and alleviate metabolic dysfunction in OVX mice. 110 Separately, a randomized human trial showed that omega-3 polyunsaturated fatty acid supplementation altered intestinal microbiota composition, 141 providing human evidence that complements the OVX fish-oil findings. Plant extracts can reduce the ratio of Firmicutes to Bacteroidetes , lower cholesterol levels, and significantly improve lipid metabolism. 46 , 119 For example, proanthocyanidin-rich grape seed extract can help prevent perimenopausal obesity, while ethanolic extract of red clover (Trifolium pratense) shows potential in reducing risk factors for coronary heart disease associated with menopause. Interestingly, a diet combining rice bran and tea seed oil can increase the levels of SCFAs, reduce the levels of endotoxin-producing Tannerellaceae , and lower pro-inflammatory cytokines such as interleukin-1β and TNF-α. These effects help alleviate peripheral metabolic inflammation and oxidative damage, as well as relieve postmenopausal neuroinflammation in the brain. 120 Most of these findings are derived from OVX rodent models. Species differences, short experimental durations, reliance on single microbial strains, the complexity of multicomponent botanical preparations, and limited dose-ranging and safety data preclude direct extrapolation of these findings to clinical efficacy. Future translation will require a stepwise process that encompasses replication verification, toxicological evaluation, and randomized controlled trials before the causal effects mediated by the microbiota and their true clinical value can be established.