bims-simsho 2025-10-12 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–10–12
25 papers selected by
Chun-Chi Chang, Lunds universitet

Androgen receptor pathway signaling inhibitors in development for prostate cancer therapy.
A bibliometric analysis of the effects of sex hormone profiles in women with polycystic ovary syndrome.
A male-dominant cell group expressing calbindin-D28K and androgen receptor in the mouse preoptic area requires postnatal testicular androgens and histone deacetylation.
Epigenetic landscape of hormone-independent sexual dimorphism and characterization of canine XIST.
Biological sex impacts immune cell proportions and epigenetic profiles in the developing pediatric immune system.
Metabolic Effects of Gender-Affirming Hormonal Therapy in Youth.
Androgen receptor-mediated regulation of BRCA1 modulates the antioxidant defense in prostate cancer.
The effect of COVID-19 and sex differences on natural killer cell cytotoxicity.
Triglyceride glucose index - body mass index predicts insulin resistance, metabolic syndrome and associates with impaired ovulation in Chinese women with polycystic ovary syndrome.
How microbiota influence maternal blood disorder in miscarriage.
The interconnection between androgen receptor and DNA damage response pathways in prostate cancer.
Uncovering hidden connections: the role of the male reproductive system microbiome and gut microorganisms in implantation: a critical review.
Age-Associated Inflammatory Monocytes Are Increased in Menopausal Females and Reversed by Hormone Replacement Therapy.
Contribution of Sex-Biased Expressed Genes in Osteoarthritis.
Engineered polysaccharides for controlling innate and adaptive immune responses.
Effects of sex but not race and geographic origin on vaccine-induced HIV-specific antibody responses.
Unveiling the microbial shift: the impact of group B Streptococcus on vaginal microbiota and inflammation in late pregnancy.
The interaction between obesity and sex alters the response to house dust mite in an experimental model of allergic lung inflammation.
Genetic variants of the androgen receptor and frailty in postmenopausal women.
Changes in the vaginal microbiome in female patients with condyloma acuminatum and its impact on persistent HPV infection.
Prior testosterone use does not appear to impact oocyte cryopreservation outcomes in transgender patients: findings from a multicenter health maintenance organization.
The genetic influence of sex on gene expression for blood in pigs.
Distinct Suppression of Prednisone on Endometrial Immune Cells in Women With Reproductive Failure.
Sex differences in brain cell-type specific chromatin accessibility in schizophrenia.
The sex related differences in health and Disease: A systematic review of sex-specific gut microbiota and Possible implications for microbial pathogenesis.

Expert Opin Investig Drugs. 2025 Oct 09.

Androgen receptor pathway signaling inhibitors in development for prostate cancer therapy.

Sara Bleve, Pier Vitale Nuzzo, Abdul Baseet Arham, Aaron Holmes, Scott T Tagawa.

   INTRODUCTION: Prostate cancer (PC), including castration-resistant disease (CRPC), remains largely driven by dysregulated androgen receptor (AR) signaling. While androgen deprivation therapy (ADT) combined with next-generation AR inhibitors improves survival, resistance inevitably arises through mechanisms such as AR amplification, mutations, and splice variants. Additionally, chronic AR suppression induces significant metabolic, musculoskeletal, and cardiovascular toxicities, highlighting the need for novel therapies that overcome resistance while minimizing systemic adverse effects.
AREAS COVERED: This review outlines the pivotal role of AR signaling in PC pathogenesis and evaluates the clinical impact and limitations of current AR-targeted therapies. In addition, it examines emerging therapeutic strategies aimed at modulating AR activity, disrupting androgen biosynthesis, and degrading the AR protein itself. Finally, we explore novel approaches targeting alternative oncogenic pathways involved in resistance and lineage plasticity, with the goal of advancing more effective and durable treatment paradigms.
EXPERT OPINION: Novel strategies such as bipolar androgen therapy (BAT), selective androgen receptor modulators (SARMs), and AR degraders like PROTACs offer context-specific or mechanistically distinct ways to overcome resistance to traditional AR antagonism in prostate cancer. These approaches, along with CYP11A1 inhibitors and resistance pathway targeting (e.g. PI3K/AKT, EZH2), mark a shift toward more personalized therapies aimed at improving efficacy while minimizing toxicity.

Keywords:  AR antagonists; Androgen receptor (AR); Bipolar androgen therapy (BAT); PROTACs; Prostate cancer; Selective androgen receptor modulators (SARMs)

DOI:  https://doi.org/10.1080/13543784.2025.2573647
Medicine (Baltimore). 2025 Oct 03. 104(40): e44965

A bibliometric analysis of the effects of sex hormone profiles in women with polycystic ovary syndrome.

Bo Li, Shuang Li, Zibo Duan, Hui Yu, Yan Zhou, Xiaohua Lin.

   BACKGROUND: Polycystic ovary syndrome (PCOS), a hormone-linked infertility disorder, severely impacts reproductive-aged women's health and societal well-being.
METHODS: Bibliometric analysis via Web of Science (2013-2023) using CiteSpace, VOSviewer, and Bibliometric.
RESULTS: Analyzed 1835 studies from 80 countries, led by China/US. Research surged post-2017. Journal of Gynecological Endocrinology was most productive; Fertility and Sterility had the highest impact. Key topics: insulin resistance, obesity, testosterone. Legro (prolific) and Azziz (highly cited) dominated authorship.
CONCLUSION: PCOS-sex hormone research holds growing scientific/social relevance. Current hotspots focus on metabolic-pathological mechanisms, guiding future investigations into personalized therapies and risk management.

Keywords:  CiteSpace; PCOS; VOSViewer; bibliometrics; sex hormones

DOI:  https://doi.org/10.1097/MD.0000000000044965
J Neuroendocrinol. 2025 Oct 09. e70097

A male-dominant cell group expressing calbindin-D28K and androgen receptor in the mouse preoptic area requires postnatal testicular androgens and histone deacetylation.

Yusa Arai, Shinji Tsukahara.

  The mouse brain is masculinized by postnatal testicular androgens, which are active after conversion to estrogens and modulate gene expression epigenetically, at least in part. The preoptic area contains a sexually dimorphic nucleus (SDN) comprising calbindin D-28K (Calb) neurons with a male-biased sex difference in cell number (Calb-SDN), although the mechanisms responsible for the sex difference are not fully understood. We have previously demonstrated that Calb neurons expressing the androgen receptor (AR) are a male-dominant cell group of the Calb-SDN in pubertal mice, while Calb neurons without AR exist in both sexes with equal cell numbers. In this study, we investigated the mechanisms by which more Calb/AR neurons emerge in the male Calb-SDN than in the female one. Immunohistochemistry for Calb and AR was performed using the brain sections from pubertal male mice subjected to sham surgery or neonatal orchidectomy, from pubertal female mice treated with vehicle, testosterone, or estradiol during the postnatal period, and from pubertal male mice whose brains were treated with trichostatin A, a histone deacetylase inhibitor, during the postnatal period. Immunostained brain sections were analyzed stereologically to determine the numbers of Calb-immunopositive and AR-immunopositive cells (Calb+/AR+ cells) and Calb-immunopositive and AR-immunonegative cells (Calb+/AR- cells) in the Calb-SDN. The number of Calb+/AR+ cells in the Calb-SDN during the pubertal period was significantly decreased in neonatally orchidectomized males compared with sham males and increased in testosterone- or estradiol-treated females compared with vehicle-treated females; however, the number of Calb+/AR- cells remained unchanged. Trichostatin A treatment significantly reduced the number of Calb+/AR+ cells, but not the number of Calb+/AR- cells, in the Calb-SDN of males. These findings suggest that estrogens synthesized from postnatal testicular androgens act selectively on the AR-expressing subpopulation of Calb neurons, contributing to the sex difference in the number of Calb neurons in the mouse Calb-SDN. Epigenetic regulation of gene expression, possibly mediated by histone deacetylation, may be involved in the emergence of the AR-expressing subpopulation of Calb neurons.

Keywords:  androgen receptor; calbindin‐D28K; sexually dimorphic nucleus

DOI:  https://doi.org/10.1111/jne.70097
Sci Rep. 2025 Oct 10. 15(1): 35431

Epigenetic landscape of hormone-independent sexual dimorphism and characterization of canine XIST.

Seong-Ju Oh, Dayeon Kang, Subin Jang, Tae-Seok Kim, Chae-Yeon Hong, Yong-Ho Choe, Chan-Hee Jo, Are-Sun You, Yoon Jung Do, Gyu-Jin Rho, Jaemin Kim, Sung-Lim Lee.

  Sexual dimorphism in dogs (Canis lupus familiaris) manifests through pronounced differences in morphology, physiology, and disease susceptibility. Despite early neutering, the persistence of sex-specific differences highlights the need to investigate factors beyond sex hormones that contribute to these characteristics. We collected whole blood tissue from spayed female (n = 4) and castrated male (n = 4) beagles and performed whole genome bisulfite sequencing (WGBS) and RNA seq. To investigate hormone-independent sex dimorphism of DNA methylation in neutered dogs, we investigated differentially methylated genes (DMGs) between sexes and candidate molecular pathways. Furthermore, we analyzed sex-related correlations between gene expression and methylation levels. Sex-related differentially methylated genes, independent of hormone influence, are associated with oncogenic signaling and neuronal pathways. Differences in methylation status between the sexes were significantly associated with alterations in gene expression, indicating that methylation plays a regulatory role in gene transcription. Identification of canine XIST, previously annotated as LOC102156855, suggests a conserved mechanism of X-chromosome inactivation across species and a sex-specific epigenetic imprint on the genome, which is maintained independent of sex hormones. These findings enrich the understanding of sex-specific biology in dogs and highlight the intricate interplay between epigenetic modifications and gene expression in determining sex-specific phenotypes and disease susceptibilities.

Keywords:  Canine XIST; DNA methylation; Dog; Gene expression; Hormone-independent sexual dimorphism

DOI:  https://doi.org/10.1038/s41598-025-19398-5
Commun Biol. 2025 Oct 09. 8(1): 1447

Biological sex impacts immune cell proportions and epigenetic profiles in the developing pediatric immune system.

Karlie Edwards, Sarah M Merrill, Chaini Konwar, Marcia S Jude, Beryl C Zhuang, Mandy Meijer, Erick Navarro-Delgado, Julie L MacIsaac, Piush Mandhane, Elinor Simons, Theo J Moraes, Meghan B Azad, Padmaja Subbarao, Mariona Bustamante, Martine Vrijheid, Stuart Turvey, Michael S Kobor.

Age- and sex-related differences in immune cell compositions and immune outcomes have been identified across the life course, but a comprehensive and nuanced characterization of these changes during the rapid developmental window of early life is lacking. We explore immune associated DNA methylation (DNAm) changes in the context of age and sex leveraging whole blood samples collected at ages one and five from CHILD, a Canadian longitudinal pediatric cohort (n = 760: 356 female and 404 male). DNAm-based computational cell type deconvolution reveals significant changes in all estimated immune cell types across time, with notable sex differences. In addition, we identify distinct DNAm signatures reflecting age- and sex-associated immune profiles in early life. While age-related DNAm changes are relatively limited, sex-associated differences are consistent across this developmental window and partially validate in independent pediatric cohorts. Together, these findings provide insights into early immune system maturation, underscoring the presence of sex differences prior to puberty.

DOI: https://doi.org/10.1038/s42003-025-08844-9
Pediatr Ann. 2025 Oct;54(10): e355-e360

Metabolic Effects of Gender-Affirming Hormonal Therapy in Youth.

Jeremy Winer, Maya McKee, Michelle B Lemelman.

Youth who are transgender and gender diverse (TGD) experience metabolic conditions with differing rates than their peers who are cisgender. Mental health, minority stress, and related behaviors likely play a significant role in these differences. At the same time, the sex hormones (ie, estrogen and testosterone) play an integral role in metabolic health with sexual dimorphic patterns. Emerging research is evaluating the positive, negative, or neutral metabolic changes seen with gender-affirming hormonal therapy (GAHT) in adolescents and young adults. In this review, we summarize these findings, specifically evaluating five domains: (1) cardiovascular health, (2) lipid metabolism, (3) insulin resistance, (4) body composition, and (5) liver function. Using the available evidence, we highlight the baseline characteristics prior to GAHT, describe the expected changes with therapy, and review the current guideline-based screening recommendations while on GAHT for metabolic conditions.

DOI: https://doi.org/10.3928/19382359-20250828-05
J Pathol. 2025 Oct 06.

Androgen receptor-mediated regulation of BRCA1 modulates the antioxidant defense in prostate cancer.

Saiganesh Sriraman, Verneri Virtanen, Antti Kukkula, Mervi Toriseva, Anni Lumiainen, Gun West, Matti Poutanen, Pekka Taimen, Maria Sundvall.

  Lethal prostate cancer (PCa) is a genetically heterogeneous disease characterized by evolving androgen receptor (AR) signaling, eventually culminating in castration resistance. The tumor suppressor gene BRCA1 has multiple functions that include secondary processes cooperating with its main function as a caretaker of genomic integrity. BRCA1 is often mutated in breast and ovarian cancer, but BRCA1 mutations are also associated with PCa, although they are less frequently observed. Most PCa patients do not, however, carry BRCA1 mutations, and interestingly, it has been shown that BRCA1 expression is enriched in castration-resistant PCa. In this study we elucidated the prostate tissue-specific role of the BRCA1 protein. Although the regulation of DNA damage response genes has been studied in PCa, comprehensive analyses of BRCA1 regulation in the context of androgen signaling are lacking. Our results indicate that BRCA1 is dynamically regulated by AR signaling and that activation of AR via its natural ligand, dihydrotestosterone, represses BRCA1 expression. Our analyses both in vitro and of patient samples and mouse xenografts showed that BRCA1 expression was induced and sustained after androgen deprivation. Moreover, we observed that oxidative stress-related pathways were regulated by BRCA1 in PCa cells and that androgen deprivation therapy-induced activation of BRCA1 supported the function of NRF2, the master regulator of antioxidant defense, and a known interactor of BRCA1. Impaired NRF2 activity, in the absence of BRCA1, decreased growth in a 3D environment. Our findings shed light on the functional role of BRCA1 protein in PCa and suggest that BRCA1 is regulated by the evolving AR signaling state during PCa progression. Thus, AR-mediated suppression of BRCA1 accumulates oncogenic alterations in the early phases of PCa tumor progression and safeguards from excessive reactive oxygen species (ROS) when upregulated during androgen deprivation therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  BRCA1; DNA damage; NRF2; androgen deprivation therapy; androgen receptor; castration‐resistant prostate cancer; oxidative stress

DOI:  https://doi.org/10.1002/path.6468
Front Cell Infect Microbiol. 2025 ;15 1635043

The effect of COVID-19 and sex differences on natural killer cell cytotoxicity.

Arushi Dagar, Maria J Polyak, Adley C H Mok, David Feehan, Michael Potemkin, Alain Tremblay, Christopher H Mody.

  COVID-19 has caused more than 7 million deaths worldwide, and according to the World Health Organization, it continues to result in more than 1000 reported deaths per month at the time of this writing. It is crucial to understand the immune response to COVID-19 since the virus continues to persist. Natural killer (NK) cells play a critical role in the immune defense against viral infections, including COVID-19. While it is well documented that infected patients have a reduction in lymphocytes and NK cells, gaps in knowledge exist regarding the function of NK cells. To study the function of NK cells in patients hospitalized with COVID-19, peripheral blood was obtained from patients admitted to the medical (non-ICU) wards at a large tertiary hospital. We demonstrated a decrease in the mature cytotoxic subset of NK cells within the peripheral blood of patients hospitalized with COVID-19. We also observed a notable reduction in the cytotoxic function of NK cells against tumor targets. We examined the mechanisms leading to NK cell killing. We found reductions in the intracellular levels of effector molecules, the degranulation of cytotoxic granules, and the extracellular concentrations of released effector molecules. We identified dysfunctional intracellular granule trafficking required to position the granules for degranulation, which would be consistent with the reduced release of effector molecules. We found clusters of inhibitory receptors were upregulated in subsets of NK cells, in keeping with inhibition of cytotoxicity. Additionally, males with COVID-19 showed NK cell defects compared to healthy males, while no significant differences were observed in females. Our findings highlight defects in cytolytic effector molecules, granule trafficking and release, and increased expression of inhibitory receptors on NK cells in patients hospitalized with COVID-19, in addition to a sex difference in cytolytic function, which contributes to defective NK cell function in COVID-19.

Keywords:  COVID-19; SARS-CoV-2; cellular cytotoxicity; cytotoxic effector molecules; granule trafficking; immunology; natural killer (Nk) cell; sex differences

DOI:  https://doi.org/10.3389/fcimb.2025.1635043
Front Endocrinol (Lausanne). 2025 ;16 1653636

Triglyceride glucose index - body mass index predicts insulin resistance, metabolic syndrome and associates with impaired ovulation in Chinese women with polycystic ovary syndrome.

Muxin Guan, Jiaxing Feng, Mengyi Zhu, Yu Wang, Baichao Shi, Fengjuan Lu, Jiannan Yu, Zhuwei Gao, Hong Yu, Xiaoke Wu.

   Background: Insulin resistance (IR) and metabolic syndrome (MetS) are highly prevalent and pathophysiologically central features of polycystic ovary syndrome (PCOS). However, their assessment is challenged by the limitations of gold-standard diagnostic methods. The clinical utility of the novel triglyceride glucose index - body mass index (TyG-BMI) for predicting IR, MetS, and its association with fertility outcomes in Chinese women with PCOS remains unexplored and warrants investigation.
Objective: To evaluate the association between TyG-BMI and IR and MetS, and fertility outcomes in women with PCOS.
Methods: We used data of 855 participants of the Acupuncture and Clomiphene for Chinese Women with Polycystic Ovary Syndrome (PCOSAct) trial. Linear trend tests and logistic regression evaluated relationships between TyG-BMI and anthropometric, hormonal, metabolic, and fertility outcomes. Receiver operating characteristic (ROC) curves assessed TyG-BMI's predictive value for IR and MetS. RCS analysis was used to examine threshold effects between TyG-BMI and IR, MetS, and ovulation. A likelihood ratio test was further incorporated to validate the model fit.
Results: TyG-BMI was positively association with IR (OR: 2.747, 95% CI: 1.942-3.887) and MetS (OR: 4.176, 95% CI: 2.278-7.653). TyG-BMI had a strong predictive performance, with AUCIR of 0.841 and AUCMetS of 0.899. For fertility outcomes, after adjusting for confounders, only ovulation showed a significant negative association (OR: 0.984, 95% CI: 0.973-0.994). The study revealed significant nonlinear associations between TyG-BMI and both IR and MetS, but a linear link with ovulation status. The inflection point occurred at a TyG-BMI of 203. Below this, IR risk increased progressively with TyG-BMI, plateauing above it. Above 203, MetS prevalence continued to increase, while ovulation rates declined inversely.
Conclusion: Elevated TyG-BMI is strongly associated with worsened IR and MetS in PCOS women, serving as a practical screening tool for these conditions, while also demonstrating a potential negative impact on ovulation.

Keywords:  fertility outcomes; insulin resistance; metabolic syndrome; polycystic ovary syndrome; triglyceride glucose index-body mass index

DOI:  https://doi.org/10.3389/fendo.2025.1653636
Mol Biol Rep. 2025 Oct 09. 52(1): 1004

How microbiota influence maternal blood disorder in miscarriage.

Malihe ParsaSefat, Aisa Bahar, Meisam Khazaei, Mojdeh Jahantigh, Hamed Tahmasebi.

  The occurrence of miscarriage signifies a significant loss during pregnancy, profoundly affecting many women internationally. The intricate and multifaceted nature of miscarriage causes has led recent investigations to propose that vaginal microbiota may be a contributing factor. A diverse array of microbes constitutes the vaginal microbiome, which plays a vital role in safeguarding vaginal health and reducing the risk of infections. The link between the vaginal microbiome and miscarriage is not yet fully understood. The gut microbiome also serves as a recognized supporting organ, reflecting its many relationships with the overall health of the host individual. Moreover, adverse effects on the microbiomes present in various body systems can significantly compromise overall health. The characterization of microorganisms, known as the microbiota, in relation to human health has involved exploring which organisms exist, how they function in interaction with human cells, and the mechanisms that govern these interactions. The purpose of this review is to investigate how distinct microbiota may influence the risk of miscarriage. Moreover, our research delves into the multiple mechanisms through which maternal blood disorders can impact the likelihood of miscarriage, also looking into the known connections between microbiota and humans, with an emphasis on their impact on blood disorders.

Keywords:  Bacterial infection; Blood disorder, gut microbiota; Hemolytic disease; Miscarriage, vaginal microbiota

DOI:  https://doi.org/10.1007/s11033-025-11113-x
Curr Urol. 2025 Nov;19(6): 376-387

The interconnection between androgen receptor and DNA damage response pathways in prostate cancer.

Mallory Sands, Samuel Adams, Jihaeng Lee, Michael Li, Maechen Wang, Thomas Walsh, Leovigildo Leon, Adriana Zablah, Matthew Haerens, Zhichao Liu, Jianneng Li.

  The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer by regulating key cellular processes such as cell proliferation and apoptosis. Although traditional AR-targeted therapies have shown initial success, acquired resistance remains a significant clinical challenge, often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency (HRD). Approximately 20% of advanced prostate cancer cases exhibit HRD, resulting in substantial genomic instability and complicating treatment. Fortunately, Food and Drug Administration-approved poly(ADP-ribose) polymerase inhibitors, including olaparib and rucaparib, exploit synthetic lethality to target prostate cancer with HRD, and additional drugs targeting DNA damage response (DDR) proteins are under development. Emerging evidence suggests that AR activity enhances DDR gene expression, with multiple DDR proteins localized near androgen-regulated regions, highlighting a close interaction between AR and DDR pathways. Consequently, recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage, such as radiation therapy, or inhibit DNA repair mechanisms. This review discusses AR's role in cellular processes, the interplay between AR and DDR, and recent advances in prostate cancer treatment strategies.

Keywords:  DNA repair; Prostate cancer; androgen receptor

DOI:  https://doi.org/10.1097/CU9.0000000000000300
Crit Rev Clin Lab Sci. 2025 Oct 06. 1-31

Uncovering hidden connections: the role of the male reproductive system microbiome and gut microorganisms in implantation: a critical review.

Magdalena Jendraszak, Mirosław Andrusiewicz.

  Recent advancements in sequencing technologies have uncovered complex and diverse microbial communities inhabiting various niches of the human body, including the reproductive system. This review explores the significance of the male genital and gut microbiomes in maintaining reproductive health, focusing on their potential roles in embryo implantation and pregnancy outcomes. A comprehensive literature search was conducted using MEDLINE, Web of Science, and Scopus for articles published between 2004 and 2024. Search terms included "microbiome," "implantation," "inflammation," "male reproductive system," "recurrent miscarriage," "recurrent implantation failure," and "probiotics." From an initial pool of 1,091 articles, 107 were selected after applying filters for clinical, comparative, and observational studies. Ultimately, 21 articles met the quality criteria and were included in the review. While the female genital microbiome has been extensively studied and its role in implantation and embryo development well established, research on the male genital microbiome remains limited, and its influence is not yet fully understood. Nevertheless, emerging data suggest that the male reproductive tract harbors its own distinct microbial community, which may affect fertility, implantation, and pregnancy outcomes. The presence of certain bacteria and leukocytes in semen has been associated with sperm DNA damage, potentially compromising fertility and embryo development. Moreover, microbial exchange between partners during intercourse may alter the composition of the female reproductive microbiome, potentially influencing implantation success. The male and female reproductive tracts are colonized by microbial communities that play crucial roles in preventing infections and supporting reproductive health. Disruptions in these ecosystems have been linked to infertility, miscarriage, and preterm birth. Additionally, the gut microbiome is believed to interact with the reproductive system, possibly influencing implantation through immune and metabolic pathways. A deeper understanding of these connections is essential for identifying new preventive and therapeutic strategies for individuals experiencing recurrent pregnancy loss or implantation failure. Identifying specific microbial patterns associated with dysbiosis is critical for the development of targeted interventions. Potential therapeutic approaches include probiotics, prebiotics, and antibiotics, which may help restore microbial balance, enhance fertility, and reduce the risk of miscarriage. Antibiotic treatment may also prove beneficial in addressing infections that disrupt implantation. As microbial exchange, sperm DNA integrity, and immune regulation are all influenced by the microbiome, further research is necessary to understand its role in reproductive outcomes fully. Microbiome-targeted therapies represent a promising frontier in reproductive medicine. However, their clinical efficacy must be validated through rigorous research. This review underscores the importance of characterizing the composition and functional roles of the genital and gut microbiomes in order to inform the development of novel diagnostic tools and therapeutic strategies aimed at improving reproductive health and pregnancy outcomes.

Keywords:  Male reproductive system microbiome; gut microbiome; implantation; inflammation; probiotics

DOI:  https://doi.org/10.1080/10408363.2025.2562894
Aging Cell. 2025 Oct 09. e70249

Age-Associated Inflammatory Monocytes Are Increased in Menopausal Females and Reversed by Hormone Replacement Therapy.

R P H De Maeyer, J Sikora, O V Bracken, B Shih, A F Lloyd, H Peckham, K Hollett, K Abdelhamid, W Cai, M James, P E Pfeffer, M Vukmanovic-Stejic, A N Akbar, E S Chambers.

Biological sex is a crucial, but poorly understood variable in age-related susceptibility to infection. Monocytes are important immune cells responsible for initiating and resolving inflammatory responses to infection. While changes in monocyte populations result in increased susceptibility to infection, there is limited research on the impact of age and sex on human monocyte phenotype and function. The aim of this work was to dissect the impact of increasing age and biological sex on human monocyte phenotype and function. Here, we show that older females have increased inflammatory intermediate and non-classical monocytes compared to young. These monocyte subsets were the most inflammatory ex vivo, and their frequency correlated with markers of inflammageing. Proteomic analysis of sorted monocyte populations demonstrated that the three human monocyte subsets have largely distinct phenotypes. Key age-associated protein pathways were identified, including complement cascade and phagocytosis. We confirmed the proteomics findings, showing that circulating C3 concentrations were reduced with age in females but not males. This decrease in complement in older females resulted in reduced monocyte phagocytosis. Crucially, we demonstrate that in peri/menopausal females, hormone replacement therapy (HRT) reversed this expansion in intermediate monocytes and decreased circulating CRP as compared to age-matched controls. Importantly, peri/menopausal females on HRT had increased C3 serum concentrations and significant improvement in monocyte phagocytosis. The data presented here indicate the importance of menopause in aging monocyte phenotype and function. These data highlight the potential use of HRT in restoring monocyte function in females during aging and potentially improving anti-pathogen immunity.

DOI: https://doi.org/10.1111/acel.70249
Smart Med. 2025 Dec;4(4): e70019

Contribution of Sex-Biased Expressed Genes in Osteoarthritis.

Cuicui Wang, Meng Shi, Tiandao Li, Shuang Liu, Liang Fang, Ming Xu, Bo Zhang, Jie Shen.

  Human osteoarthritis (OA) displays sex-specific patterns in its clinical presentation. Key features of the disease-such as prevalence, age of onset, progression, and response to treatment-vary between males and females. These differences have been associated with sex hormones, as well as anatomical, biomechanical, and behavioral distinctions between the sexes. However, the underlying mechanisms driving these sex-specific disparities in OA pathogenesis remain largely unknown. In this study, we analyzed transcriptomic data from human knee articular cartilage to investigate sex-specific gene expression in articular chondrocytes. We identified genes that are uniquely or predominantly expressed in either males or females in healthy cartilage. Notably, many of these sex-biased genes were significantly dysregulated in osteoarthritic cartilage, particularly those with higher expression in females. Furthermore, female-specific OA genes may exert protective effects on cartilage degeneration, whereas male-specific OA genes could impair cartilage homeostasis. Our findings provide insights into the genetic regulation of OA and highlight the influence of sex on its molecular pathology.

Keywords:  cartilage; hormone; osteoarthritis; sex; transcriptomics; transposable element

DOI:  https://doi.org/10.1002/smmd.70019
Nat Rev Bioeng. 2024 Sep;2(9): 733-751

Engineered polysaccharides for controlling innate and adaptive immune responses.

Jutaek Nam, April Kim, Kidong Kim, Jeong Hyun Moon, Juwon Baig, May Phoo, James J Moon, Sejin Son.

Therapeutic interventions can be designed by exploiting the immune system's ability to initiate specific responses to various stimuli. However, specific T cell activation, which is a key target for vaccines and immunotherapies, remains challenging. Polysaccharides derived from microbial cell walls are promising immunomodulators that interact with pathogen-recognition receptors (PRRs) on dendritic cells and macrophages, triggering robust immune responses for modulating T cell function and activating effector or regulatory pathways. In this Review, we discuss the role of polysaccharides as pathogen-associated molecular patterns (PAMPs) recognized by PRRs and their immunomodulatory potential for biomedical applications. We examine the engineering aspects of polysaccharides, investigating their potential in vaccine, immunoadjuvant, immune-modulation and drug-delivery applications and highlighting their immune-activating or immune-regulatory functions. We also explore how trained immunity can be induced by polysaccharides to trigger immune responsiveness upon re-encountering pathogens. By leveraging materials engineering principles, polysaccharides can offer a platform for effective vaccines and immunotherapies against autoimmune and other diseases.

DOI: https://doi.org/10.1038/s44222-024-00193-2
Front Immunol. 2025 ;16 1601865

Effects of sex but not race and geographic origin on vaccine-induced HIV-specific antibody responses.

Wilbert Mbuya, Augusta Horvath, Kathrin Held, Lucas Maganga, Michael Hoelscher, Linda-Gail Bekker, Ann Duerr, Zoe Moodie, Gavin Churchyard, Michael C Keefer, Edna Viegas, Christiane Moog, Christof Geldmacher, Mkunde Chachage.

   Background: Sex, race and geographic location may affect vaccine-induced immune responses, yet few preventive HIV vaccine trials have systematically evaluated such effects. The main objective of this study was therefore to examine the role of these factors on vaccine-induced HIV-specific immune responses within the HVTN 204 trial. This randomized, double-blinded, placebo-controlled phase 2 trial enrolled 480 Black and Caucasian adults from Africa and the Americas, who received a trivalent DNA-HIV-1 vaccine prime followed by a rAd5 vector HIV-1 vaccine boost.
Methods: Available serum samples from baseline and four weeks after the final vaccination boost from Black (n=85, 59% female) and Caucasian (n=49, 51% female) HVTN 204 vaccine recipients from South Africa and the United States of America were studied using an Enzyme-Linked Immunosorbent Assay to determine titers of Envelope-specific IgG1, IgG3 and IgA antibodies. Recognition of linear Envelope peptide-specific IgG responses was mapped in a randomly selected subgroup analysis using a custom-designed peptide microarray (n = 41, 49% female). Associations between vaccine-induced Envelope-specific antibody responses and sex assigned at birth (female or male), race and geographic location were then analyzed by the Mann-Whitney U test, Fisher's exact test and multivariate logistic regression.
Results: Four weeks post-final vaccination boost, we observed that Envelope-specific antibody titers were significantly increased for IgG1 but reduced for IgA in females (female vs. male median titer: 900 vs. 300, p=0.030 and <100 vs. 100, p=0.007, respectively). Multivariate logistic regression confirmed that female sex increased the odds for higher Envelope-specific IgG1 and low IgA titers compared to males. In terms of antibody epitopes, the V2 region was more frequently recognized in females than males (p=0.008). Race and geographic location had no apparent influence on antibody isotype titers investigated.
Conclusion: Female sex was associated with higher vaccine-induced IgG Envelope-specific binding antibody titers and recognition of V2 region of HIV Envelope in HVTN 204 volunteers. No such associations were detected for race or geographic location. Understanding biological factors driving these sex-based differences may improve the design of a new generation of HIV vaccine candidates.

Keywords:  HIV-1; HVTN 204; antibody; race; sex; vaccines

DOI:  https://doi.org/10.3389/fimmu.2025.1601865
BMC Microbiol. 2025 Oct 08. 25(1): 640

Unveiling the microbial shift: the impact of group B Streptococcus on vaginal microbiota and inflammation in late pregnancy.

Wenkai Yu, Mengyi Sun, Renzhe Li, Yanming Xin, Kang Zheng.

   BACKGROUND: Group B Streptococcus (GBS) commonly colonizes the female reproductive tract and rectum. An estimated 19.7 million pregnant women worldwide are colonized with GBS. Infection during late pregnancy can lead to adverse pregnancy outcomes. Pregnant women infected with GBS face a significantly increased risk of transmitting the bacteria to their newborns during delivery, potentially resulting in serious conditions such as sepsis, pneumonia, and meningitis major contributors to neonatal morbidity and mortality. While previous studies have primarily focused on the prevalence of GBS colonization in pregnant women, its effects on the vaginal microbiota and systemic inflammation remain underexplored. This study aims to investigate the alterations in vaginal microbiota associated with GBS colonization during late pregnancy and to examine correlations between microbiota composition and systemic inflammatory markers in GBS-positive pregnant women.
METHODS: Pregnant women in late gestation undergoing routine prenatal care were classified into GBS-negative (n = 19) and GBS-positive (n = 20) groups based on their GBS infection status. Vaginal microbiota composition was analyzed using 16 S rRNA gene sequencing to assess the impact of GBS infection. Additionally, the relationship between microbiota profiles and systemic inflammatory markers was evaluated in the GBS-positive group.
RESULTS: GBS-positive women exhibited significant shifts in vaginal microbiota, notably a reduction in Lactobacillus dominance and an increased abundance of pathogenic taxa such as Gardnerella vaginalis and Streptococcus agalactiae. These microbial changes were associated with elevated systemic inflammatory markers, including neutrophil count (NEU), neutrophil percentage (NEU%), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), procalcitonin (PCT), and erythrocyte sedimentation rate (ESR), suggesting a link between vaginal dysbiosis and systemic inflammation. LEfSe analysis revealed an enrichment of Gemella in GBS-negative women and a predominance of Gardnerella in the GBS-positive group. Correlation analysis showed that Bifidobacterium was positively associated with hs-CRP and IL-6 levels, while Lactobacillus was inversely correlated with hs-CRP, IL-6, and ESR (P < 0.05). Additionally, Dialister and Prevotella were positively associated with ESR (P < 0.05).
CONCLUSION: GBS colonization disrupts the balance of the vaginal microbiota, contributing to a pro-inflammatory state that may heighten the risk of adverse pregnancy outcomes. In comparison to women who are not colonized by GBS, GBS colonization may be associated with a decrease in the abundance of Lactobacillus jensenii and Lactobacillus reuteri, as well as an increase in Gardnerella vaginalis and Lactobacillus johnsonii. Restoring Lactobacillus (specific microbial species) dominance may help mitigate inflammation and promote maternal and fetal health. Future research should focus on longitudinal monitoring of microbiota dynamics and the development of targeted interventions to prevent or manage GBS-related complications.

Keywords:  16S rRNA sequencing; Group Streptococcus ; Inflammation; Pregnancy; Vaginal microbiota

DOI:  https://doi.org/10.1186/s12866-025-04387-5
Front Pharmacol. 2025 ;16 1672504

The interaction between obesity and sex alters the response to house dust mite in an experimental model of allergic lung inflammation.

Amanda Santos-Cavalcante, Alembert Lino Alvarado, Vinicius Cooper Capetini, Julia Camargo Ricci, Gabriel Forato Anhê, Clive Peter Page, Yanira Riffo-Vasquez.

   Introduction: Previous reports have shown that the prevalence of asthma among women is modified by puberty, implying a role for sex hormones in this difference. Additionally, it has been demonstrated that obesity is a significant predisposing factor for asthma, particularly among women. In this regard, populational studies have suggested that severe asthma is more prevalent among obese patients, with worse symptoms, frequent exacerbations and hospitalisations among these patients. This study aimed to elucidate how sex and obesity interact in a murine model of lung allergic inflammation induced by house dust mite (HDM) in male and female animals.
Methods: Male and female C57Bl/6 mice were maintained on a 60% high-fat diet (HFD) or a standard chow diet (SC) for 13 weeks, and on week 11, they underwent an experimental allergic lung inflammation protocol induced by HDM.
Results: Our data showed that, compared to SC-fed male mice, SC-fed female mice exhibit a more severe inflammatory response to HDM exposure. Conversely, the same difference was not observed between HFD female and male mice, with female HFD/HDM mice showing reduced infiltration of leukocytes into the lungs compared to SC/HDM female mice. Similarly, HFD/HDM mice produce lower levels of IgE, IL-5, and IL-13 in the lungs after HDM challenge. However, HFD/Sham female mice displayed notable collagen accumulation in the airways, higher concentrations of SP-D in BAL, and a decrease in the relative gene expression of PECAM-1 in their lungs prior to HDM sensitisation.
Conclusion: Our findings indicate that obesity and sex interact to affect allergic asthma progression in female mice by inducing a pro-inflammatory state in the lung of Sham mice, potentially altering their response to HDM.

Keywords:  allergy; asthma; females; inflammation; lungs; obesity; sex difference

DOI:  https://doi.org/10.3389/fphar.2025.1672504
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2565238

Genetic variants of the androgen receptor and frailty in postmenopausal women.

Aitana Monllor-Tormos, Miguel Ángel García-Pérez, Juan J Tarín, Alicia García-Vigara, Arturo Artero, Antonio Cano.

  Epidemiological evidence suggests a relationship between frailty and age at menopause. The hormonal fluctuations associated with menopause may contribute to frailty, with androgens being prime candidates due to their anabolic properties. This study aimed to elucidate whether single nucleotide polymorphisms (SNPs) within the androgen receptor (AR) gene are associated with frailty. A cross-sectional study was conducted within the frailty sub-cohort of a population-based sample of community-dwelling postmenopausal women. Two SNPs of the AR gene, selected for their potential to modulate AR functionality, were analyzed. A multinomial ordinal regression model was applied to estimate phenotypic variance. A total of 392 women (mean age: 64.1 years) were included, with a frailty status distribution of 29.6% being frail, 38.5% prefrail, and 31.9% robust, consistent with population-based data for this age group. Neither of the selected AR gene SNPs (rs5919427 and rs2497942) showed a statistically significant association with frailty status. Age, reproductive factors (including number of deliveries and miscarriages), number of comorbidities, and body mass index were independently associated with frailty. Further research is warranted to comprehensively explore the potential role of AR gene variants in frailty susceptibility.

Keywords:  Frailty; androgen receptor; androgens; menopause; single nucleotide polymorphisms; women

DOI:  https://doi.org/10.1080/09513590.2025.2565238
Sci Rep. 2025 Oct 07. 15(1): 34996

Changes in the vaginal microbiome in female patients with condyloma acuminatum and its impact on persistent HPV infection.

Zhiyu Liu, Yinhua Wu, Chen Wang, Ningning Hou, Xiaoyan Liu.

  Condyloma acuminatum (CA) is one of the most common sexually transmitted diseases, and is characterized by a long incubation period and a high recurrence rate. The vaginal microbiome significantly impacts female reproductive health, influencing susceptibility to human papillomavirus (HPV) infections and related conditions such as CA. However, the role of the vaginal microbiome in the development of CA, especially regarding persistent HPV infection and CA recurrence, remains unclear. We aimed to investigate changes in the vaginal microbiota among female patients with vaginal CA and to determine if disturbances in vaginal flora contribute to persistent HPV infection and CA recurrence. In this study, vaginal swabs were collected from 63 female patients with vaginal CA and 20 healthy females. Furthermore, in the patient cohort, CA patients were stratified into two groups, the HPV persistent-positivity (HPV_PP) group and the HPV turn-negative (HPV_TN) group, based on whether the HPV status converted to negative after a 2-year follow-up. 16S V3-V4 rRNA gene sequencing was performed on these collected samples, followed by a comprehensive analysis of the sequencing data. We performed clinical feature analysis, assessment of the alpha and beta diversity of the vaginal microbiota, comparative analysis of microbial taxa, and functional prediction analysis. We further analyzed the relative abundance and functional profiles between the HPV_PP and HPV_TN groups. The composition and function of the vaginal microflora differed between female patients with vaginal CA and healthy controls, with an increase in alpha diversity observed in the CA group. The relative abundances of P. bivia, Gemella asaccharolytica, Streptococcus agalactiae and Metamycoplasma hominis in the CA group were significantly higher than those in the control group. Moreover, P. bivia and Anaerococcus prevotii were more highly expressed in the HPV_PP group than in the HPV_TN group. With respect to the functional profile, the Kyoto Encyclopedia of Genes and Genomes (KEGG) categories of signal transduction, drug resistance antimicrobial, xenobiotic biodegradation and metabolism, and MAPK signaling pathway, were significantly enriched in the HPV_PP group. In conclusion, the composition and function of the vaginal flora in female patients with vaginal CA are altered, and P. bivia is expected to be a diagnostic biomarker for persistent HPV infection. An imbalance in the vaginal flora is significantly associated with the recurrence of CA and HPV persistent infection.

Keywords:  16S rRNA sequencing; Condyloma acuminatum; Human papillomavirus; Vaginal microbiome

DOI:  https://doi.org/10.1038/s41598-025-18900-3
F S Rep. 2025 Sep;6(3): 328-334

Prior testosterone use does not appear to impact oocyte cryopreservation outcomes in transgender patients: findings from a multicenter health maintenance organization.

Natasha Raj-Derouin, Snunit Ben-Ozer, Amy Shah Dhesi, Tracy Harrison, Ashley Kim, Mandana Ghahremani, Sami Jabara, Marsha Baker.

   Objective: To compare the outcomes of oocyte cryopreservation in transgender patients with and without prior testosterone use.
Design: Retrospective cohort study.
Subjects: Transmasculine/non-binary patients assigned female at birth who were referred for fertility preservation from January 2012 to March 2024 at a multicenter health maintenance organization.
Exposure: Gender-affirming hormone therapy with testosterone.
Main Outcome Measures: The primary outcome measure was the number of mature oocytes collected. Secondary outcomes included the total number of oocytes, percentage of mature to total oocytes, total dose of gonadotropins used, baseline antimüllerian hormone, baseline antral follicle count, and baseline endometrial thickness.
Results: Data from 50 transgender oocyte cryopreservation cycles were analyzed in the time period studied. A total of 34 subjects (68%) had no exposure to testosterone, whereas prior testosterone use was reported in 16 subjects (32%). The mean duration of testosterone was 4.1 ± 2.6 years. Testosterone was discontinued 3 weeks to 3 months before cycle start. There were no significant differences in baseline demographics, such as age and body mass index, between the two patient groups. The total number of oocytes retrieved was statistically the same between transgender patients with prior testosterone use (17.3 ± 10.1) and those without (21.3 ± 10.1). Additionally, there were no differences in the number of mature oocytes (12.0 ± 7.5 vs. 16.1 ± 9.1) or ratio of mature/total oocytes between the two groups (72.3% ± 18.3% vs. 70.9% ± 22.4%). Secondary outcomes such as baseline antral follicle count, baseline antimüllerian hormone, total dose of gonadotropins used, and baseline endometrial thickness demonstrated no significant difference between the two study groups.
Conclusion: Our study suggests that prior testosterone use does not appear to impact oocyte cryopreservation outcomes in transgender patients. As a growing number of transgender patients seek fertility care, there is a need for evidence-based research that can guide clinical practice and empower this population to realize their aspirations for parenthood.

Keywords:  LGBTQIA+; Transgender; fertility; preservation; testosterone

DOI:  https://doi.org/10.1016/j.xfre.2025.06.011
BMC Genomics. 2025 Oct 09. 26(1): 899

The genetic influence of sex on gene expression for blood in pigs.

Qing Lin, Junxiong Huang, Tianru Zhou, Teddy Tinashe Chitotombe, Jinyan Teng, Jiaqi Li.

   BACKGROUND: Pigs are one of the most important farm animals in the agrifood industry. Many complex traits and patterns of gene expression exhibit sexual dimorphisms in pigs. However, the impact of sex on gene expression remains poorly understood.
RESULTS: In this study, we utilized the gene expression data of blood tissue derived from PigGTEx project to explore the genetic influence of sex on gene expression in pigs. Differential gene expression analysis identified 116 male-biased and 248 female-biased genes. Sex-combined and sex-stratified cis-heritability (cis-h2) were highly positively correlated, while the low correlation were observed between male-stratified and female-stratified cis-h2. Sex-interaction expression quantitative trait locus (eQTL) mapping identified 16 genes with at least one sex-biased eQTL (sb-eGenes) in blood, including 7 female-specific eGenes and 4 male-specific eGenes. Notable examples included the immunology-associated male-specific eGene SLC4A1 and the female-specific eGene PRR14, illustrating sex-specific regulation of gene expression in blood. We further found that sb-eGenes were associated with various complex traits through distinct genetic regulation mechanisms. For example, the male-specific gene SLC4A1 was associated with average daily gain with the identical effect, while the female-specific gene MFGE8 exhibited opposite effect.
CONCLUSIONS: This study revealed sex-biased gene expression patterns and sex-dependent regulatory effect of gene expression of blood tissues in pigs. Additionally, this study found the sexually dimorphic regulation of gene expression underlying complex traits. These findings provided a comprehensive insight and resource and advance our understanding of sexual dimorphism in genetic mechanism underlying complex traits in blood.

Keywords:  Blood; Expression quantitative trait locus; Gene expression; Pig; Sex-biased gene

DOI:  https://doi.org/10.1186/s12864-025-12029-3
Am J Reprod Immunol. 2025 Oct;94(4): e70151

Distinct Suppression of Prednisone on Endometrial Immune Cells in Women With Reproductive Failure.

Lu Chen, Xiaoyan Chen, Qianhan Xu, Joshua Jing Xi Li, Wen-Jui Yang, Hanbin Wu, Chi Chiu Wang, Xiaodan Fan, Jie Ji, Jacqueline Pui Wah Chung, Mingqing Li, Tin Chiu Li, Tao Zhang.

   RESEARCH QUESTION: For women with reproductive failure, prednisone is widely used but remains controversial as a therapy for improving clinical outcomes. This study aimed to investigate the impact of prednisone on various endometrial immune cells.
DESIGN: A total of 24 women with repeated implantation failure and recurrent miscarriage underwent their first endometrial biopsy precisely 7 days after luteinizing hormone surge (LH surge +7). Prednisone was administered from the first day of the subsequent menstrual cycle, followed by the second endometrial sampling on day LH surge +7 again. The density and cell-cell clustering of CD3-CD56+CD16- NK cells, CD3-CD56+CD16+ NK cells, CD68+CD16- macrophages, CD68+CD16+ macrophages, CD3+CD56- T cells, and CD3+CD56+ NK-T cells were analyzed by multiplex staining and compared before and after prednisone treatment.
RESULTS: Following prednisone treatment, a significant decrease in the percentage of CD3-CD56+CD16- NK cells (p < 0.001), CD68+CD16- macrophages (p = 0.007), and their clustering degree (p = 0.038) was observed. No significant changes were noted in CD3-CD56+CD16+ NK cells, CD68+CD16+ macrophages, CD3+CD56- T cells, CD3+CD56+ NK-T cells, and their cell-cell clustering.
CONCLUSION: Prednisone does not generally reduce all endometrial immune cells; instead, it selectively suppresses specific immune cell subtypes in women with reproductive failure.

Keywords:  NK cells; endometrium; macrophages; prednisone; reproductive failure

DOI:  https://doi.org/10.1111/aji.70151
Biol Psychiatry. 2025 Oct 08. pii: S0006-3223(25)01517-3. [Epub ahead of print]

Sex differences in brain cell-type specific chromatin accessibility in schizophrenia.

Yixuan Ma, Kiran Girdhar, Gabriel E Hoffman, John F Fullard, Jaroslav Bendl, Panos Roussos.

BACKGROUND: Our understanding of the sex-specific role of the non-coding genome in serious mental illnesses, particularly schizophrenia (SCZ), remains largely incomplete.
METHODS: To address this gap, we explored sex differences in 1,393 chromatin accessibility profiles, derived from neuronal and non-neuronal nuclei of two distinct cortical regions from 234 cases with serious mental illness and 235 controls.
RESULTS: We identified sex-specific enhancer-promoter interactions and showed that they regulate genes involved in X-chromosome inactivation (XCI). Additionally, examining chromosomal conformation allowed us to identify sex-specific cis- and trans-regulatory domains (CRDs and TRDs). Co-localization of sex-specific TRDs with schizophrenia common risk variants pinpointed male-specific regulatory regions controlling a number of metabolic pathways. Moreover, enhancers from female-specific TRDs were associated with two genes known to escape XCI-XIST, which encodes a long non-coding RNA (lncRNA) that coats the X chromosome and initiates XCI, and JPX, a regulatory lncRNA that activates XIST transcription-underlying the importance of TRDs in deciphering sex differences in schizophrenia.
CONCLUSIONS: Overall, these findings provide extensive characterization of sex differences in the brain epigenome and disease-associated regulomes.

DOI: https://doi.org/10.1016/j.biopsych.2025.09.016
Microb Pathog. 2025 Oct 06. pii: S0882-4010(25)00819-8. [Epub ahead of print]209 108094

The sex related differences in health and Disease: A systematic review of sex-specific gut microbiota and Possible implications for microbial pathogenesis.

Tehreema Ghaffar, Federica Valeriani, Vincenzo Romano Spica.

   BACKGROUND: The gut microbiota, a complex ecosystem influenced by various physiological and environmental factors, has been increasingly recognized for its role in health and disease. Emerging evidence suggests that sex differences, particularly mediated by sex hormones and physiological variations, significantly influence the composition and diversity of the gut microbiome. This systematic review aimed to evaluate and synthesize the current knowledge on sex-related variations in gut microbiota across human and animal studies.
METHODS: We conducted a systematic review of 24 eligible studies, selected from an initial 13,205 articles, focusing on healthy populations and next-generation sequencing-based microbiota profiling in both humans and animal models.
RESULTS: The results reveal sex-specific differences in microbial diversity and taxa abundance; however, the consistency and significance of these findings vary across studies, with females generally exhibiting higher levels of Akkermansia and Bifidobacterium, while males showed increased levels of Prevotella and Escherichia. These findings suggest that sex may be a contributing, but not necessarily dominant, biological variable shaping microbiome architecture across various species, including mice, pigs, deer, and humans, and highlight the influence of hormonal fluctuations, body composition, and lifestyle factors on gut microbial ecosystems.
CONCLUSION: Our findings underscore the importance of considering sex as a key biological variable in microbiome research and its potential implications for disease susceptibility, therapeutic interventions, and microbiome-targeted strategies in microbial pathogenesis. Moreover, evidence from human studies remains limited, especially those using 16S rRNA gene sequencing, which may lack the resolution to detect strain-level or functional differences. Incorporating multi-omics approaches such as metagenomics, metatranscriptomics, and metabolomics may offer deeper insights into sex-dependent microbial dynamics.However, these implications remain largely associative and require mechanistic validation in future studies.

Keywords:  Gut microbiota; Hormonal influence; Microbial diversity; Microbial pathogenesis; Sex differences

DOI:  https://doi.org/10.1016/j.micpath.2025.108094