bims-simsho 2025-11-23 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–11–23
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

Chromosomal and hormonal factors involved in human sexual dimorphism.
Comprehensive androgen-dependent transcriptome analysis in human genital tissue.
Sex differences in microglia morphology and function across the lifespan are mediated by the early hormone environment.
The intricate interplay between circadian rhythm, androgen signaling, hormone therapy, and cellular senescence in prostate cancer.
Sex Differences and Androgen Regulation Shape Mucosal Immune Phenotype, Gut Microbiota, and Microbiota-Derived Lactate in SKG Arthritis Model.
Role and interaction of LncRNAs and insulin resistance in polycystic ovary syndrome: a narrative review.
Immunoglobulin G and Aging: Biological Functions and Its Crosstalk with the Gut Microbiota.
The sex hormone-gut microbiome axis: mechanistic drivers of sex-disparate bacterial infection outcomes and precision clinical interventions.
Quercetin protects the survival and decidualization of endometrial stromal cells in PCOS mice by enhancing autophagy through PI3K/Akt/FoxO1.
Pyruvate kinase M2 -mediated histone lactylation alters three-dimensional genomic architecture in polycystic ovary syndrome.
Sex differences in cytokine induction by activated T cells from hypertensive BPH/2 and normotensive BPN/3 mice.
Cutibacterium acnes induces skin region-specific innate immune memory alterations in human keratinocytes.
Generation of Rat Monoclonal Antibodies for Human and Mouse Androgen Receptor.
Methylomes of human CD4 and CD8 memory T lymphocytes reveal tissue-specific epigenetic signatures for maintenance and recall function.
Sex differences in abnormal gluten response and predictors of gluten sensitivity in patients with schizophrenia.
The pulmonary commensal Lactobacillus regulated lung γδ T cells to enhance resistance against bacterial infections.
Single-cell transcriptomic analysis reveals T cell heterogeneity and metabolic reprogramming in human immune-mediated glomerulonephritis.
Conserved CD8 T cell vaccines without B cell epitopes drive robust protection against SARS-CoV-2 that is enhanced by intranasal boost.
Cross-sectional study of the relationship between dietary inflammatory index and inflammatory hormonal and metabolic profiles in polycystic ovary syndrome.
Blood and tissue correlates of steroid non-response in checkpoint inhibition-induced immune-related adverse events.
Effects of supplementation with two probiotic strains (Lactobacillus helveticus and Bifidobacterium longum) on hormonal status, oxidative stress, and clinical symptoms in women with polycystic ovary syndrome: a randomized clinical trial.
Early-life gut and oral microbiota development: a multi-niche study including mother-partner-infant triads.
Gut-ovary axis in polycystic ovary syndrome: mechanistic insights and gut microbiota-targeted therapeutic strategies.
Glucose-dependent insulinotropic peptide (GIP) suppresses androgen biosynthesis in PCOS mouse models and cellular systems.
Interferon-mediated NK cell activation increases cytolytic activity against T follicular helper cells and limits antibody response to SARS-CoV-2.
Postoperative Ileum Transcriptomics Implicate Sex-Biased Mechanisms in Crohn's Disease Recurrence.

Endocr J. 2025 Nov 19.

Chromosomal and hormonal factors involved in human sexual dimorphism.

Maki Fukami, Kohji Okamura, Shoko Sasaki, Masayo Kagami, Sumito Dateki.

  Males and females show significant differences in body structure, typical behavior, average life expectancy, and disease susceptibility. This review article introduces the current understanding and recent findings on the factors that lead to sexual dimorphism. First, recent studies have shown that sex chromosomes underlie male- and female-specific phenotypes through various mechanisms. For example, X chromosome inactivation exerts both positive and negative effects on female health, independent of sex hormone actions. Furthermore, differences in the frequency and clinical consequences of the mosaic loss of X and Y chromosomes have been implicated in sex differences in disease susceptibility and average life expectancy. In addition, sex-specific epigenetic regulation of the pseudoautosomal gene SHOX has been linked to the relative short stature of females. Second, an alternative steroidogenic pathway and novel non-aromatizable androgens have been specified in humans. These factors, together with classical sex hormones, likely contribute to the phenotypic differences between males and females. Elucidating the molecular basis of sexual dimorphism helps us understand the factors involved in human diversity.

Keywords:  Androgen; Estrogen; SHOX; X chromosome inactivation

DOI:  https://doi.org/10.1507/endocrj.EJ25-0379
BMC Genomics. 2025 Nov 17. 26(1): 1047

Comprehensive androgen-dependent transcriptome analysis in human genital tissue.

Radhika Sivaprasad, Kristian Händler, Almuth Caliebe, Malte Spielmann, Paul-Martin Holterhus, Nadine C Hornig.

   BACKGROUND: Androgen signalling through the androgen receptor (AR) is crucial for male genital development. Disruptions in this pathway are associated with androgen insensitivity syndrome (AIS), which is typically caused by mutations in the AR gene, although the underlying genetic mechanisms remain unknown in many cases. To better understand androgen-dependent transcriptional changes in human genital tissue, we performed transcriptomic profiling of foreskin- and scrotum-derived human genital skin fibroblasts (GSFs) treated with dihydrotestosterone.
RESULTS: Differential gene expression analysis revealed 409 and 260 reproducibly up-regulated genes in foreskin- and scrotum-derived GSFs, respectively. GSFs from individuals with complete androgen insensitivity syndrome, carrying inactivating mutations in the AR gene, showed no reproducible androgen response. Androgen response element motif scanning confirmed direct AR binding in key up-regulated genes, including AOX1, APOD, FKBP5, and FAM107A. Gene ontology analysis revealed enrichment in pathways related to neuronal, muscle, cardiovascular, and sex development.
CONCLUSION: Identifying new AR target genes broadens the current understanding of androgen signalling and aids in better understanding the aetiology of AIS, and other androgen-related conditions.

Keywords:  Androgen insensitivity syndrome; Androgen receptor; Transcriptional regulation

DOI:  https://doi.org/10.1186/s12864-025-12212-6
Brain Behav Immun. 2025 Nov 19. pii: S0889-1591(25)00429-5. [Epub ahead of print] 106187

Sex differences in microglia morphology and function across the lifespan are mediated by the early hormone environment.

Lourdes K Davis, Miranda M Anders, Steven P Guerin, Sophia E Khoury, Lindsay M Thompson, Jeffrey S Darling, Andrea C Gore, Laura K Fonken.

  Microglia, the resident immune cell of the central nervous system (CNS), contribute to a range of physiological processes across the lifespan. Microglia exhibit notable sex differences in morphology, reactivity, and transcriptomic profiles. Steroid hormones in early life are believed to elicit sex differences in many cells, including microglia, in the CNS. However, few studies have examined how neonatal hormone environment impacts microglial morphology and function across the lifespan. Therefore, here we used steroid hormones to manipulate the early hormone environment to assess the appearance and persistence of sex differences in a rat model of healthy aging. Rat pups were dosed with steroid hormones on postnatal day (P)0 and 1: females received testosterone to "masculinize" them and males received flutamide, an androgen antagonist, to "feminize" them. Brain tissue was then collected at three distinct developmental timepoints: adolescence (P30), adulthood (P150), and aging (P700) for immunohistochemistry and ex vivo microglial stimulation. Transcriptomic changes in hippocampal tissue of aged animals were also assessed using 3'UTR biased transcriptome sequencing (Tag-seq). We report that testosterone treatment in females leads to lifelong alterations in body size and vaginal morphology and results in microglia that display a more "masculinized" phenotype compared to controls. Flutamide had more moderate effects on microglia morphology in males, contributing to a more "feminized" phenotype in the hippocampus in adult and aged males. Testosterone treatment also resulted in greater transcriptomic changes in the aged hippocampus compared to flutamide treatment, especially in genes related to mitochondrial function and inflammation. These results indicate that (1) early hormone environment is critical for the induction of sex differences in microglial morphology and (2) sex differences in microglial morphology reverse during aging, and this reversal is also recapitulated with early hormone treatment.

Keywords:  Aging; Flutamide; Hormones; Microglia; Neuroimmunology; Sex differences; Testosterone

DOI:  https://doi.org/10.1016/j.bbi.2025.106187
Cancer Metastasis Rev. 2025 Nov 20. 44(4): 84

The intricate interplay between circadian rhythm, androgen signaling, hormone therapy, and cellular senescence in prostate cancer.

Mehdi Heidari Horestani, Aria Baniahmad.

  Prostate cancer (PCa) is the second most diagnosed cancer and the fifth leading cause of cancer death among men worldwide. Androgen receptor (AR), as a ligand-activated transcription factor, is important for both prostate development and PCa progression. Understanding the molecular mechanisms of prostate carcinogenesis has led to the development of therapeutic strategies targeting AR. Inhibiting AR is currently the gold standard for hormone therapy. However, eventually resistance to therapy occurs. The activation of AR by supraphysiological androgen levels (SAL) used currently in clinical trials paradoxically also inhibits PCa progression and induces cellular senescence. Interestingly, circadian rhythm controls hormone biosynthesis including androgens. Intriguingly, SNPs in several clock genes have been associated with PCa risk linking increased cancer risk with day-night shifts. Here, we discuss whether the efficacy of hormone therapeutics depends on the biological clock. It emerges that androgens control the expression of clock genes also intersecting with SAL-induced cellular senescence suggesting a complex and understudied network that governs PCa progression. This review highlights the multifaceted roles of AR signaling in PCa, emphasizing its ability to promote cellular senescence by AR-targeted therapy via genomic and non-genomic pathways and crosstalk with the regulation of circadian clock genes. The intricate interplay between circadian rhythm, androgen signaling, and cellular senescence presents a promising yet underexplored research area in PCa and suggests a multilayered regulatory network that could shape PCa progression and treatment outcomes. Unraveling this network may uncover novel chronotherapeutic strategies and provide new insights into disease, prognosis, and therapy options.

Keywords:  Androgen receptor; Cancer; Cellular senescence; Circadian rhythm; Clock genes; Prostate cancer

DOI:  https://doi.org/10.1007/s10555-025-10302-1
J Inflamm Res. 2025 ;18 15911-15924

Sex Differences and Androgen Regulation Shape Mucosal Immune Phenotype, Gut Microbiota, and Microbiota-Derived Lactate in SKG Arthritis Model.

Xinran Wu, Lingjuan Jiang, Yubin Cao, Peng Wang, Wenjing Wang, Xuan Zhang.

   Objective: This study aimed to investigate the role of sex differences and androgen regulation in the development of arthritis, focusing on their effects on gut microbiota, metabolic profiles, and immune responses in the SKG mouse model of arthritis.
Methods: Eight-week-old male and female SKG mice were injected with zymosan to explore sex-related differences in arthritis progression. Androgen regulation was assessed in 4-week-old male SKG mice through castration and sham surgeries. Flow cytometry, 16S rDNA sequencing, metabolomics, histopathology, and immunofluorescence were used to evaluate immune responses, microbiota composition, and metabolic alterations.
Results: Sex differences significantly impacted immune cell composition, particularly dendritic cells (DCs), in the mesenteric and popliteal lymph nodes. Male mice exhibited an increased proportion of conventional type I DCs (cDC1), while female mice displayed a higher proportion of conventional type II DCs (cDC2). Androgen deprivation in male mice worsened disease severity, with reduced cDC1 cells and increased inflammatory infiltration. Sex differences also influenced gut microbiota, with higher levels of Lactobacillus in females, and castrated males resembling females in microbiota composition. Metabolomic analysis revealed significant sex-related differences, with lactate showing the most pronounced androgen-related changes. Additionally, androgen regulated hypoxia inducible factor-1 alpha (HIF1α) expression in mucosal DCs, promoting an immune tolerance phenotype.
Conclusion: This study highlights the significant role of sex and androgen regulation in arthritis development, revealing complex interactions between hormones, microbiota, and immune regulation. These findings suggest new avenues for sex-specific therapeutic strategies and precision interventions targeting microbiota and metabolic modulation in arthritis and other autoimmune diseases.

Keywords:  androgen regulation; arthritis; dendritic cells; gut microbiota; immune tolerance; microbiota-derived lactate

DOI:  https://doi.org/10.2147/JIR.S552491
J Ovarian Res. 2025 Nov 18. 18(1): 267

Role and interaction of LncRNAs and insulin resistance in polycystic ovary syndrome: a narrative review.

Mengfan Peng, Xiaofang Zhang, Xue Yang, Tingting Ye, Baosong Liu.

  Polycystic ovary syndrome (PCOS) is a complex disorder involving reproductive, endocrine, and metabolic abnormalities and is characterized by irregular menstruation, infrequent or absent ovulation, elevated androgen levels, insulin resistance (IR), and polycystic ovarian morphology (PCOM). It is the main cause of female infertility and high miscarriage rates and leads to high incidence of metabolic diseases. The pathogenesis of PCOS is complex, and IR is a crucial pathophysiological mechanism involved in multiple processes, such as ovulatory dysfunction, reproductive endocrine abnormalities, and metabolic disorders. Notably, long noncoding RNAs (lncRNAs), potential novel biomarkers and intervention targets for predicting the development of PCOS, have been shown to have a reciprocal regulatory relationship with IR in the context of PCOS therapy. A comprehensive analysis of lncRNAs and IR in PCOS is presented in this paper, highlighting the potential for mutual synergistic effects. Specifically, we discuss the mechanisms underlying lncRNAs and IR, emphasizing their ability to regulate reproductive endocrine disorders and metabolic abnormalities. Furthermore, we investigated the interactions between lncRNAs and IR in the pathogenesis, treatment, and prognosis of PCOS. We aim to provide a prospective view of the promising value of combining lncRNAs and IR in the treatment of PCOS by elucidating the roles and mutual regulatory network of lncRNAs and IR.

Keywords:  Insulin resistance; Long noncoding RNA; Pathogenesis; Polycystic ovary syndrome

DOI:  https://doi.org/10.1186/s13048-025-01858-1
Rejuvenation Res. 2025 Nov 18.

Immunoglobulin G and Aging: Biological Functions and Its Crosstalk with the Gut Microbiota.

Xin-Yi Zhang, De-Guan Li.

  Aging is characterized by a progressive decline in physiological integrity, often accompanied by chronic inflammation and immune dysregulation. Immunoglobulin G (IgG), a key effector of humoral immunity, undergoes substantial structural and functional remodeling with age, particularly through changes in its glycosylation profile. These modifications shift IgG toward a proinflammatory state, linking it to inflammaging and multiple age-related diseases. This review synthesizes recent advances in understanding how IgG contributes to immune aging, with a specific focus on its glycosylation-dependent functions, tissue accumulation, and bidirectional crosstalk with the gut microbiota. We also highlight the potential of IgG as a biomarker and therapeutic target in aging-related interventions. We discuss the dual functional architecture of IgG and how age-related glycan shifts-namely, increased agalactosylation, afucosylation, and bisecting N-acetylglucosamine (GlcNAc)-enhance binding to activating Fcγ receptors, amplifying proinflammatory signaling. Experimental studies demonstrate that IgG accumulation in adipose tissue contributes to metabolic dysfunction via Neonatal Fc Receptor (FcRn)-dependent pathways. Additionally, sex hormones modulate IgG glycosylation patterns, partially explaining sex-specific differences in immune aging. The concept of "glycan clocks" has emerged as a tool to assess biological age and intervention responsiveness. Moreover, the gut microbiota plays a critical role in shaping the IgG repertoire, and aging disrupts this IgG-microbiota axis, resulting in altered mucosal immunity and systemic inflammation. Interventions targeting this axis-including microbiota modulation and glycoengineering-offer promising translational avenues for immune rejuvenation. Finally, we review emerging therapeutic strategies that leverage the gut-immune interface to mitigate aging-associated cardiovascular and metabolic diseases. IgG is not merely a biomarker but an active participant in the aging process, functioning at the intersection of immune regulation, microbial symbiosis, and systemic inflammation. Its age-associated transformation reflects broader changes in host immunity and highlights new opportunities for precision interventions in immunosenescence.

Keywords:  Fcγ receptors; aging; biological age; glycosylation; gut microbiota; immune senescence; immunoglobulin G; inflammaging

DOI:  https://doi.org/10.1177/15491684251396176
Clin Microbiol Rev. 2025 Nov 20. e0023625

The sex hormone-gut microbiome axis: mechanistic drivers of sex-disparate bacterial infection outcomes and precision clinical interventions.

Li Tang, Peilu Xie, Hao Wang, Xinhuizi Hong, Zhengwen Gong, Guoping Zhao, Min Yue.

  SUMMARYSex disparities in bacterial infections pose significant challenges in clinical microbiology, influencing diagnostic approaches, antimicrobial stewardship, and patient outcomes. Males frequently exhibit heightened severity in conditions like Helicobacter pylori-associated gastritis and Vibrio cholerae outbreaks, whereas females face amplified risks during reproductive phases for pathogens, such as Listeria monocytogenes and Salmonella spp. Beyond genetic and behavioral factors, the bidirectional sex hormone-gut microbiome axis emerges as a key mechanistic driver: estrogens bolster innate immunity and microbial diversity (e.g., enriching short-chain fatty acid-producing taxa like Bifidobacterium), while androgens and progesterone impose immunosuppressive effects, altering colonization resistance and virulence modulation. Microbial contributions-via β-glucuronidase-mediated hormone deconjugation, bile acid biotransformations, and metabolite signaling-further calibrate host responses, as evidenced in Clostridioides difficile recurrence and enterohemorrhagic Escherichia coli virulence upregulation. This review synthesizes epidemiological, preclinical, and emerging clinical data, highlighting the axis's role in pathogen-specific immune evasion and dysbiosis-driven exacerbations. Clinically, these insights advocate for sex-stratified microbiome diagnostics (e.g., 16S rRNA sequencing for risk profiling) and targeted therapies, including hormone-modulated probiotics to restore barrier function, fecal microbiota transplantation to curb antibiotic-associated vulnerabilities, and selective estrogen receptor modulators to enhance clearance in high-risk cohorts. Despite advances, gaps in human longitudinal studies and pathogen-strain interactions limit translation. Future research integrating multi-omics with clinical trials could refine precision interventions, optimizing infection management in diverse populations and aligning with evolving demands for personalized microbiology.

Keywords:  bacterial pathogens; gut microbiome; intestinal mucosal immunity; sex hormones

DOI:  https://doi.org/10.1128/cmr.00236-25
Pak J Pharm Sci. 2025 Nov-Dec;38(6):38(6): 2409-2422

Quercetin protects the survival and decidualization of endometrial stromal cells in PCOS mice by enhancing autophagy through PI3K/Akt/FoxO1.

Jinglu Yu, Xiaoling Feng, Wei Jiang, Ying Huang, Miao Sun, Yongwei Du, Ge Yu.

  Polycystic ovary syndrome (PCOS) can lead to increased abortion rates. Quercetin treats PCOS, but its specific mechanism has not been fully clarified. PCOS was induced in mice by dehydroepiandrosterone, and decidualization was induced by corn oil. Mice were treated with quercetin, autophagy inhibitor 3-MA, autophagy inducer rapamycin, PI3K inhibitor LY294002, and PI3K inducer 740Y-P. Pathological damage in the ovary and uterus was observed by HE staining. The levels of sex hormones, metabolism, and inflammatory factors were detected using ELISA. The survival and decidualization of endometrial stromal cells were identified by immunohistochemistry, immunofluorescence, qRT-PCR, and Western blot. Autophagy and the PI3K/Akt/FoxO1 pathway-related protein levels were detected by Western blot. The theca cell layer and endometrium of PCOS mice were significantly thinner. The levels of sex hormone, pro-inflammatory factors, COX-2, integrin ανβ3, and autophagy-related proteins were obviously raised, while Vimentin, IGFBP-1, PRL, and PI3K/Akt/FoxO1 pathway expression were significantly decreased. The above indices were reversed considerably after quercetin treatment. 3-MA could reduce the level of autophagy, LY294002 could reduce the levels of PI3K/Akt/FoxO1 pathway, Vimentin, and PRL, and increase the level of autophagy. In conclusion, quercetin enhanced autophagy through the PI3K/Akt/FoxO1 pathway; thereby protecting endometrial stromal cells and improving decidualization disorders.

Keywords:   Autophagy ; Decidualization ; PCOS ; PI3K/Akt/FoxO1 pathway ; Quercetin

DOI:  https://doi.org/10.36721/PJPS.2025.38.6.REG.14133.1
Signal Transduct Target Ther. 2025 Nov 19. 10(1): 376

Pyruvate kinase M2 -mediated histone lactylation alters three-dimensional genomic architecture in polycystic ovary syndrome.

Chuanjin Yu, Tingting Liu, Yishu Wang, Xinghui Guo, Yujie Chen, Yifan Zhao, Xia Liu, Weiwei Huang, Shuoyang Zhao, Jiaying Mo, Hongtao Hu, Pingping Lv, Xiaotao Wang, Zuwei Yang, Jiexue Pan, Guolian Ding, Jianzhong Sheng, Xinmei Liu, Hongbo Yang, He-Feng Huang.

Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer-promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1. In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2-tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.

DOI: https://doi.org/10.1038/s41392-025-02468-5
bioRxiv. 2025 Oct 01. pii: 2025.09.30.679479. [Epub ahead of print]

Sex differences in cytokine induction by activated T cells from hypertensive BPH/2 and normotensive BPN/3 mice.

Devon A Dattmore, Jeffrey R Leipprandt, Saamera Awali, Tina Fu, McKenzie Mahlmeister, Hannah Garver, Afolashade Onunkun, D Adam Lauver, Cheryl E Rockwell.

Over the past two decades, considerable evidence has emerged to implicate a role for the immune system in the development of hypertension. Previous studies have shown immune cells contribute to the development of hypertension in multiple animal models, however the role of the immune system in spontaneously hypertensive BPH/2 mice is not clear. In the current studies, found T cells derived from male hypertensive BPH/2 mice demonstrated an attenuated activation as compared to those derived from male BPN/3 normotensive mice. However, we also observed striking sex differences in T cell cytokine production in these strains. At 24 h post activation, in comparison to male BPH/2 mice, activated T cells from male BPN/3 mice secreted more IL-2, IL-3, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-22 and TNFα. In contrast to male mice, less than half of these cytokines were different between strains in female mice. We also noted marked differences in early Th17 cytokine production in which IL-17A, IL-17F and IL-22 were greater in the male, but not female, BPN/3 groups. Taken together, the data suggest that polyclonally activated T cells from male, and to a much lesser extent, female BPH/2 mice have a weaker cytokine response as compared to T cells from BPN/3 mice which may be due to an overall attenuated activation of T cells from male BPH/2 mice. Overall, while there are striking differences in T cell response between the BPH2 and BPN/3 strains in male mice, the data indicate far fewer differences between the strains in female mice.

DOI: https://doi.org/10.1101/2025.09.30.679479
J Invest Dermatol. 2025 Nov 14. pii: S0022-202X(25)03544-4. [Epub ahead of print]

Cutibacterium acnes induces skin region-specific innate immune memory alterations in human keratinocytes.

Fanni Balogh, Anett Magyari, Lilla Erdei, Beáta Szilvia Bolla, Balázs Koncz, Laura Bagi, Máté Manczinger, Blanka Toldi, Bálint Baráth, Katalin Burián, Rolland Gyulai, Lajos Kemény, Kornélia Szabó.

  External insults can cause immune activation in immune cells, resulting in persistent molecular changes that can lead to innate immune memory (IIM) changes in these cells. This study investigated the potential for cellular reprogramming in response to Cutibacterium acnes in keratinocytes. We exposed normal human epidermal keratinocytes obtained by mammoplasty (NHEK-B) or abdominoplasty (NHEK-A) to C. acnes, followed by stimulation with Pam3CSK4 to assess immune activation and cellular responses. In NHEK-B cells, C. acnes and Pam3CSK4 treatment induced trained immunity-type responses, higher expression of selected immune target genes, and a diminished response compared with trained and Pam3CSK4-induced NHEK-A cells. Total transcriptome analysis delineated regional differences, with the activation of immune-related pathways in NHEK-B cells and alterations in keratinocyte differentiation processes in NHEK-A cells. We detected differences in metabolic regulation, and utilizing pharmacological inhibitors, we demonstrated the necessity of the optimal regulation of histone acetylation and DNA methylation for the aforementioned changes. This study demonstrated that C. acnes triggers IIM processes in keratinocytes, characterized by signaling, epigenetic, and metabolic reprogramming that influences cellular responses to subsequent stimuli. The observation that analogous insults might elicit skin region-specific responses offers insights into the etiology and mechanisms underlying common inflammatory skin diseases.

Keywords:  Cutibacterium acnes; epigenetics; innate immune; innate immune memory; microbiota

DOI:  https://doi.org/10.1016/j.jid.2025.10.610
Monoclon Antib Immunodiagn Immunother. 2025 Nov 19.

Generation of Rat Monoclonal Antibodies for Human and Mouse Androgen Receptor.

Momo Koike, Tomoka Kawabata, Norikazu Kiguchi, Yu Hatano, Kentaro Suzuki, Taro Tachibana, Chikako Yokoyama.

  Androgen receptor (AR) is activated by binding to androgens, which leads to nuclear translocation, dimerization, and binding to androgen response elements (AREs) to regulate gene transcription. AR is important in masculinization during mammalian development and is a major driver of tumor growth in prostate cancer, for which AR pathway inhibitors are the standard treatment. However, the mechanisms by which AR participates in these processes remain unclear. In this study, we describe rat monoclonal antibodies (mAbs) that were generated against human and mouse AR. These mAbs recognize endogenous AR and were shown to be effective in the immunofluorescence staining of human cell lines and mouse tissue sections and in immunoprecipitation experiments. We expect these mAbs to be useful for functional analyses of AR.

Keywords:  androgen receptor; human cancer cell line; monoclonal antibody; mouse tissue; prostate cancer

DOI:  https://doi.org/10.1177/21679436251398987
Immun Inflamm. 2025 ;1(1): 13

Methylomes of human CD4 and CD8 memory T lymphocytes reveal tissue-specific epigenetic signatures for maintenance and recall function.

Xiangyi Deng, Weijie Du, Gilles Gasparoni, Abdulrahman Salhab, Karl Nordström, Jinchan Li, Viktoria Wagner, Erping Zhang, Joachim Wachtlin, Juliane Bodo, Simon Reinke, Hong Lei, Carsten Perka, Sebastian Hardt, Thomas Dörner, Christoph Holmer, Mario Tönnies, Torsten Bauer, Hyun-Dong Chang, Julia K Polansky, Jörn Walter, Pawel Durek, Andreas Radbruch, Jun Dong.

  Adaptive immunity relies on antibodies and memory B and T cells, with memory T cells providing "reactive memory". These cells either circulate in the blood or remain as tissue-resident memory T cells, yet the epigenetic mechanisms underlying their recall function and maintenance are not well understood. Here, we present a comprehensive analysis of 56 reduced representation bisulfite sequencing (RRBS) datasets from 22 memory CD4 and CD8 T-cell populations isolated from human bone marrow, intestine, spleen, lung, skin, and peripheral blood, including surface CD69-positive and CD69-negative cells. Our study reveals unique DNA hypomethylation patterns in tissue-resident memory T cells, particularly in regions associated with genes involved in tissue homing, residency, and transcription factors regulating recall effector memory. The methylomes and differential methylation signatures identified here serve as a valuable resource for understanding the epigenetic program of memory T lymphocytes, their roles in immunological recall, and their maintenance within specific tissues.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at 10.1007/s44466-025-00009-x.

Keywords:  Chemokine receptors; DNA methylation; Epigenetic memory; Integrins; Maintenance; Tissue-resident memory T cells; Transcription factors; human tissues

DOI:  https://doi.org/10.1007/s44466-025-00009-x
Front Immunol. 2025 ;16 1696763

Sex differences in abnormal gluten response and predictors of gluten sensitivity in patients with schizophrenia.

Michał Dzikowski, Joanna Rog, Dariusz Juchnowicz, Anna Rymuszka, Hanna Karakula-Juchnowicz.

   Introduction: Immune-inflammatory dysregulations are linked to shifts in specific gut microbiota genera, underscoring the importance of the gut-brain connection in schizophrenia (SZ). However, the immune-inflammatory aspects of sex differences in SZ remain largely unexplored. The aims of this study were (1) to identify sex-related differences in inflammatory response, intestinal biomarkers, and gluten sensitivity in SZ and (2) to determine potential factors underlying variability in the immune response to gluten in this population.
Methods: A total of 102 individuals with SZ and 60 healthy controls (HC) were included in the study.
Results: Elevated titers of anti-gliadin (AGA) IgA were found in 26% of individuals with SZ compared to 22% of HC and elevated AGA IgG in 30% of SZ patients compared to 20% of HC. The IgG levels were higher in men than in women, regardless of health status. Significant differences in the levels of AGA IgG and deamidated gliadin (dGP) IgG were observed between men and women with SZ, with higher concentrations detected in men. Factors differentiating patients with positive AGA IgA antibodies included tissue transglutaminase (tTG) IgA levels, high-sensitivity C-reactive protein (hs-CRP) levels, and age. Factors associated with positive AGA IgG antibodies included dGP and anti-Saccharomyces cerevisiae (ASCA) antibody levels, negative symptoms of SZ, and age of onset.
Discussion: This is the first study to examine sex-related differences and illness stage in the immune response to gluten among SZ patients. Stronger inflammatory responses were found in men, suggesting sex-related disparities in gluten-related immune activation. These findings highlight a complex interplay between hormones, immune function, intestinal barrier integrity, and psychiatric symptoms. Further longitudinal research is needed to clarify these mechanisms and their clinical significance.

Keywords:  cytokines; food immune reactivity; gluten; inflammation-dependent psychiatric disorders; low-grade inflammation

DOI:  https://doi.org/10.3389/fimmu.2025.1696763
Microbiome. 2025 Nov 19. 13(1): 235

The pulmonary commensal Lactobacillus regulated lung γδ T cells to enhance resistance against bacterial infections.

Haochi Zhang, Xuemei Bao, Chunhe Li, Yanchen Liang, Na Pan, Yubing Fu, Bin Ma, Ting Wang, Jian Chen, Lipeng Zhang, Xiao Wang.

   BACKGROUND: Pulmonary commensals play a crucial role in regulating host immune homeostasis and combating infections. Nevertheless, the deep mechanisms remain unclear.
RESULTS: Long-term antibiotics pre-exposure enhanced the susceptibility to bacterial pneumonia, while intranasal reconstitution of the pulmonary microbiota mitigated these adverse effects, restoring host resilience to infections. We isolated two pulmonary commensals, Lactobacillus plantarum and Lactobacillus murinus, demonstrating that they induced IL-17A-mediated antibacterial immunity and promoted resistance to lung infections. Moreover, antibiotics-treatment reduced the frequency of pulmonary IL-17A secreting Vγ4+ γδ T cells and made the mice more susceptible to pneumonia, which was reversed by transferring pulmonary Lactobacillus commensals. In addition, our data indicated that L. plantarum and L. murinus-derived metabolites, particularly extracellular polysaccharides, can activate lung Vγ4+ γδ T cells to secrete IL-17A in defense against bacterial lung infections.
CONCLUSIONS: In this study, we report for the first time that pulmonary commensal Lactobacillus, specifically L. plantarum and L. murinus, activate Vγ4+ γδ T cells to secrete IL-17A, thereby mitigating susceptibility to Staphylococcus aureus and Pseudomonas aeruginosa infections. Additionally, we identified the metabolite of L. plantarum and L. murinus, extracellular polysaccharides, as the key immunomodulatory molecules. This research highlights the importance of pulmonary commensals in the regulation of anti-infection immunity and provides a theoretical foundation for clinical studies on the role of lung microbiota in combating infections. Video Abstract.

Keywords:  Antibiotics; IL-17A; Infection; Pulmonary commensals; γδ T cells

DOI:  https://doi.org/10.1186/s40168-025-02205-8
Autoimmunity. 2025 Dec 31. 58(1): 2582720

Single-cell transcriptomic analysis reveals T cell heterogeneity and metabolic reprogramming in human immune-mediated glomerulonephritis.

Jianbo Qing, Yiting Zhao, Wisit Cheungpasitporn, Jing Miao, Charat Thongprayoon, Henglan Wu, Junnan Wu.

  Immune-mediated glomerulonephritis (IMGN) is a major cause of kidney failure worldwide, yet the precise roles of T cells in its pathogenesis remain poorly understood. However, existing studies lack a comprehensive understanding of the characteristics and functional roles of IMGN T cells in the human context. Addressing this gap is crucial for advancing targeted therapies. By integrating single-cell RNA sequencing (sc-RNA-seq) data from three primary IMGN types-IgA nephropathy (IgAN), lupus nephritis (LN), and membranous nephropathy (MN)-we identified T cell subtype alterations at single-cell resolution. Utilizing advanced sc-RNA-seq computational pipelines, we constructed gene co-expression networks (GCNs), inferred T-cell differentiation trajectories, and assessed metabolic and intercellular signaling features. IMGN kidneys presented expanded T-cell compartments, with significant enrichment of cytotoxic natural killer T (NKT) cells and GZMK⁺ effector memory T (GZMK⁺ Tem) cells. Notably, LTB⁺ memory T cells (LTB⁺ Tm) were selectively elevated in IgAN and LN patients. A coexpression module centered on RGS1 was significantly correlated with 24-h proteinuria (p < 0.001). Metabolic profiling revealed subtype-specific disruptions in the glutathione (GSH) and 3-phospho-D-glyceroyl phosphate (3PD) pathways. Interaction analysis highlighted endothelial cells, mesangial cells, and fibroblasts as key mediators of pathogenic T-cell activation via defined ligand‒receptor pairs. This study provides the first comprehensive single-cell atlas of human IMGN T cells, revealing disease-specific T-cell states, metabolic signatures, and activation mechanisms. Our findings offer new insights into human renal immunopathology and identify promising therapeutic targets for IMGN.

Keywords:  Immune-mediated glomerulonephritis (IMGN); T cell; cell crosstalk; heterogeneity; metabolic reprogramming; single cell

DOI:  https://doi.org/10.1080/08916934.2025.2582720
Sci Adv. 2025 Nov 21. 11(47): eadx0037

Conserved CD8 T cell vaccines without B cell epitopes drive robust protection against SARS-CoV-2 that is enhanced by intranasal boost.

Genghao Chen, Thao Nguyen, Lindsay G A McKay, Sravya Sowdamini Nakka, Pan Hu, Julia McBride, Anthony C Liang, Rachel Olson, James J Moon, Andrew D Luster, Anthony Griffiths, Stephen J Elledge.

The emergence of SARS-CoV-2 variants has challenged the current spike protein-focused COVID-19 vaccine strategy due to neutralizing antibody escape and waning antibody-mediated immunity. In contrast, T cell-mediated immunity targeting conserved epitopes may offer broad and long-lasting protection. However, whether T cells alone can provide sufficient protection remains unclear. Here, we identified both Omicron BA.1-specific and ancestral (Wuhan)-conserved CD8 T cell epitopes in the SARS-CoV-2 spike protein and evaluated them as carrier-protein fusion vaccines in mouse models. Subcutaneous immunizations with two CD8 epitope peptides substantially lowered lung viral load and conferred protection against low-dose viral challenge, but not against high-dose challenge. Notably, intranasal boosting-with or without adjuvant-enhanced lung resident memory T cell responses and conferred potent, durable protection against high-dose infection. These findings emphasize the importance of mucosal vaccination to boost protective T cell immunity against SARS-CoV-2 and support the potential of T cell-based vaccines targeting conserved epitopes for broad immunity against SARS-CoV-2 and other respiratory viral threats.

DOI: https://doi.org/10.1126/sciadv.adx0037
Sci Rep. 2025 Nov 17. 15(1): 40211

Cross-sectional study of the relationship between dietary inflammatory index and inflammatory hormonal and metabolic profiles in polycystic ovary syndrome.

Nava Morshedzadeh, Vahideh Behrouz, Amirhossein Ramezani Ahmadi.

  Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by obesity, hyperandrogenism, and dyslipidemia, with chronic inflammation playing a key role in its pathogenesis. While the Dietary Inflammatory Index (DII) has been linked to metabolic diseases, its association with PCOS-specific hormonal and inflammatory markers remains underexplored. This cross-sectional study aimed to investigate relationships between DII scores and metabolic/hormonal profiles in 200 women with PCOS (aged 18-48 years) diagnosed using Rotterdam criteria. Participants' dietary intake was assessed using a validated 168-item food frequency questionnaire. Anthropometric measurements, biochemical markers (including fasting blood glucose (FBG), lipid profile, high-sensitive C-reactive protein (hs-CRP), and Erythrocyte sedimentation rate (ESR)), and hormonal levels (prolactin, follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and total testosterone), and blood pressure were analyzed. Statistical analyses were performed using SPSS version 20.0 (IBM Corporation), employing multivariate linear regression with the ENTER method. Models were adjusted for age, BMI, smoking status, physical activity, and energy intake. The mean ± SD for the age of the participants was 38.23 ± 9.52 years. The mean BMI for the total sample was 24.40 ± 2.64 kg/m². Higher DII scores (indicating more pro-inflammatory diets) were significantly associated with elevated levels of FBG (β=+13.34, P < 0.001), hs-CRP (β=+1.18, P < 0.001), ESR (β=+3.39, P < 0.001), prolactin (β=+6.68, P < 0.001), FSH (β=+1.81, P < 0.001), and LH (β=+3.97, P < 0.001) in initial analyses. These associations remained significant after full adjustment (all P < 0.05). No significant relationships were observed between DII scores and lipid profiles or total testosterone levels after full adjustment (P > 0.05). These findings indicate that pro-inflammatory dietary patterns are associated with worsened inflammatory markers, glycemic control, and gonadotropin levels in women with PCOS. The results suggest a possible beneficial role of anti-inflammatory dietary interventions in PCOS management, although longitudinal studies are needed to establish causal relationships.

Keywords:  Dietary inflammatory index; Dyslipidemia; Glycemic control; Hyperandrogenism; Inflammation; Obesity; PCOS

DOI:  https://doi.org/10.1038/s41598-025-24046-z
Commun Med (Lond). 2025 Nov 18. 5(1): 472

Blood and tissue correlates of steroid non-response in checkpoint inhibition-induced immune-related adverse events.

UNICIT Consortium

BACKGROUND: High-dose steroids constitute the cornerstone of first-line treatment for immune-related adverse events (irAEs) associated with immune checkpoint inhibitors, but compromise antitumor immunity. A deeper understanding of irAEs and their response to steroids can improve management.
METHODS: Using a multi-omics approach, we investigated blood- and tissue-based correlates of steroid response, focusing on gastro-intestinal irAEs, in the largest cohort to date.
RESULTS: Here we show clear trends for elevated TC1/TC17 CD8+ T cells and Th1/Th7-associated interleukins before steroid initiation, and persistent (CD8+) T cell activation after initiation of steroids in blood of steroid non-responders. Cross-sectional analysis of colitis tissue suggested lower lymphocyte infiltration within 24 h in steroid responders. Peripheral T cell PD-1 receptor occupancy was unrelated to steroid response. Non-responders' colitis tissue was enriched with activated CD4+ memory T cells and a pronounced type 1/17 immune response.
CONCLUSIONS: These findings highlight rapid steroid effects on circulating cells and irAE-affected tissue and support that an enhanced type 1/type 17 response may be associated with steroid non-response in irAEs. Validation of these findings in larger cohorts is warranted.

DOI: https://doi.org/10.1038/s43856-025-01164-3
Nutr J. 2025 Nov 18. 24(1): 175

Effects of supplementation with two probiotic strains (Lactobacillus helveticus and Bifidobacterium longum) on hormonal status, oxidative stress, and clinical symptoms in women with polycystic ovary syndrome: a randomized clinical trial.

Mahsa Shirani, Mohammad Bagherniya, Omid Sadeghi, Hatav Ghasemi Tehrani, Mohammad Hadi Eskandari, Manoj Sharma, Gholamreza Askari.

  Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women. This study investigates the impact of 8-week supplementation with two probiotic strains, Lactobacillus helveticus and Bifidobacterium longum, on hormonal status, oxidative stress, and clinical symptoms in women with PCOS. Conducted as a double-blind, placebo-controlled, randomized clinical trial, the research involved 90 women with PCOS from Shahid Beheshti Hospital, Isfahan, Iran. Serum markers were assessed before and after the intervention. After adjusting for baseline values and confounding variables, the 8-week supplementation with two probiotic strains resulted in a significant increase in sex hormone binding globulin (24.39; 95% CI (15.23,33.55) vs. -11.99; 95% CI (-20.12, -3.86) nmol/L, P < 0.001), total antioxidant capacity (125.53; 95% CI (53.78,197.28) vs. -42.90; 95% CI (-78.32, -7.48) nmol/mL, P = 0.002) and Superoxide dismutase activity (0.19; 95% CI (0.09,0.30) vs. -0.11; 95% CI (-0.18, -0.04) U/mL, P < 0.001), in the intervention group compared to the placebo. While free androgen index (-57.05; 95% CI (-80.33, -33.76) vs. 49.86; 95% CI (28.81,70.92), P < 0.001), C-reactive protein (-0.50; 95% CI (-0.95, -0.04) vs. 0.05; 95% CI (-0.39,0.50), P = 0.046), and malondialdehyde levels (- 23.69; 95% CI (-30.02, -17.35) vs. -2.70; 95% CI (-9.19,3.77), P < 0.001), significantly decreased in the intervention group compared to the placebo. Furthermore, testosterone total levels showed a decreasing trend in the intervention group, although the between-group changes were not statistically significant after baseline value and other confounders adjustment (-3.37; 95% CI (-11.85, 5.11) vs. 6.48; 95% CI (3.43, 9.53) ng/dL, P = 0.08). Regarding clinical symptoms, including acne, alopecia, and hirsutism, the between-group changes were insignificant (P > 0.05). In conclusion, these findings suggest that 8 weeks of probiotic supplementation may alleviate oxidative stress, modulate certain hormonal factors, and reduce inflammation in women with PCOS. Trial registration, the current study was registered in the Iranian Registry of Clinical Trials on 30 March 2024 (ID: IRCT20121216011763N62) ( https://irct.behdasht.gov.ir/trial/76067 ). https://irct.behdasht.gov.ir/trial/76067 .

Keywords:  Inflammation; Oxidative stress; Polycystic ovary syndrome; Probiotics; RCT

DOI:  https://doi.org/10.1186/s12937-025-01240-3
BMC Microbiol. 2025 Nov 15. 25(1): 751

Early-life gut and oral microbiota development: a multi-niche study including mother-partner-infant triads.

Kotryna Simonyté Sjödin, Andreas Sjödin, Patrik Rydén, Ingrid Mogren, Magnus Domellöf, Pernilla Lif Holgerson, Christina E West.

   BACKGROUND: Early gastrointestinal microbiota establishment is crucial for host metabolism and immune development, with delivery mode and breastfeeding playing key roles. Vaginal delivery promotes colonization by maternal vaginal and gut microbes, while Caesarean section delivery leads to exposures of environmental and skin-derived microbiota. Although maternal contributions have been studied, the role of paternal exposure in shaping infant microbiota remains underexplored. We hypothesized that both parents influence infant microbiota establishment and therefore investigated the contributions of maternal and paternal microbes, as well as delivery mode, on infant oral and fecal microbiota within 48 h of birth and at 1 month of age.
METHODS: We analysed the gut and oral microbiota of 264 pregnant women, 261 partners, and 266 infants using 16S rRNA gene amplicon sequencing. α-diversity (Shannon Index) was compared using Wilcoxon tests, and β-diversity (Bray-Curtis dissimilarity) was assessed with PERMANOVA and PERMDISP. Principal component analysis (PCA) based on centered log-ratio (CLR)-transformed genus-level data was used for ordination and visualisation of taxonomic structure. Differentially abundant taxa across niches and delivery modes were identified using Kruskal-Wallis and Wilcoxon tests with false discovery rate (FDR) correction, followed by linear discriminant analysis (LDA). Putative amplicon sequence variant (ASV) sharing between infants and family members was explored using tree-based phylogenetic plots showing taxon presence and relative abundance across sample types. All analyses were performed in R using established packages.
RESULTS: Adults showed significantly higher microbial α-diversity than infants in both gut and oral samples. β-diversity analyses revealed distinct microbial community structures influenced by ecological niches and delivery mode. Within the first 48 h after birth, differential abundance analyses identified Lactobacillus crispatus in meconium and Blautia_A in oral swabs enriched in vaginally delivered infants. L. crispatus also emerged as a key marker of the vaginal microbiota in our cohort-wide comparison, while Blautia, typically a gut-associated genus, was also detected in parental rectal and meconium samples. This co-occurrence may reflect transient microbial seeding during vaginal delivery. However, due to the limited resolution of 16S rRNA gene sequencing, these patterns suggest ecological overlap rather than definitive evidence of vertical transmission.
CONCLUSIONS: Our findings demonstrate that delivery mode influences early gut and oral microbiota composition, with vaginal delivery associated with taxa also found in maternal samples. While we observed microbial continuity between infant and parental niches, we could not clearly distinguish partner-specific contributions-likely due to the limited resolution of 16S rRNA gene sequencing. These results highlight the importance of delivery-associated exposures in early microbial development and underscore the need for high-resolution approaches to better resolve microbial acquisition within families.

Keywords:  Caesarean section; Gut microbiota; Infant; NorthPop; Oral microbiota; Vaginal delivery

DOI:  https://doi.org/10.1186/s12866-025-04521-3
Front Endocrinol (Lausanne). 2025 ;16 1684492

Gut-ovary axis in polycystic ovary syndrome: mechanistic insights and gut microbiota-targeted therapeutic strategies.

Mei Zhao, Danlin Chen, Xiumei Hu, Caiping Xie, Lianwei Xu, Fuhua Zhou.

  Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that significantly affects women's reproductive health and quality of life. Its pathogenesis involves multiple factors, including genetics, environment, and metabolism. In recent years, with the growing body of research on PCOS, the "gut-ovary axis" hypothesis has become a prominent research focus. This hypothesis suggests that an imbalance in gut bacteria may significantly influence the onset and progression of PCOS through various pathways, such as immune regulation, metabolic disturbances, and hormonal imbalances. This article aims to review the role of the "gut-ovary axis" in PCOS and to explore novel treatment strategies based on gut microbiota modulation, including probiotics, fecal microbiota transplantation, and dietary interventions. These strategies represent promising research avenues for future PCOS treatments, with preliminary studies demonstrating their potential to improve clinical symptoms. However, it is crucial to note that these are not yet established therapies and require substantial further validation. Novelty and Significance of this Review: This review moves beyond a descriptive catalog of associations to provide a critical appraisal of the gut-ovary axis in PCOS. We systematically differentiate well-established mechanisms from speculative hypotheses, explicitly identify persistent knowledge gaps, and evaluate the translational potential of microbiota-targeted therapies, thereby offering a refined framework for future basic and clinical research.

Keywords:  gut microbiota; gut-ovary axis; metabolic disorders; novel treatment; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fendo.2025.1684492
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2582506

Glucose-dependent insulinotropic peptide (GIP) suppresses androgen biosynthesis in PCOS mouse models and cellular systems.

Mengru Pan, Yifan Qian, Linlin Jiang, Chunwei Cao, Lin Li.

   OBJECTIVE: To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism.
METHODS: Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis in vivo. Additionally, NCI-H295R cells were utilized for in vitro studies to investigate the effects of GIP on androgen synthesis using various techniques, including CCK8, flow cytometry, RT‒qPCR, WB, ELISA, and RNA sequencing (RNA-seq).
RESULTS: Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that PSENEN was the most significantly downregulated gene upon GIP stimulation. Knockdown of PSENEN in NCI-H295R cells further decreased testosterone levels in the culture medium, confirming the inhibitory effect of GIP on androgen synthesis.
CONCLUSIONS: Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS.

Keywords:  Glucose-dependent insulinotropic peptide (GIP); PSENEN; androgen synthesis; hyperandrogenism (HA); polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.1080/09513590.2025.2582506
Nat Immunol. 2025 Nov 21.

Interferon-mediated NK cell activation increases cytolytic activity against T follicular helper cells and limits antibody response to SARS-CoV-2.

Stanford COVID-19 Biobank

Natural killer (NK) cells are innate lymphocytes known for their ability to kill infected or malignant cells, but they have an overlooked role in regulating antibody responses. In mice, NK cells can kill T follicular helper (TFH) cells, decreasing somatic hypermutation and antibody titers. Although human NK cell activation correlates with poor vaccine response, the mechanisms of NK cell regulation of adaptive immunity in humans are poorly understood. Here we found that, in ancestral severe acute respiratory syndrome coronavirus 2 infection, individuals with the broadest neutralization profile had fewer NK cells that expressed inhibitory and immaturity markers, whereas NK cells from narrow neutralizers were highly activated and expressed interferon-stimulated genes. ISG-mediated activation in NK cells from healthy donors increased cytotoxicity toward induced TFH-like cells via NKG2D and NKp30. This work reveals that NK cell activation and dysregulated inflammation play a role in poor antibody response to severe acute respiratory syndrome coronavirus 2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens.

DOI: https://doi.org/10.1038/s41590-025-02341-1
Gastroenterology. 2025 Nov 18. pii: S0016-5085(25)05983-9. [Epub ahead of print]

Postoperative Ileum Transcriptomics Implicate Sex-Biased Mechanisms in Crohn's Disease Recurrence.

Kyle Gettler, Sini Nagpal, Savannah Washburn, Christopher Tastad, Jiayu Zhang, Ksenija Sabic, Mark Lazarev, Alain Bitton, Rita Cohen, Marc B Schwartz, Arthur Barrie, Philip Gu, Philip Fleshner, Michelle Bao, Cristian Hernández-Rocha, Jacob McCauley, Maria Abreu, Subra Kugathasan, Dermot P McGovern, Steven R Brant, Richard H Duerr, Mark S Silverberg, John D Rioux, Greg Gibson, Judy H Cho.

   BACKGROUND & AIMS: Despite widespread biologic use, more than 70% of patients with Crohn's disease require resectional surgery, most commonly of the terminal ileum. Gene expression and genetics of the neoterminal ileum at postoperative, surveillance colonoscopies highlight pathways of disease recurrence. Postoperative colonoscopy transcriptomes were interrogated to evaluate the hypothesis that specific molecular mechanisms contribute to recurrent Crohn's pathophysiology.
METHODS: Ribo-depleted, paired-end sequencing was run on 339 neoterminal ileal pinch biopsies from 267 patients with (Rutgeerts i2b+) and without (Rutgeerts i2a or lower) recurrent disease. Differential gene and transcript usage were assessed. Expression quantitative trait loci link genetic variation with gene expression. Serial sampling was performed on 70 patients.
RESULTS: At colonoscopy, 4171 genes increased and 3579 genes decreased in recurring vs nonrecurring patients. Although gene expression was highly correlated (r = 0.71), we observed and replicated higher dynamic ranges of gene expression in male compared with female patients. Activation of both pro- (tumor necrosis factor, interferon gamma) and anti-inflammatory (transforming growth factor beta) pathways was observed; importantly, multiple nuclear hormone receptor pathways demonstrated activation, including both estrogen and dihydrotestosterone pathways, whereas progesterone was inhibited. We observed sex-specific expression quantitative trait loci driven by recurrent samples and differential transcript usage related to lipid metabolism, membrane trafficking, and the extracellular matrix.
CONCLUSIONS: In recurrent disease of the postoperative neoterminal ileum, markedly greater dynamic ranges of gene expression occur in male compared with female patients. Pathway analyses implicate numerous nuclear hormone pathways, highlighting new mechanisms for therapeutic targeting beyond pro-inflammatory cytokine blockade. This study identifies key covariates and pathways of disease recurrence, many of which are distinct from drivers of initial disease susceptibility.

Keywords:  Crohn’s Disease; Genomics; Inflammatory Bowel Disease; RNA-Seq; Single Cell

DOI:  https://doi.org/10.1053/j.gastro.2025.08.038