bims-bac4me 2025-08-17 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–08–17
thirty-two papers selected by
Chun-Chi Chang, Lunds universitet

Staphylococcus aureus phenol-soluble modulins have dispersal and anti-aggregation activity towards corynebacteria.
Metabolic imprinting drives epithelial memory during mucosal fungal infection.
Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.
Exploring the vaginal ecosystem: insights into host-microbe interactions and microbial community dynamics.
Long-term effects of BCG vaccination on telomere length and telomerase activity.
Commensal acidification of specific gut regions produces a protective priority effect against enteropathogenic bacterial infection.
Inflammasome-independent IL-1β activation via staphopain A protease of Staphylococcus aureus.
TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells.
A φSa3int (NM3) Prophage Domestication in Staphylococcus aureus Leads to Increased Virulence Through Human Immune Evasion.
Commensal bacterial glycosylation at the interface of host-bacteria interactions.
Macrophage polarization and allergic rhinitis: A review.
The diverse interaction of metabolism, immune response, and viral pathogens.
Individual subsets of alternatively-activated macrophages differentially contribute to tissue repair and the resolution of inflammation.
Epithelial cells provide immunocompetence to the early embryo for bacterial clearance.
LCCPs exposure induces pulmonary inflammatory injury via AIM2 mediated pulmonary macrophage PANoptosis and M1 polarization.
Dysbiotic gut fungi exacerbate Klebsiella peumoniae lung infection via Dectin-1-mediated alveolar macrophage hyperactivation.
A reconceptualized framework for human microbiome transmission in early life.
One bacterium's trash is another's treasure.
Commensal glycolipid structure shapes gut immunity.
Arctigenin relieves inflammation and remodels the nasal epithelial barrier function in allergic rhinitis via the KLF5/BIRC3/NFκB axis.
New Pathways to Treat Staphylococcus aureus Bacteremia: Connecting the DOTS.
TNF gives plasmacytoid dendritic cells a new life.
Metabolic Master Switch: Pyruvate Carboxylase Fuels Antimicrobial Resistance and Virulence in Foodborne Staphylococcus aureus.
CXCL1 augments host defense against Legionella pneumophila through the IL-18-IFN-γ axis and neutrophil homeostasis.
Setting the table for immune tolerance.
CD4+ skin resident memory T cells preferentially colocalize with dermal Folr2hi macrophages in contact hypersensitivity.
Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.
BCG and beyond: unlocking new frontiers in TB vaccine development.
Non-Canonical Functions of Adenosine Receptors: Emerging Roles in Metabolism, Immunometabolism, and Epigenetic Regulation.
Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.
Lactiplantibacillus plantarum promotes lactoferrin synthesis and secretion in bovine mammary epithelial cells through STAT3 and AP-1 transcription factor pathways.
The Roles of Lactate and Lactylation in Diseases Related to Mitochondrial Dysfunction.

J Bacteriol. 2025 Aug 14. e0018325

Staphylococcus aureus phenol-soluble modulins have dispersal and anti-aggregation activity towards corynebacteria.

Joshua T Huffines, Megan R Kiedrowski.

  Staphylococcus aureus is a common upper respiratory tract (URT) pathobiont with high carriage rates in the upper airway disease chronic rhinosinusitis (CRS). CRS is associated with increased prevalence and abundance of S. aureus, and S. aureus-secreted toxins are implicated in CRS pathogenesis. Conversely, in CRS disease, the abundance of non-pathogenic commensal species has been observed to decline, leading to microbial dysbiosis that contributes to persistent inflammation. Here, we investigated possible mechanisms S. aureus could employ to outcompete commensal organisms and contribute to establishing the S. aureus-dominant microbiome found in individuals with CRS. We performed a targeted screen to identify S. aureus-secreted factors that affect the growth and aggregation of a URT commensal bacterium, Corynebacterium pseudodiphtheriticum, which is negatively correlated with S. aureus in CRS. S. aureus cell-free conditioned media prevented C. pseudodiphtheriticum aggregation; however, anti-aggregation activity was significantly reduced in S. aureus mutants lacking a functional accessory gene regulator (agr) quorum-sensing system, phenol-soluble modulin (PSM) transporters, and the PSM toxin δ-toxin. Addition of purified recombinant δ-toxin peptide or a related PSM, PSMα3, inhibited C. pseudodiphtheriticum aggregation and induced dispersal of aggregates. Recombinant δ-toxin also reduced C. pseudodiphtheriticum adherence and aggregation on human nasal epithelial cells. PSMs are known to play a role in biofilm structure and remodeling in staphylococci, and here, we demonstrate that PSMs have activity against other bacteria. These results identify a novel mechanism by which S. aureus can disrupt the commensal lifestyle of microbes that inhabit the same upper respiratory niche via secreted PSM toxins.IMPORTANCEIncreased Staphylococcus aureus abundance and microbial dysbiosis are associated with the pathogenesis of chronic rhinosinusitis disease. Here, we show that S. aureus δ-toxin, a secreted phenol-soluble modulin (PSM) toxin, can inhibit the ability of commensal Corynebacterium species to aggregate, adhere to, and grow in association with human nasal epithelial cells. PSMs are known to play a key role in the S. aureus biofilm life cycle, regulating S. aureus biofilm structure and detachment; however, a role for these toxins in modifying biofilm and aggregate structures of other bacteria has not been previously demonstrated. These results suggest a potential mechanism for S. aureus to establish dominance in the upper respiratory tract microbiome in disease through direct antagonism of commensal microbes with PSM toxins.

Keywords:  Corynebacterium; aggregation; nasal colonization; polymicrobial interactions; quorum sensing

DOI:  https://doi.org/10.1128/jb.00183-25
bioRxiv. 2025 Jul 17. pii: 2025.07.11.664387. [Epub ahead of print]

Metabolic imprinting drives epithelial memory during mucosal fungal infection.

Jinendiran Sekar, Norma V Solis, Jian Miao, Nicolas Millet, Bryce Tom, Derek Quintanilla, Aize Pellon, David L Moyes, Joseph A Gogos, Harry B Rossiter, Scott G Filler, Mihai G Netea, Jennifer K Yee, Marc Swidergall.

Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to Candida albicans confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.

DOI: https://doi.org/10.1101/2025.07.11.664387
STAR Protoc. 2025 Aug 09. pii: S2666-1667(25)00430-7. [Epub ahead of print]6(3): 104024

Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.

Yongxiang Liu, Huan Jin, Bitao Huo, Xiaojun Xia, Jinyun Liu.

  Multiple metabolic pathways and metabolites are involved in innate immune memory induction of macrophages; however, protocols for in vitro-trained immunity assays induced by metabolites in mouse macrophages are limited. Here, we present a protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages. We describe steps for sample preparation, measurement of 24(S),25-epoxycholesterol, and establishment of an in vitro-trained immunity model. We then detail procedures for assays measuring cytokine concentration and for assay for transposase-accessible chromatin using sequencing (ATAC-seq). For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Keywords:  Cell Biology; Immunology; Metabolism; Molecular Biology; model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2025.104024
Infect Immun. 2025 Aug 11. e0049924

Exploring the vaginal ecosystem: insights into host-microbe interactions and microbial community dynamics.

Emily F Landolt, Jéssica da Conceição Mendonça, Abbey E Behler, Stephen W Lumsdaine, Tamanna Jafar, Lindsey R Burcham.

  The vaginal tract is a complex environment that changes throughout various life stages. Recent advances have improved our understanding of the vaginal microbiota and the influence of host factors on microbial colonization. The vaginal niche is characterized by unique qualities such as high abundances of glycogen and mucin, low pH, active cellular immunity, and fluctuations in hormone signaling that support a complex microbiota. While traditionally thought to be dominated by Lactobacillus species, emerging research highlights a more diverse microbiota, including both commensal and potentially pathogenic microbes. Given the interconnectedness of the microbial and host factors in this environment, minor shifts can lead to significant downstream effects on health. This review takes an ecosystems approach to explore the multifaceted relationship between the vaginal mucosa, the microbiota, and influences of environmental factors on shaping the two. We discuss the contribution of hormone signaling in shaping microbial communities, concepts of vaginal community stability and dysbiosis, and the emerging understanding of microbial metabolism and cross-feeding dynamics within the vaginal tract. Additionally, we will examine the interactions between microbes and immune cells in the vaginal mucosa, including mechanisms by which the immune system modulates the local environment. By considering the feedback loops between the host and the resident microbiota, we propose key knowledge gaps and suggest interdisciplinary avenues for future research aimed at improving our understanding of vaginal health and disease. Understanding these complex interactions is important for advancing vaginal healthcare across all individuals.

Keywords:  vaginal microbiome

DOI:  https://doi.org/10.1128/iai.00499-24
iScience. 2025 Aug 15. 28(8): 113159

Long-term effects of BCG vaccination on telomere length and telomerase activity.

Ozlem Bulut, Valerie A C M Koeken, Simone J C F M Moorlag, Charlotte J de Bree, Vera P Mourits, Gizem Kilic, Priya A Debisarun, Marijke P A Baltissen, Joost H A Martens, Jorge Domínguez-Andrés, Leo A B Joosten, Mihai G Netea.

  This study explores the effects of Bacillus Calmette-Guérin (BCG) vaccination on telomere maintenance, an aging-related process, in immune cells. While BCG reduces systemic inflammation and enhances innate immune responsiveness by inducing trained immunity, its effects on other immune aging hallmarks, such as telomere shortening, are not fully understood. We assessed telomere length in two independent human cohorts before and three months after BCG vaccination. Telomere shortening was consistently observed after BCG, but not after placebo vaccination. Trained immunity non-responders were likelier to lose telomere length, but only among males. Higher pre-vaccination testosterone levels were associated with greater telomere loss in males. In vitro, BCG training activated telomerase, particularly in females, and this was partially prevented by exogenous testosterone. These findings suggest BCG vaccination influences telomere dynamics in a sex-specific manner, contributing to understanding BCG's broader effects on aging-related processes.

Keywords:  Age; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.113159
Appl Environ Microbiol. 2025 Aug 13. e0070725

Commensal acidification of specific gut regions produces a protective priority effect against enteropathogenic bacterial infection.

Jane L Yang, Haolong Zhu, Puru Sadh, Kevin Aumiller, Zehra T Guvener, William B Ludington.

  The commensal microbiome has been shown to protect against newly introduced enteric pathogens in multiple host species, a phenomenon known as a priority effect. Multiple mechanisms can contribute to this protective priority effect, including antimicrobial compounds, nutrient competition, and pH changes. In Drosophila melanogaster, Lactiplantibacillus plantarum has been shown to protect against enteric pathogens. However, the strains of L. plantarum studied were derived from laboratory flies or non-fly environments and have been found to be unstable colonizers of the fly gut that mainly reside on the food. To study the priority effect using a naturally occurring microbial relationship, we isolated a wild fly-derived strain of L. plantarum that stably colonizes the fly gut in conjunction with a common enteric pathogen, Serratia marcescens. Flies stably associated with the L. plantarum strain were more resilient to oral Serratia marcescens infection as seen by longer life span and lower S. marcescens load in the gut. Through in vitro experiments, we found that L. plantarum inhibits S. marcescens growth due to acidification. We used gut imaging with pH indicator dyes to show that L. plantarum reduces the gut pH to levels that restrict S. marcescens growth in vivo. In flies colonized with L. plantarum prior to S. marcescens infection, L. plantarum and S. marcescens are spatially segregated in the gut, and S. marcescens is less abundant where L. plantarum heavily colonizes, indicating that acidification of specific gut regions is a mechanism of a protective priority effect.IMPORTANCEThe gut microbiomes of animals harbor an incredible diversity of bacteria, some of which can protect their hosts from invasion by enteric pathogens. Understanding the mechanisms behind this protection is essential for developing precision probiotics to support human and animal health. This study used Drosophila melanogaster as a model system due to its low cost, experimentally tractable gut microbiome, and overlap with bacterial species found in mammals. While resident microbes can protect hosts through various means, including toxin production and immune stimulation, we found that acidification was sufficient to limit a pathogen that normally reduces life span. Remarkably, specific gut regions are acidified either by host mechanisms or by the resident bacterium, Lactiplantibacillus plantarum, highlighting joint microbial and host control of gut chemistry. These findings are broadly relevant to microbiology and gut health, providing insight into how hosts may manage pathogens through their symbiotic microbiota.

Keywords:  Drosophila; Lactobacillus; Serratia; acidification; gut microbiome; priority effect

DOI:  https://doi.org/10.1128/aem.00707-25
J Biol Chem. 2025 Aug 08. pii: S0021-9258(25)02425-1. [Epub ahead of print] 110574

Inflammasome-independent IL-1β activation via staphopain A protease of Staphylococcus aureus.

Stefan Bauernfried, Tobias Komar, Katja Sterle, Maria C Tanzer, Alexander R Horswill, Matthias Mann, Veit Hornung.

  Interleukin-1β (IL-1β) is a pivotal mediator of innate immunity, essential for orchestrating the acute inflammatory response. While the canonical activation of IL-1β involves cleavage of its inactive precursor (pro-IL-1β) by the inflammatory cysteine protease caspase-1, certain bacterial proteases, such as those secreted by group A Streptococcus and Pseudomonas aeruginosa, can also activate pro-IL-1β. In this study, we demonstrate that infection of human N/TERT-1 immortalized keratinocytes by Staphylococcus aureus induces IL-1β processing independently of the classical inflammasome pathways. Biochemical analysis reveals that a secreted factor from S. aureus cleaves pro-IL-1β at a site proximal to the canonical caspase-1 cleavage site, rendering the cytokine bioactive. Specifically, we identify the secreted cysteine protease staphopain A as responsible for this cleavage. Our findings highlight a novel mechanism of inflammasome-independent IL-1β activation through microbial proteases, expanding the understanding of pathogen-host interactions in immune responses, specifically in the skin.

Keywords:  Interleukin-1β; NLRP1; Staphylococcus aureus; inflammasome; keratinocytes; microbial proteases; staphopain A

DOI:  https://doi.org/10.1016/j.jbc.2025.110574
Nat Immunol. 2025 Aug 12.

TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells.

Rebeca Arroyo Hornero, Raul A Maqueda-Alfaro, Miguel A Solís-Barbosa, Rebecca A Leylek, Olin Medina Chavez, Olivia M Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga.

Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.

DOI: https://doi.org/10.1038/s41590-025-02234-3
MedComm (2020). 2025 Aug;6(8): e70313

A φSa3int (NM3) Prophage Domestication in Staphylococcus aureus Leads to Increased Virulence Through Human Immune Evasion.

Roshan Nepal, Ghais Houtak, George Bouras, Sholeh Feizi, Gohar Shaghayegh, Keith Shearwin, Mahnaz Ramezanpour, Alkis James Psaltis, Peter-John Wormald, Sarah Vreugde.

  Staphylococcus aureus with varying virulence is often isolated from chronic rhinosinusitis (CRS) patients and impacts disease severity. Prophage-mediated virulence, particularly encoded by φSa3int (NM3) prophages, which often encodes human immune-evasion cluster genes is well known, but how a new prophage domestication impacts overall expression of core bacterial genes, and the expression of resident prophages is understudied. To understand this, we transduced a φSa3int prophage recovered from hyper-biofilm forming mucoid S. aureus (SA333) into a high-biofilm forming non-mucoid S. aureus (SA222) recovered from same CRS patient but at different time points. Upon φSa3int prophage domestication, we observed a significant upregulation of 21 exoproteins including human immune-evasion toxins and an intercellular adhesion protein B (IcaB). Further, φSa3int prophage domestication led to reduced phagocytosis implying φSa3int prophage mediates escape of S. aureus from human innate immunity. Our data further show that in addition to adding novel prophage-encoded virulence, φSa3int prophage domestication also affects the expression of non-prophage (bacterial) genes and suppresses expression of structural proteins of resident prophages. Since strains without prophage or with specific prophages have varying virulence and pathogenicity, targeted identification virulence factors associated with mobile genetic elements (MGEs) in addition to species identification may lead to better personalized therapy, particularly in chronic infections.

Keywords:  NM3 prophage; Sa3int prophage; bacteriophage; chronic rhinosinusitis; microbe–host interaction; phage

DOI:  https://doi.org/10.1002/mco2.70313
Gut Microbes. 2025 Dec;17(1): 2545421

Commensal bacterial glycosylation at the interface of host-bacteria interactions.

Chao Lei, Ting Wang, Jingzhi Wang, Yi Tan, Zhongbin Deng.

  Commensal bacteria produce a diverse array of glycosylated molecules, including glycoproteins, glycolipids, peptidoglycan, capsular polysaccharides, and exopolysaccharides, which play fundamental roles in host-microbe interactions. Recent advances have highlighted the intricate mechanisms by which bacterial glycosylation contributes to immune regulation, epithelial barrier integrity, and microbial community stability, with implications for a range of conditions, including infectious diseases, chronic inflammatory disorders such as inflammatory bowel disease (IBD) and Alzheimer's disease, and metabolic diseases such as diet-induced obesity. This review provides a comprehensive synthesis of historical and recent insights into commensal bacterial glycosylation, emphasizing its role as a key mediator of host-bacteria interactions and its broader impact on gut homeostasis and systemic health.

Keywords:  Glycoprotein; capsular polysaccharides; colitis; glycolipids; metabolic disease

DOI:  https://doi.org/10.1080/19490976.2025.2545421
Int Immunopharmacol. 2025 Aug 11. pii: S1567-5769(25)01325-6. [Epub ahead of print]164 115334

Macrophage polarization and allergic rhinitis: A review.

Man Niu, Huidong Wu, Yanyun Wang, Ruochen Li, Yue Zhang, Zihan Xu, Yaxuan Qin, Hongyuan Liu, Jinge Han, Siqi Dong, Weiling Yuan.

  Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa mediated by immunoglobulin E (IgE). Its global prevalence continues to rise, posing a significant public health burden. Macrophages (Mϕ), a key component of the innate immune system, regulate AR pathology through phenotypic polarization. Their roles include antigen presentation, modulation of inflammatory microenvironment homeostasis and tissue repair. Previous studies have primarily focused on single signaling pathways or specific cytokines, which is a limitation to a comprehensive understanding of the multidimensional role of macrophages in allergic rhinitis. This review breaks through the limitations of traditional research by systematically integrating the mechanisms of M1/M2 macrophage polarization in AR and the progress in targeted regulation studies. It particularly focuses on exploring regulatory strategies based on targeting macrophage polarization, aiming to provide a theoretical foundation and innovative directions for the clinical diagnosis, treatment, and mechanistic research of AR.

Keywords:  Allergic rhinitis; Inflammatory response; Macrophages polarization

DOI:  https://doi.org/10.1016/j.intimp.2025.115334
Front Immunol. 2025 ;16 1619926

The diverse interaction of metabolism, immune response, and viral pathogens.

Toshio Kanno, Keisuke Miyako, Yusuke Endo.

  During viral infections, both innate and adaptive immune responses are activated to establish host defense mechanisms. In innate immunity, the STING and MAVS pathways, which recognize viral genomes, play a central role in inducing type I interferons (IFN-I), a group of antiviral cytokines. Concurrently, adaptive immune responses, particularly those mediated by T cells, contribute to viral clearance and the establishment of immune memory through the recognition of viral antigens. Recently, numerous studies have highlighted the impact of alterations in lipid metabolism on host immune cells during viral infections. Because viruses lack the ability to synthesize their own lipid membranes, they rely on host lipid metabolic pathways to support their replication. In addition, IFN-I signaling has been shown to suppress the expression of lipid metabolic genes and promote the generation of antiviral lipids. Furthermore, following viral infection, both innate and adaptive immune cells rewire various metabolic pathways, including lipid metabolism, glycolysis, the tricarboxylic acid cycle, and amino acid metabolism, to mount effective antiviral responses. This review focuses on recent advances in our understanding of lipid metabolic reprogramming during viral infection at both the cellular and systemic levels, and how such metabolic changes shape and regulate immune responses.

Keywords:  SCD2; T cells; cGAS-STING; immunometabolism; lipid metabolism; pathogen nucleotide sensor; virus infections; virus lipid

DOI:  https://doi.org/10.3389/fimmu.2025.1619926
J Immunol. 2025 Aug 07. pii: vkaf164. [Epub ahead of print]

Individual subsets of alternatively-activated macrophages differentially contribute to tissue repair and the resolution of inflammation.

Katharina Weishaupt, Jochen Ackermann, Philipp Burger, David Chambers, Karolina Grimm, Rita Weinkam, Alexandra Correa Zamora, Jean-Philippe Auger, Benjamin Frey, Georg Schett, Gerhard Krönke.

  Although alternatively-activated macrophages (AAM) have been implicated in the resolution of inflammation and tissue repair, their exact role, heterogeneity and origin in vivo remain incompletely defined. Here we show that distinct subsets of macrophages can acquire alternatively activated phenotypes in response to tissue injury where these cellular subsets display contrasting spatiotemporal dynamics and differentially contribute to the resolution of inflammation and tissue repair. By studying a model of cardiotoxin-induced muscle injury, we identify a population of monocyte-derived AAM characterized by expression of arginase-1 (Arg-1) and triggering receptor expressed on myeloid cells 2 (Trem2) that emerged in response to injury and fostered clearance of dying neutrophils and necrotic myofibers as well as the subsequent resolution of inflammation. A second population of AAM, which were marked by robust expression of resistin-like molecule alpha (Relmα) and mannose receptor C-type 1 (CD206), displayed a predominantly resident character and clustered around capillaries where they coordinated the recruitment of eosinophils as well as the subsequent process of tissue repair. Our data thus indicate a substantial heterogeneity among AAM subsets and help to define their specialized functions and roles during inflammation and tissue repair.

Keywords:  cardiotoxin-induced muscle injury; macrophage polarization; resolution of inflammation; tissue damage

DOI:  https://doi.org/10.1093/jimmun/vkaf164
Cell Host Microbe. 2025 Jul 09. pii: S1931-3128(25)00208-2. [Epub ahead of print]33(7): 1106-1120.e8

Epithelial cells provide immunocompetence to the early embryo for bacterial clearance.

Joan Roncero-Carol, June Olaizola-Muñoa, Begoña Arán, Loris Sebastiano Mularoni, Marta Miret Cuesta, Nuria Blanco-Cabra, Marc Casals, Mireia Rumbo, Miquel Solé Inarejos, Samuel Ojosnegros, Berta Alsina, Eduard Torrents, Anna Veiga, Manuel Irimia, Esteban Hoijman.

  Early embryos are exposed to environmental perturbations that may influence their development, including bacteria. Despite lacking a proper immune system, the surface epithelium of early embryos (trophectoderm in mammals) can phagocytose defective pluripotent cells. Here, we explore the dynamic interactions between early embryos and bacteria. Quantitative live imaging of infection models developed in zebrafish embryos reveals the efficient phagocytic capability of surface epithelia in detecting, ingesting, and destroying infiltrated E. coli and S. aureus. In vivo single-cell interferences uncover actin-based epithelial zippering protrusions mediating bacterial phagocytosis, safeguarding developmental robustness upon infection. Transcriptomic and inter-scale dynamic analyses of phagocyte-bacteria interactions identify specific features of this epithelial phagocytic program. Notably, live imaging of mouse and human blastocysts supports a conserved role of the trophectoderm in bacterial phagocytosis. This defensive role of the surface epithelium against bacterial infection provides immunocompetence to early embryos, with relevant implications for understanding failures in human embryogenesis.

Keywords:  bacterial infections; cell dynamics; embryonic development; epithelial tissue; host-pathogen interactions; human embryo; phagocytosis; quantitative live imaging; zebrafish

DOI:  https://doi.org/10.1016/j.chom.2025.05.025
Environ Pollut. 2025 Aug 11. pii: S0269-7491(25)01353-3. [Epub ahead of print]384 126980

LCCPs exposure induces pulmonary inflammatory injury via AIM2 mediated pulmonary macrophage PANoptosis and M1 polarization.

Haochu Deng, Chenhui Xu, Guoxia Wang, Ruoting Zhang, Yuebing Kong, Deyi Wu, Meng Zhang, Xue Tian, Shuang Ma, Hainan Lan.

In recent years, with the wide application of long-chain chlorinated paraffins (LCCPs), long-chain chlorinated paraffins have been detected all over the world. High concentrations of LCCPs are being detected in the air of human living environments. As the main gas exchange organ of the human body, the lungs are responsible for transporting oxygen throughout the body, but there are no studies on the toxicological effects of LCCPs on the lungs. In this study, in vitro and in vivo models were used to investigate the toxicological damage of LCCPs to the lungs and its potential mechanism. In vitro, this study found that LCCPs induced mitochondrial damage and oxidative stress in alveolar epithelial cells (AECs) and alveolar macrophages (AMs), and promoted apoptosis in AECs as well as PANoptosis in AMs. Molecular mechanism studies have revealed that mtDNA leakage into the cytoplasm through VDAC protein channels activated AIM2 to assemble inflammasomes, which in turn triggered the cellular innate immune response. At the same time, AIM2 activation triggered a macrophage phenotype towards pro-inflammatory (M1) polarization, reducing macrophage phagocytosis and repair. In vivo, alveolar macrophages were found to be the key regulators of LCCPs-induced pneumonia, and the upregulation of AIM2 led to the secretion of pro-inflammatory cytokines by alveolar macrophages, which recruited neutrophils to the alveoli, along with the loss of their ability to clear dead cells and to repair tissue damage. The pro-inflammatory response of macrophages exacerbates the alveolar homeostatic imbalance, ultimately leading to AIM2-dependent lung inflammation. The results of this study indicate that LCCPs may have a harmful effect in promoting pneumonia, suggesting that humans need to control the use of LCCPs in the future.

DOI: https://doi.org/10.1016/j.envpol.2025.126980
ISME J. 2025 Aug 16. pii: wraf181. [Epub ahead of print]

Dysbiotic gut fungi exacerbate Klebsiella peumoniae lung infection via Dectin-1-mediated alveolar macrophage hyperactivation.

Shengfu He, Yating Sun, Jiawen Yu, Mingyang Tang, Qingyue Zhang, Bao Meng, Renyu Fan, Zhiqiang Liu, Yanyan Liu, Lifen Hu, Ting Wu, Jiabin Li.

  Escalating antibiotic resistance of Klebsiella pneumoniae underscores the urgent need for therapeutic strategies. Whereas gut bacterial dysbiosis exacerbates pulmonary infections, the role of gut fungi in modulating lung immunity remains understudied. Here, we demonstrate that antibiotic-induced gut fungal expansion aggravates pneumonia by enhancing alveolar macrophage-driven inflammation via Dectin-1 signaling. Clinical analyses demonstrated that pneumonia patients receiving ineffective prehospital antibiotic therapy showed gut bacterial depletion accompanied by fungal overgrowth (primarily Candida spp.), with a positive correlation observed between fungal abundance and hospitalization duration. In murine models, antibiotic-induced gut microbiota disruption promoted fungal proliferation, subsequently upregulating Dectin-1 expression in alveolar macrophages. This activation triggered excessive IL-1β secretion and neutrophil recruitment, exacerbating lung injury and mortality. Our results demonstrated that both antifungal intervention and Dectin-1 knockout reversed these pathological effects, resulting in improved survival rates, reduced bacterial dissemination, and attenuated inflammatory cytokine levels. Mechanistically, gut fungi remotely potentiated pulmonary inflammation through the alveolar macrophage "Dectin-1/IL-1β/neutrophil axis", independent of pathogen clearance. Although recent studies have begun to uncover "mycobiome-lung" disease associations, our findings specifically demonstrate that fungal dysbiosis mediates the "gut-lung axis" during multidrug-resistant Klebsiella pneumoniae infections. This study provides mechanistic insights into microbial crosstalk and advances translational approaches for combating antibiotic-exacerbated pneumonias.

Keywords:  Klebsiella pneumoniae; alveolar macrophage; dectin-1; gut fungi; gut-lung Axis

DOI:  https://doi.org/10.1093/ismejo/wraf181
Nat Commun. 2025 Aug 14. 16(1): 7546

A reconceptualized framework for human microbiome transmission in early life.

Seth Rakoff-Nahoum, Justine Debelius, Mireia Valles-Colomer, Hanna Theodora Noordzij, Maria Esteban-Torres, Alexandra Zhernakova, Nele Brusselaers, Veronika Kuchařová Pettersen.

Human development and physiology are fundamentally linked with the microbiome. This is particularly true during early life, a critical period for microbiome assembly and its impact on the host. Understanding microbial acquisition in early life is thus central to both our basic understanding of the human microbiome and strategies for disease prevention and treatment. Here, we review the historical approaches to categorize microbial transmission originating from the fields of infectious disease epidemiology and evolutionary biology and discuss how this lexicon has influenced our approach to studying the early-life microbiome, often leading to confusion and misinterpretation. We then present a conceptual framework to capture the multifaceted nature of human microbiome acquisition based on four key components: what, where, who, and when. We present ways these parameters may be assigned, with a particular focus on the 'transmitted strain' through metagenomics to capture these elements. We end with a discussion of approaches for implementing this framework toward defining each component of microbiome acquisition.

DOI: https://doi.org/10.1038/s41467-025-61998-2
Cell Host Microbe. 2025 Aug 13. pii: S1931-3128(25)00289-6. [Epub ahead of print]33(8): 1308-1310

One bacterium's trash is another's treasure.

Samuel C Syberg, Lauren J Rajakovich.

Human gut microbes are often thought to compete with other microbes for nutrients. However, they can also work together to share resources. In this issue of Cell Host & Microbe, Zhou et al. discover that two distinct species of commensal bacteria metabolize a dietary antioxidant through a novel cross-feeding pathway.

DOI: https://doi.org/10.1016/j.chom.2025.07.017
Nat Rev Microbiol. 2025 Aug 12.

Commensal glycolipid structure shapes gut immunity.

Shimona Starling.

DOI: https://doi.org/10.1038/s41579-025-01232-4
Toxicol Appl Pharmacol. 2025 Aug 11. pii: S0041-008X(25)00286-8. [Epub ahead of print]504 117510

Arctigenin relieves inflammation and remodels the nasal epithelial barrier function in allergic rhinitis via the KLF5/BIRC3/NFκB axis.

Lili Xu, Yujuan An, Ting Liu, Yanan Zhang, Xiaoyu Chen, Xing Liu, Gang Wei, Hongzhou Ge.

  Allergic rhinitis (AR) is a significant global health issue that necessitates effective treatments. This paper investigates the mechanism of arctigenin (ATG) in alleviating AR. An AR mouse model was constructed and administered with different doses of ATG or positive control dexamethasone. Human nasal epithelial cells (HNEpCs) were stimulated with IL-4 and IL-13 to mimic AR-induced epithelial cell damage. Bioinformatic analysis was performed to predict target proteins of ATG and downstream factors of KLF5. AR mice and HNEpCs were treated with KLF5 overexpression lentivirus and BIRC3 knockdown lentivirus. HNEpCs were treated with NF-κB pathway agonist TWEAK. Our results revealed that ATG remodeled the nasal epithelial barrier function and alleviated inflammation in AR mice and inhibited IL-4/IL-13-induced inflammatory injury in HNEpCs. Mechanistically, ATG inhibited the expression of KLF5 protein. KLF5 transcriptionally activated BIRC3 and the NF-κB pathway. KLF5 overexpression exacerbated inflammatory injury in AR mice and HNEpCs, which was reversed by BIRC3 knockdown. NF-κB pathway agonist exacerbated inflammatory injury in HNEpCs. In conclusion, ATG remodels the nasal epithelial barrier function and alleviates AR in mice by inhibiting KLF5 protein expression and BIRC3 transcription and impairing the NF-κB pathway.

Keywords:  Allergic rhinitis; Arctigenin; BIRC3; KLF5; Nasal epithelial barrier function

DOI:  https://doi.org/10.1016/j.taap.2025.117510
JAMA. 2025 Aug 13.

New Pathways to Treat Staphylococcus aureus Bacteremia: Connecting the DOTS.

Erin K McCreary, Preeti N Malani.

DOI: https://doi.org/10.1001/jama.2025.13717
Nat Immunol. 2025 Aug 15.

TNF gives plasmacytoid dendritic cells a new life.

Elodie Segura.

DOI: https://doi.org/10.1038/s41590-025-02254-z
Foods. 2025 Jul 22. pii: 2566. [Epub ahead of print]14(15):

Metabolic Master Switch: Pyruvate Carboxylase Fuels Antimicrobial Resistance and Virulence in Foodborne Staphylococcus aureus.

Zifeng Mai, Jiahui Li, Zeqiang Zhan, Xiaorong Tian, Wanwan Hou, Mu He, Chunlei Shi.

  Staphylococcus aureus, a major cause of foodborne illness globally, presents significant challenges due to its multidrug resistance and biofilm-forming capabilities. Pyruvate carboxylase (PycA), a metabolic master switch linking glycolysis and the tricarboxylic acid (TCA) cycle, is a potential target for controlling S. aureus. In this study, a pycA mutant was constructed and analyzed using phenotypic assays and proteomics to investigate its role in virulence and antimicrobial resistance. The results showed that deletion of pycA in the foodborne methicillin-resistant strain ATCC BAA1717 resulted in a 4- to 1024-fold reduction in resistance to β-lactams, aminoglycosides, and macrolides; a 23.24% impairment in biofilm formation; and a 22.32% decrease in staphyloxanthin production, a key antioxidant essential for survival in oxidative food environments. Proteomic analysis revealed downregulation of the TCA cycle, purine biosynthesis, surface adhesins (FnbA/B, SasG), and β-lactamase (BlaZ), linking PycA-mediated metabolism to phenotypes relevant to food safety. These findings underscore the importance of PycA as a metabolic regulator crucial for S. aureus resilience in food systems, suggesting novel strategies to combat foodborne staphylococcal infections through metabolic interference.

Keywords:  Staphylococcus aureus; TCA cycle; antimicrobial resistance; biofilm; purine metabolism; pyruvate carboxylase

DOI:  https://doi.org/10.3390/foods14152566
J Immunol. 2025 Aug 08. pii: vkaf191. [Epub ahead of print]

CXCL1 augments host defense against Legionella pneumophila through the IL-18-IFN-γ axis and neutrophil homeostasis.

Ky V Hoang, John Le, Xiaoqian Shan, Samithamby Jeyaseelan.

  Legionella pneumophila causes severe pneumonia, resulting in acute lung injury. L. pneumophila pneumonia induces neutrophil recruitment to the lung through CXC chemokines. Previously, blocking CXCR2, the common receptor for CXC chemokines, but not CXCL1 or CXCL2, resulted in attenuated neutrophil accumulation and reduced survival following pulmonary L. pneumophila infection. However, gene-deficient mice were unavailable at that time and therefore, mechanisms of host protection and neutrophil homeostasis, including granulopoiesis and neutrophil release from the bone marrow, have not been investigated. Here, we delineated the role of CXCL1 and CXCL2 in host defense and neutrophil homeostasis using gene-deficient mice. Deficiency of CXCL1, but not CXCL2, impairs bacterial clearance and neutrophil accumulation in the lung. Furthermore, the increase of IL-18 and IFN-γ proteins in the lung caused by L. pneumophila infection is decreased in Cxcl1-/- mice. Moreover, this reduction in IFN-γ production in Cxcl1-/- mice is associated with a decrease in the γδTCR-expressing IFN-γ+ subset. In vivo treatment with IL-18 or IFN-γ was found to restore neutrophil-dependent bacterial clearance in Cxcl1-/- mice. Production of CXCL1 not only by hematopoietic cells, but also by nonhematopoietic cells, is critical to augment host defense. In Cxcl1-/- mice, there is an impairment in emergency granulopoiesis in bone marrow and in neutrophil release to the blood. Also, Il-18-/- mice displayed impairment of neutrophil recruitment to the lung and bacterial clearance, neutrophil release, and emergency granulopoiesis. Collectively, CXCL1 derived from both hematopoietic and nonhematopoietic cells is essential to control L. pneumophila infection through the IL-18-IFN-γ axis and neutrophil homeostasis.

Keywords:  CXCL1; IFN-γ; T cell; acute lung injury; granulopoiesis

DOI:  https://doi.org/10.1093/jimmun/vkaf191
Science. 2025 Aug 14. 389(6761): 684-685

Setting the table for immune tolerance.

Michael Silverman, Kathryn Knoop.

Interaction between breast milk antibodies and gut microbes shape immune responses during weaning.

DOI: https://doi.org/10.1126/science.adz8687
Front Immunol. 2025 ;16 1590687

CD4+ skin resident memory T cells preferentially colocalize with dermal Folr2hi macrophages in contact hypersensitivity.

Akihiko Murata, Koji Tokoyoda.

  In contact hypersensitivity (CHS), local immune memory is established in previously affected skin through the formation of CD4+ and CD8+ tissue-resident memory T (TRM) cells. This memory contributes to disease recurrence by enhancing local antigen responsiveness and is maintained in the long term by TRM cells, particularly CD4+ TRM cells. However, the mechanisms underlying the maintenance and reactivation of CD4+ TRM cells remain unclear. We herein examined the cellular niches persistently interacting with CD4+ T cells in naïve and CHS-healed mouse ear skin. Most CD4+ T cells were scattered in the dermis and colocalized with Folr2hi macrophages, a previously unrecognized skin macrophage population, suggesting a physical interaction. In contrast, fewer than 20% of CD4+ T cells colocalized with dendritic cells (DCs) or other cell lineages. The administration of an anti-colony stimulating factor 1 receptor (CSF1R) antibody depleted nearly all Folr2hi macrophages and several other myeloid cells, while the maintenance and reactivation of CD4+ T cells as well as other αβ T cells in healed skin remained unaffected. Moreover, in macrophage-depleted healed skin, CD4+ T cells did not establish new interactions with remaining antigen-presenting cells, and their contact rate with DCs remained unchanged. These results indicate that local immune memory in CHS-experienced skin is maintained and functions independently of CSF1R-dependent myeloid cells, including Folr2hi macrophages, despite their predominant colocalization with skin CD4+ TRM cells.

Keywords:  Folr2hi macrophages; allergic contact dermatitis; contact hypersensitivity; local immune memory; tissue-resident memory T cells

DOI:  https://doi.org/10.3389/fimmu.2025.1590687
Curr Allergy Asthma Rep. 2025 Aug 11. 25(1): 35

Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.

Hangyu Li, Yuemei Liang, Jingyi Deng, Yisen Cheng, Su Chen, Xinlong Lian, Suidong Ouyang.

   PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of the role of arginine and its metabolic pathways in regulating immune cell function, with a particular focus on their involvement in pulmonary inflammatory diseases. Additionally, it highlights recent advances in therapeutic strategies that target arginine metabolism as a potential therapeutic approach for the treatment of these conditions.
RECENT FINDINGS: Arginine is a conditionally essential amino acid that plays a pivotal role in numerous physiological processes, including immune regulation, tissue repair, airway tone modulation, and vasodilation. We found emerging evidence underscores that arginine metabolism is tightly controlled by various regulatory mechanisms, with two key enzymes-nitric oxide synthase (NOS) and arginase (ARG)-occupying central roles. These enzymes exert opposing yet coordinated effects within immune cells, contributing to the delicate balance between immune activation and resolution. Dysregulation of arginine metabolism has been implicated in the pathogenesis of several pulmonary inflammatory diseases, including respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. Aberrant arginine metabolic activity in immune cells promotes either excessive inflammation or impaired immune defense, depending on the context. Understanding the immunometabolic functions of arginine offers valuable insights into the mechanisms underlying pulmonary inflammatory diseases. Therapeutic modulation of the arginine metabolic pathway represents a promising strategy for controlling disease progression and improving clinical outcomes, paving the way for the development of novel targeted treatments.

Keywords:  Arginine metabolism. immune cells. pulmonary inflammatory diseases. therapeutic targets

DOI:  https://doi.org/10.1007/s11882-025-01216-7
Front Immunol. 2025 ;16 1608104

BCG and beyond: unlocking new frontiers in TB vaccine development.

Aishwarya Shaji, Akanksha Verma, Ashima Bhaskar, Ved Prakash Dwivedi.

  Please confirm that the below Frontiers AI generated Alt-Text is an accurate visual description of your Figure(s). These Figure Alt-text proposals won't replace your figure captions and will not be visible on your article. If you wish to make any changes, kindly provide the exact revised Alt-Text you would like to use, ensuring that the word-count remains at approximately 100 words for best accessibility results. Further information on Alt-Text can be found here.With over 10 million new cases and 1.6 million deaths annually, tuberculosis (TB) continues to be a significant worldwide health-burden. To assist in curbing the spread of TB, the century-old BCG, which is a live-attenuated vaccine, is now the only licensed TB vaccine used in humans. However, BCG's limited efficacy and poor antigenicity in adults have evoked the need to design new vaccines against TB. The limited parameter is the availability of potent antigens; as a consequence, it is imperative to study the Mycobacterium tuberculosis (Mtb)-specific antigens that can provide a stronger immune response if included in vaccine candidates. Through this review, we aim to concentrate on the progress of current vaccine-candidates undergoing preclinical and clinical-studies. Moreover, it is not the pathogen but the genetics of the host that plays an essential role in fine-tuning the immune-response and susceptibility to TB. Over the past 50 years, a systematic approach to treating TB patients has overlooked factors like pharmacokinetics, immune-response, and treatment duration. Henceforth, this review highlights the precision medicine-guided approach considering genetic-makeup and host immunity that could influence clinical management choices. The consolidated review will shed light on advancements in vaccine-candidates, which can be harnessed in prophylactic development against TB.

Keywords:  BCG; host genetics; trained immunity; tuberculosis; vaccine

DOI:  https://doi.org/10.3389/fimmu.2025.1608104
Int J Mol Sci. 2025 Jul 26. pii: 7241. [Epub ahead of print]26(15):

Non-Canonical Functions of Adenosine Receptors: Emerging Roles in Metabolism, Immunometabolism, and Epigenetic Regulation.

Giovanni Pallio, Federica Mannino.

  Adenosine receptors (ARs) are G protein-coupled receptors that are widely expressed across tissues, traditionally associated with cardiovascular, neurological, and immune regulation. Recent studies, however, have highlighted their non-canonical functions, revealing critical roles in metabolism, immunometabolism, and epigenetic regulation. AR subtypes, particularly A2A and A2B, modulate glucose and lipid metabolism, mitochondrial activity, and energy homeostasis. In immune cells, AR signaling influences metabolic reprogramming and polarization through key regulators such as mTOR, AMPK, and HIF-1α, contributing to immune tolerance or activation depending on the context. Additionally, ARs have been implicated in epigenetic modulation, affecting DNA methylation, histone acetylation, and non-coding RNA expression via metabolite-sensitive mechanisms. Therapeutically, AR-targeting agents are being explored for cancer and chronic inflammatory diseases. While clinical trials with A2A antagonists in oncology show encouraging results, challenges remain due to receptor redundancy, systemic effects, and the need for tissue-specific selectivity. Future strategies involve biased agonism, allosteric modulators, and combination therapies guided by biomarker-based patient stratification. Overall, ARs are emerging as integrative hubs connecting extracellular signals with cellular metabolic and epigenetic machinery. Understanding these non-canonical roles may unlock novel therapeutic opportunities across diverse disease landscapes.

Keywords:  adenosine receptors; cancer immunotherapy; epigenetic regulation; immunometabolism; inflammation; metabolism

DOI:  https://doi.org/10.3390/ijms26157241
Front Syst Biol. 2024 ;4 1466368

Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.

Mouly F Rahman, Andre H Kurlovs, Munender Vodnala, Elamaran Meibalan, Terry K Means, Nima Nouri, Emanuele de Rinaldis, Virginia Savova.

  Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled disease-specific and common cell-cell communications involved in chemotaxis and extravasation to shed light on shared immune responses across tissues and diseases. Further, we performed experimental validation of two understudied cell-cell communications. Insights gleaned from this meta-analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

Keywords:  cell communication; chemokine; extravasation; immune disease; meta-analysis; scRNA-seq

DOI:  https://doi.org/10.3389/fsysb.2024.1466368
In Vitro Cell Dev Biol Anim. 2025 Aug 13.

Lactiplantibacillus plantarum promotes lactoferrin synthesis and secretion in bovine mammary epithelial cells through STAT3 and AP-1 transcription factor pathways.

Jinyu Zhou, Shuai Lian, Zijian Geng, Yuejie Yang, Rui Wu, Jianfa Wang.

  Probiotics can support the immune function of dairy cows and contribute to the synthesis of milk components in mammary gland tissue. Bovine lactoferrin (bLF) possesses immune-regulating and nutritional properties; however, the impact of probiotics on bLF remains unclear. This study aimed to investigate whether probiotics can enhance the synthesis and secretion of bLF in the mammary gland, with a particular focus on the specific mechanisms by which Lactiplantibacillus plantarum (L. plantarum) regulates bLF. Primary bovine mammary epithelial cells (BMECs) were cultured in six-well plates and treated with various types of probiotics. The expression of bLF was evaluated using quantitative real-time PCR (qRT-PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). The expression of transcription factors associated with the bLF promoter region, specifically, was analyzed through qRT-PCR and Western blot. Lacticaseibacillus rhamnosus (L. rhamnosus), Streptococcus thermophilus (S. thermophilus), Bifidobacterium (Bifido.), and L. plantarum upregulated bLF gene and protein expression to varying extents, with L. plantarum exhibiting the most pronounced effect. Furthermore, L. plantarum was found to regulate the expression of phosphorylated STAT3 and AP-1. These findings indicate that probiotics can influence the expression of bLF in mammary gland tissue. Additionally, L. plantarum modulates the production of bLF via the STAT3 and AP-1 transcription factor pathways.

Keywords:   Lactiplantibacillus plantarum ; Bovine lactoferrin; Bovine mammary epithelial cells; Gene expression regulation; Probiotics

DOI:  https://doi.org/10.1007/s11626-025-01055-w
Int J Mol Sci. 2025 Jul 24. pii: 7149. [Epub ahead of print]26(15):

The Roles of Lactate and Lactylation in Diseases Related to Mitochondrial Dysfunction.

Fei Ma, Wei Yu.

  Glycolysis and oxidative phosphorylation are the main pathways of cellular energy production. Glucose is metabolized via glycolysis to generate pyruvate, which, under anaerobic conditions, is converted into lactate, while, under aerobic conditions, pyruvate enters mitochondria for oxidative phosphorylation to produce more energy. Accordingly, mitochondrial dysfunction disrupts the energy balance. Lactate, historically perceived as a harmful metabolic byproduct. However, emerging research indicates that lactate has diverse biological functions, encompassing energy regulation, epigenetic remodeling, and signaling activities. Notably, the 2019 study revealed the role of lactate in regulating gene expression through histone and non-histone lactylation, thereby influencing critical biological processes. Metabolic reprogramming is a key adaptive mechanism of cells responding to stresses. The Warburg effect in tumor cells exemplifies this, with glucose preferentially converted to lactate for rapid energy, accompanied by metabolic imbalances, characterized by exacerbated aerobic glycolysis, lactate accumulation, suppressed mitochondrial oxidative phosphorylation, and compromised mitochondrial function, ultimately resulting in a vicious cycle of metabolic dysregulation. As molecular bridges connecting metabolism and epigenetics, lactate and lactylation offer novel therapeutic targets for diseases like cancer and neurodegenerative diseases. This review summarizes the interplay between metabolic reprogramming and mitochondrial dysfunction, while discussing lactate and lactylation's mechanistic in the pathogenesis of related diseases.

Keywords:  epigenetics; lactate; lactylation; metabolic reprogramming; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms26157149