bims-bac4me 2025-06-08 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–06–08
nineteen papers selected by
Chun-Chi Chang, Lunds universitet

Arginine metabolism supports metabolic reprogramming in trained immunity.
Innate immune memory in macrophage differentiation and cardiovascular diseases.
Macrophages: sentinels, warriors, and healers.
Mechanisms and therapeutic potential of epithelial-immune crosstalk in airway inflammation.
GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during Legionella infection.
Distal airway epithelial progenitors mediate TGF-β release to drive lung CD8+ TRM induction following mucosal BCG vaccination.
Immune mechanisms mediating the heterologous effects of BCG vaccination: a systematic review.
Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro.
The innate immune protein calprotectin incapacitates the bactericidal activity of β-lactam antibiotics.
Skin microbiota in atopic dermatitis: victim or executioner?
Crosstalk of immunity and metabolism: interaction of toll-like receptors (TLRs) and gut microbiota.
Chromatin Remodeling and Transcriptional Silencing Define the Dynamic Innate Immune Response of Tissue Resident Macrophages After Burn Injury.
Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages through TLR-MyD88 Signaling and Lipid Remodeling.
Crosstalk between metabolic reprogramming and microbiota: implications for cancer progression and novel therapeutic opportunities.
The Role of CDKs in the Regulation of the Monocyte/Macrophage Immune Response.
Coordination of innate immune responses by connexins.
Therapeutic Potential of Probiotics: A Review of Their Role in Modulating Inflammation.
Human Milk Oligosaccharides Mediate the Host-Microbe Interface in a Model Vaginal Community.
Histone lactylation-induced premature senescence contributes to 1-nitropyrene-Induced chronic obstructive pulmonary disease.

J Leukoc Biol. 2025 Jun 04. pii: qiaf080. [Epub ahead of print]

Arginine metabolism supports metabolic reprogramming in trained immunity.

Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea.

  Trained immunity, also termed innate immune memory, is supported by metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan-training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.

Keywords:  arginine; metabolism; monocytes; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf080
Inflamm Regen. 2025 Jun 03. 45(1): 17

Innate immune memory in macrophage differentiation and cardiovascular diseases.

Yukiteru Nakayama, Katsuhito Fujiu.

  Innate immune memory (trained immunity) refers to the ability of innate immune cells, such as monocytes and macrophages, to retain a long-term imprint of a prior stimulus through epigenetic and metabolic adaptations, enabling amplified responses upon restimulation. Recent studies have classified innate immune memory into central and peripheral types. Central innate immune memory originates in hematopoietic stem cells (HSCs) within the bone marrow, where epigenetic reprogramming generates a sustained inflammatory bias, contributing to chronic diseases such as atherosclerosis, heart failure, and stroke. Peripheral innate immune memory occurs in monocytes or macrophages that acquire heightened responsiveness after repeated exposure to stimuli in peripheral tissues. This review explores the mechanisms underlying both central and peripheral innate immune memory, their roles in chronic inflammatory diseases, focusing on cardiovascular diseases, and potential strategies to target innate immune memory for therapeutic purposes. Advancing the understanding of these processes could facilitate the development of novel approaches to control inflammatory diseases and immune-related disorders.

Keywords:  Central innate immune memory; Heart failure; Macrophage; Peripheral innate immune memory

DOI:  https://doi.org/10.1186/s41232-025-00382-5
Hum Mol Genet. 2025 Jun 06. pii: ddaf087. [Epub ahead of print]

Macrophages: sentinels, warriors, and healers.

Eduardo D Bernier, Eric Bartnicki, Kamal M Khanna.

  Macrophages are versatile innate immune cells that act as sentinels, warriors, and healers in virtually every tissue. This review synthesizes current insights into their developmental origins and the organ-specific cues that imprint diverse tissue-resident and monocyte-derived programs. We detail how pattern-recognition pathways, metabolic and epigenetic rewiring, and environmental signals govern macrophage plasticity, steering transitions between pro-inflammatory and reparative phenotypes during homeostasis, infection, and sterile injury. Dysregulated macrophage responses drive chronic inflammatory, autoimmune, metabolic, neurodegenerative, and neoplastic diseases; inter-individual variability rooted in genetic polymorphisms and enhancer landscapes further modulates susceptibility. Advances in single-cell and spatial multi-omics are redefining macrophage subsets and exposing disease-associated states, while approaches such as checkpoint blockade, chimeric antigen receptor macrophages, nanoparticles, metabolic modulators, and pro-resolving mediators showcase the therapeutic promise of re-programming these cells. Remaining challenges include integrating the layered genetic, metabolic, and microenvironmental inputs that dictate macrophage fate. Addressing these gaps will unlock precision strategies that harness macrophage plasticity to combat infection, resolve inflammation, repair tissue, and augment anti-tumor immunity.

Keywords:  immunoregulation; inflammation; innate immunity; macrophages

DOI:  https://doi.org/10.1093/hmg/ddaf087
Expert Rev Clin Immunol. 2025 Jun 04. 1-15

Mechanisms and therapeutic potential of epithelial-immune crosstalk in airway inflammation.

Ying Chen, Yujuan Yang, Huifang Liu, Yan Hao, Xinjun Xu, Yu Zhang, Hongfei Zhao, Ting Zuo, Hang Yu, Jiali Yin, Xicheng Song.

   INTRODUCTION: Chronic airway inflammatory diseases mainly comprise chronic rhinosinusitis (CRS), allergic rhinitis (AR), asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Epithelial cells fulfill a protective role as a barrier; however, when stimulated, these cells also release a variety of cytokines that attract and activate immune cells, including macrophages, neutrophils, and T-lymphocytes. Excessive activation and aggregation of immune cells disrupts the balance of the cellular microenvironment, and leads to impaired immune defense of the airway mucosa, which can further exacerbate an inflammatory response.
AREAS COVERED: In this article, we discuss the key cytokines and immune pathways involved in epithelial-immune cell interactions, and we detail discoveries in the emerging field of single-cell sequencing and summarize monoclonal antibody-targeted therapies. A comprehensive search was conducted using the search terms 'epithelial cell,' 'immune,' 'interaction,' 'cytokines,' 'asthma,' 'chronic sinusitis,' 'allergic rhinitis,' 'monoclonal antibodies,' and 'single-cell sequencing' by querying Google Scholar and PubMed.
EXPERT OPINION: The intricate pathophysiology of airway inflammation remains to be fully elucidated. Emerging technologies, such as single-cell sequencing, have led to a more comprehensive characterization of the immune mechanisms underlying the pathophysiology of airway inflammatory diseases, which points the way to further precision medicine in the future.

Keywords:  Epithelial cells; allergic rhinitis; asthma; chronic sinusitis; immune cells

DOI:  https://doi.org/10.1080/1744666X.2025.2514604
Infect Immun. 2025 Jun 05. e0056524

GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during Legionella infection.

Víctor R Vázquez Marrero, Madison Dresler, Mikel D Haggadone, Allyson Lu, Sunny Shin.

  The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for host defense against a wide range of pathogens. During infection with the intracellular bacterial pathogen Legionella pneumophila, we previously found that GM-CSF enhances inflammatory cytokine production in murine monocytes and is required for in vivo control of Legionella. It is unclear whether GM-CSF similarly augments cytokine production in human monocytes during bacterial infection. Here, we find that GM-CSF enhances inflammatory cytokine expression in Legionella-infected human monocytes by engaging multiple signaling pathways. Legionella- and Toll-like receptor-dependent NF-[Formula: see text]B signaling is a prerequisite signal for GM-CSF to promote cytokine expression. Then, GM-CSF-driven Janus kinase 2/signal transducer and activator of transcription 5 signaling is required to augment cytokine expression in Legionella-infected human monocytes. We also found a role for phosphatidylinositol-3-kinase/Akt/mTORC1 signaling in GM-CSF-dependent upregulation of cytokine expression. Finally, glycolysis and amino acid metabolism are also critical for GM-CSF to boost cytokine gene expression. Our findings show that GM-CSF-mediated enhancement of cytokine expression in infected human monocytes is regulated by multiple signaling pathways, thereby allowing the host to fine-tune antibacterial immunity.

Keywords:  Akt; GM-CSF; Legionella pneumophila; NF-kB; PI-3K; TLR; amino acid metabolism; glycolysis; human monocytes; mTORC1

DOI:  https://doi.org/10.1128/iai.00565-24
Mucosal Immunol. 2025 May 30. pii: S1933-0219(25)00054-6. [Epub ahead of print]

Distal airway epithelial progenitors mediate TGF-β release to drive lung CD8+ TRM induction following mucosal BCG vaccination.

Judith A Blake, Julia Seifert, Socorro Miranda-Hernandez, Roland Ruscher, Paul R Giacomin, Denise L Doolan, Andreas Kupz.

  A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG), as intradermal BCG does not induce local pulmonary immune memory. Animal studies have shown that inhalation of BCG vaccination provides superior mucosal protection against TB due to generation of lung resident memory T cells (TRM). Here, we demonstrated that following mucosal vaccination with the genetically modified more virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their integrin-mediated activation of latent TGF-β, lung CD8+ TRM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of integrin-mediated activation of TGF-β, resulted in significantly lower numbers of lung CD8+ TRM with subsequent reduced protection against Mycobacterium tuberculosis (Mtb)-induced lung pathology in mice. The results link airway epithelial progenitor-mediated repair of injured lung tissue with a role in the induction of resident CD8+ T cell memory. These findings provide further explanation why mucosal vaccination with virulent BCG strains is more protective against TB and thus has implications for future TB vaccine development.

Keywords:  Airway epithelial progenitors; BCG; Mucosal; Resident memory T cells; TGF-β; Tuberculosis

DOI:  https://doi.org/10.1016/j.mucimm.2025.05.007
Front Immunol. 2025 ;16 1567111

Immune mechanisms mediating the heterologous effects of BCG vaccination: a systematic review.

Louis Torracinta, Nino Gogichadze, Rachel Tanner.

   Introduction: BCG vaccination can have heterologous or non-specific effects (NSE) that confer resistance against pathogens other than its target Mycobacterium tuberculosis, but the underlying mechanisms are not fully understood.
Methods: We conducted a systematic review synthesising existing literature on immune mechanisms mediating the heterologous/NSE of BCG. Searches were conducted using MEDLINE and Scopus.
Results: 1032 original records were identified, of which 67 were deemed eligible. Several potentially relevant immune pathways were identified, although there may be variation by pathogen. Recent studies have focused on trained immunity whereby innate cells, or the hematopoietic stem and progenitor cells from which they are derived, undergo epigenetic and metabolic reprogramming allowing them to respond more effectively to antigen exposures unrelated to the original stimulus. However, other processes such as granulopoiesis and cross-reactive adaptive immunity may also play a role. Heterologous immunity and NSEs may be influenced by several endogenous and exogenous variables.
Discussion: We discuss the quality of available data, the importance of understanding mechanisms of heterologous protection, and its implications for vaccination strategies.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023400375, identifier CRD42023400375.

Keywords:  BCG; T cells; heterologous effects of vaccination; humoral immunity; trained immunity; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2025.1567111
Nat Commun. 2025 Jun 04. 16(1): 5180

Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro.

Viral S Shah, Avinash Waghray, Brian Lin, Atharva Bhagwat, Isha Monga, Michal Slyper, Bruno Giotti, Sunghyun Kim, Dawei Sun, Ke Xu, Eric Park, Mohamad Bairakdar, Jiajie Xu, Julia Waldman, Danielle Dionne, Lan T Nguyen, Wendy Lou, Peiwen Cai, Christoph Muus, Jiawei Sun, Manalee V Surve, Lujia Cha Cha Yang, Orit Rozenblatt-Rosen, Toni M Delorey, Srinivas Vinod Saladi, Aviv Regev, Jayaraj Rajagopal, Alexander M Tsankov.

Human airways contain specialized rare epithelial cells including CFTR-rich ionocytes that regulate airway surface physiology and chemosensory tuft cells that produce asthma-associated inflammatory mediators. Here, using a lung cell atlas of 311,748 single cell RNA-Seq profiles, we identify 687 ionocytes (0.45%). In contrast to prior reports claiming a lack of ionocytes in the small airways, we demonstrate that ionocytes are present in small and large airways in similar proportions. Surprisingly, we find only 3 mature tuft cells (0.002%), and demonstrate that previously annotated tuft-like cells are instead highly replicative progenitor cells. These tuft-ionocyte progenitor (TIP) cells produce ionocytes as a default lineage. However, Type 2 and Type 17 cytokines divert TIP cell lineage in vitro, resulting in the production of mature tuft cells at the expense of ionocyte differentiation. Our dataset thus provides an updated understanding of airway rare cell composition, and further suggests that clinically relevant cytokines may skew the composition of disease-relevant rare cells.

DOI: https://doi.org/10.1038/s41467-025-60441-w
bioRxiv. 2025 May 14. pii: 2025.05.14.654040. [Epub ahead of print]

The innate immune protein calprotectin incapacitates the bactericidal activity of β-lactam antibiotics.

Amanda Z Velez, Jana N Radin, Emily N Kennedy, Joshua B Parsons, Heather M Tong, Emma Jung, Emily Alam, Lauren C Radlinski, Nikki J Wagner, Vance G Fowler, Sarah E Rowe, Thomas Kehl-Fie, Brian P Conlon.

β-lactam antibiotics are widely used to treat bacterial infections, yet treatment failures frequently occur even without resistance. Here, we show that the innate immune protein calprotectin (CP), released by neutrophils and abundant at infection sites, induces tolerance to β-lactam antibiotics in Staphylococcus aureus . CP is a potent zinc chelator and was found to inhibit the activity of S. aureus autolysins, zinc-dependent enzymes essential for bacterial lysis following β-lactam-mediated inhibition of cell wall synthesis. This protection was independent of bacterial growth or metabolism and was specific to β-lactam antibiotics. Mechanistically, CP inactivated the amidase activity of Atl, the major S. aureus autolysin, through zinc sequestration. In vivo , oxacillin was significantly more effective in CP-deficient mice, demonstrating that CP reduces β-lactam efficacy during infection. These findings reveal a host-derived mechanism of antibiotic tolerance and suggest that zinc availability at infection sites may directly influence β-lactam treatment outcomes.

DOI: https://doi.org/10.1101/2025.05.14.654040
Clin Microbiol Rev. 2025 Jun 03. e0027724

Skin microbiota in atopic dermatitis: victim or executioner?

Chiara Maria Teresa Boggio, Federica Veronese, Marta Armari, Elisa Zavattaro, Elia Esposto, Paola Savoia, Barbara Azzimonti.

  SUMMARYAtopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder, affecting 10%-20% of the population, characterized by dryness, intense itching, and recurrent rashes. The pathophysiology of AD is multifactorial, involving skin barrier dysfunction, immune dysregulation, genetic factors (such as filaggrin mutations), and environmental factors. The skin microbiota also plays a pivotal role in AD, serving both as a target and a driver of the disease. In AD, the delicate balance of the skin microbiota is disrupted, leading to a decrease in beneficial bacteria such as Streptococcus, Cutibacterium, and Corynebacterium. Concurrently, bacterial pathobionts, notably Staphylococcus aureus, proliferate and express their virulence factors excessively. This imbalance exacerbates symptoms by damaging the skin barrier, releasing toxins, and triggering a Th2-driven immune response, thus weakening the skin defenses and making individuals with AD more susceptible to bacterial, fungal, and viral infections, thereby complicating treatment and worsening disease outcomes. Effective AD management requires a thorough understanding of the interplay among the skin microbiota, the immune system, and microbial pathobionts. Strategies that restore the microbial balance, preserve the skin barrier, and modulate the immune response show significant potential for reducing infections and improving AD symptoms, highlighting the microbiota's dual role in AD pathology. This review examines the complex role of the skin microbiota in AD, emphasizing how dysbiosis both drives disease progression and influences immune responses, and vice versa. It also explores emerging microbiota-targeted therapies aimed at improving disease outcomes.

Keywords:  Staphylococcus aureus; Staphylococcus epidermidis; atopic dermatitis; chronic inflammatory skin disorders; immune dysregulation; skin barrier disfunction; skin microbiota

DOI:  https://doi.org/10.1128/cmr.00277-24
Acta Diabetol. 2025 Jun 05.

Crosstalk of immunity and metabolism: interaction of toll-like receptors (TLRs) and gut microbiota.

Shabana, Saleem Ullah Shahid, Uzma Irfan, Sumreen Hayat, Sumbal Sarwar.

  The human gut is the largest interface between the external environment and the human body. The gut immune system should, therefore, be able to differentiate between the normal nonpathogenic residents of the gut and any pathogenic invaders. This differentiation is based on the tiny molecular differences on the cell surfaces of the microorganisms. The first interaction between the pathogen and the immune system is thus crucial. This sensing by the immune system is done by a family of pattern recognition receptors (PRRs), among which the most important are the toll-like receptors (TLRs). The distribution of TLRs in the different areas of gastrointestinal tract (GIT)c depends on the type of commensal residents of that area. The interaction between gut microbiota and TLRs on one hand restricts the colonization of particular microbes to a particular area and on the other hand, dictates the type of TLRs distributed in a particular gut location. This interaction promotes tolerance to the normal residents, but the same time enables the gut associated lymphoid tissue to be able to detect any foreign and potentially pathogenic invaders. The numbers and polarization of the underlying populations of macrophages and dendritic cells beneath the Paneth and M-cells depends upon the trophic factors released by the intestinal epithelial cells as a result of signaling through TLRs. The interaction between these two players is not only immune related, but also has many metabolic consequences. The link between inflammation and many metabolic diseases has been consistently reported. The role of TLRs in the metabolic reprogramming of immune cells is crucial which facilitates the conservation of metabolic energy to be harnessed for immune functions. The knowledge on the TLR-microbiota interaction, its role in immune and metabolic functions, and the results of manipulations with this interaction are the subject of this review.

Keywords:  Immune system; Inflammation; Lymphoid tissue; Pattern recognition receptors; Toll-like receptors

DOI:  https://doi.org/10.1007/s00592-025-02532-0
bioRxiv. 2025 May 20. pii: 2025.05.15.654340. [Epub ahead of print]

Chromatin Remodeling and Transcriptional Silencing Define the Dynamic Innate Immune Response of Tissue Resident Macrophages After Burn Injury.

Han G Kim, Marie-Pierre L Gauthier, Aidan Higgs, Denise A Hernandez, Mingqi Zhou, Jason O Brant, Rhonda L Bacher, Dijoia B Darden, Shannon M Wallet, Clayton E Mathews, Philip A Efron, Michael P Kladde, Robert Maile.

Severe burn injury induces long-lasting immune dysfunction, but the molecular mechanisms underlying this phenomenon remain unclear. We hypothesized that burn injury leads to epigenetic and transcriptional reprogramming of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at days 2, 9, and 14 days post-20% contact burn injury. Targeted transcriptomics and MAPit single-molecule chromatin profiling were used to assess immune, metabolic, and epigenetic changes. Canonical pathway analysis was performed to infer functional shifts over time. Burn injury induced a biphasic response in macrophages. Early after injury (Day 2), there was broad transcriptional suppression and epigenetic silencing of inflammatory regulators, including Stat3 , Traf6 , and Nfkb1 . Over time (Days 9 and 14), loci associated with anti-inflammatory mediators such as Il-10 and Socs3 exhibited progressive chromatin opening and transcriptional upregulation. Metabolic gene profiles revealed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis demonstrated early IL-10 signaling activation with sustained suppression of classical macrophage activation pathways. Chromatin architecture changes included nucleosome sliding and ejection events, consistent with dynamic, locus-specific regulation. This work challenges the classical notion of burn-induced immune suppression as purely a consequence of systemic inflammation. Instead, we reveal a programmed and locus-specific epigenetic architecture that may shape macrophage immune and metabolic function long after the acute phase.

DOI: https://doi.org/10.1101/2025.05.15.654340
bioRxiv. 2025 May 23. pii: 2025.05.19.654724. [Epub ahead of print]

Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages through TLR-MyD88 Signaling and Lipid Remodeling.

Gauri Mirji, Sajad Ahmad Bhat, Mohamed El Sayed, Sarah Kim Reiser, Siva Pushpa Gavara, Ying Ye, Taito Miyamoto, Qin Liu, Aaron R Goldman, Andrew Kossenkov, Nan Zhang, Rahul S Shinde.

The gut microbiome generates a diverse array of metabolites that actively shape host immunity, yet the pro-inflammatory potential of microbial metabolites remains poorly understood. In this study, we identified hippuric acid, an aromatic gut microbe-derived metabolite, as a potent enhancer of pro-inflammatory responses using a murine bacterial infection model and a non-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics. Administering hippuric acid intraperitoneally in murine models of Escherichia coli infection or LPS-induced inflammation significantly heightened pro-inflammatory responses and innate immune cell activation. In vitro , hippuric acid selectively potentiated M1-like macrophage polarization (LPS + IFNγ) but had no effect on M2-like polarization (IL-4). Hippuric acid further enhanced responses to diverse MyD88-dependent TLR ligands, but not TRIF-dependent TLR3, implicating a possible mechanism of action via activation of TLR-MyD88 signaling. Genetic deletion of MyD88 abrogated the pro-inflammatory effects of hippuric acid both in vitro and in vivo , confirming its dependence on the MyD88 pathway. Transcriptomic and lipidomic analyses revealed that hippuric acid promoted cholesterol biosynthesis and lipid accumulation, linking microbial metabolism to lipid-driven immune activation. Notably, hippuric acid similarly enhanced pro-inflammatory responses in human macrophages, and its elevated levels correlated with increased sepsis mortality, highlighting its potential clinical relevance. These findings establish hippuric acid as a previously unrecognized microbial-derived inflammatory modulator, bridging gut microbial metabolism, lipid remodeling, and innate immune signaling, and offer new insights into its role in infection and inflammation.

DOI: https://doi.org/10.1101/2025.05.19.654724
Front Immunol. 2025 ;16 1582166

Crosstalk between metabolic reprogramming and microbiota: implications for cancer progression and novel therapeutic opportunities.

Xingchen Li, Yidi Jia, Yanqing Li, Hu Hei, Songtao Zhang, Jianwu Qin.

  Metabolic reprogramming is a process by which cells adapt to the nutrient microenvironment by regulating energy metabolism. Compared with normal cells, tumor cells tend to undergo metabolic reprogramming, which is one of the hallmarks of concurrent genomic instability, and immune evasion in tumor cells. The microbial community, known as "second genome" of human beings, can cause systemic disease by predisposing cells to tumors, and modulating immune responses to cancer. Metabolic reprogramming and microorganisms can crosstalk with each other in multiple ways to influence various physiological and pathological responses in cancer progression. The products of increased synthesis by tumor cells can reach the intestinal tract via the circulation and act on the microorganisms, promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. In addition, the metabolites of the microorganisms can in turn be transported to the tumor microenvironment (TME) through the systemic circulation and participate in the process of tumor metabolic reprogramming. Different molecular mechanisms related to metabolic reprogramming and microbiota imbalance control the outcome of tumor or anti-tumor responses, depending on the type of cancer, stage of the disease and the TME. In this review, we focus on the fundamental role of metabolic reprogramming in the interaction between microorganisms and cancers and explore the molecular mechanisms by which metabolic reprogramming modulates this complex biological process. This comment aims to provide valuable resources for clinicians and researchers and promote further research in the field.

Keywords:  anti-tumor therapy; cancer progression; metabolic reprogramming; microbiota; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1582166
Curr Med Chem. 2025 May 29.

The Role of CDKs in the Regulation of the Monocyte/Macrophage Immune Response.

Alexander N Neznamov, Yulia P Baykova, Marina V Kubekina.

  Monocytes/macrophages play an important role in controlling the onset and progression of inflammatory responses by changing their activation state. Inflammation accompanies some slowly progressing pathologies, such as neurodegenerative diseases, rheumatoid arthritis, atherosclerosis, and other inflammatory disorders. Monocyte/- macrophage differentiation and polarization are accompanied by transcriptional profile changes. A better understanding of the specific ligands and receptors involved in the regulation of immune cell transcription will help to identify selective molecular targets for the therapy of inflammatory diseases. CDKs are key regulators of cell cycle and transcription in eukaryotes. Thus, this review is aimed to examine the role of CDKs in the monocyte-macrophage response and the data obtained from relevant experiments. M1 macrophages can trigger harmful inflammatory responses. A potential solution is to shift the polarization of macrophages towards the protective anti-inflammatory M2 phenotype (macrophage reprogramming). The mechanisms regulating this switch are crucial for the proper functioning of monocytes and macrophages. Inhibition of different types of CDKs leads to changes in the functional activity of monocytes/macrophages. It has been shown that monocytes/macrophage differentiation and immune functions are dependent on CDK activity. Recent studies on CDKs and their role in the immune system have concluded that their activity plays an essential role in monocyte/macrophage differentiation and immune functions. However, the role of CDKs in monocytes, macrophages, and the immune response is not fully understood. Unraveling the role of transcriptional regulators could provide valuable insights for the development of new treatments for macrophage-mediated inflammatory diseases.

Keywords:  CDKs; Monocytes/macrophages; cell signaling; inflammatory diseases; macrophage immune response; macrophage polarization; transcriptional reprogramming.

DOI:  https://doi.org/10.2174/0109298673365178250414074531
Front Immunol. 2025 ;16 1594015

Coordination of innate immune responses by connexins.

Qirou Wu, Tiejun Zhao, Pinglong Xu.

  Innate immunity comprises intricate cellular and tissue responses critical for host defense and tissue homeostasis. Intercellular communication is central to these responses and significantly influences infection, inflammatory disorders, and cancer. Connexins form hemichannels, gap junctions, and connexosomes to mediate signaling molecule transfer, including nucleotide derivatives, ions, antigens, and mitochondria, which occur between adjacent cells or between cells and their microenvironments. By modulating intercellular communication, connexins regulate various immune cell functions and contribute significantly to the coordination of innate immunity. This review summarizes recent insights into connexin-mediated innate immune networks and their implications in pathological contexts such as viral infections, inflammation, and tumorigenesis. Additionally, we discuss targeting connexins as an emerging pharmacological strategy for clinical intervention.

Keywords:  connexins; gap junctions; inflammation; innate immunity; intercellular communication; mitochondria transfer; signaling molecules; viral infection

DOI:  https://doi.org/10.3389/fimmu.2025.1594015
Probiotics Antimicrob Proteins. 2025 Jun 04.

Therapeutic Potential of Probiotics: A Review of Their Role in Modulating Inflammation.

Mahsa Beikmohammadi, Saba Halimi, Najaf Allahyari Fard, Weijie Wen.

  Probiotics are characterized as beneficial live microorganisms which, when consumed in sufficient quantities, provide measurable health advantages to the host organism. These beneficial microbes, primarily comprising specific strains of bacteria and yeasts, play a critical role in restoring and maintaining gut microbiota homeostasis, enhancing gastrointestinal health, strengthening immune responses, and exerting systemic physiological effects beyond the digestive tract. This review explores the therapeutic potential of probiotics in managing immune-mediated and inflammatory conditions, with a particular emphasis on their role in reestablishing gastrointestinal equilibrium. Emerging clinical evidence underscores the efficacy of probiotics in addressing conditions such as inflammatory bowel disease (IBD), metabolic syndrome, and other gastrointestinal disorders. Notably, strains of Bifidobacterium and Lactobacillus have demonstrated therapeutic benefits by enhancing mucosal barrier integrity and modulating immune responses through the regulation of cytokine production. Furthermore, chronic inflammatory states are increasingly linked to the pathogenesis of complex diseases, highlighting the importance of probiotics as a preventive and therapeutic strategy. This review also emphasizes the anti-inflammatory mechanisms of probiotics and their implications for public health, advocating for greater awareness of their potential in mitigating inflammation-related diseases.

Keywords:  Gastrointestinal health; Immunomodulation; Inflammation; Probiotics; Therapeutic potential

DOI:  https://doi.org/10.1007/s12602-025-10609-z
ACS Infect Dis. 2025 Jun 03.

Human Milk Oligosaccharides Mediate the Host-Microbe Interface in a Model Vaginal Community.

Julie A Talbert, Sabrina K Spicer, Shannon D Manning, Jennifer A Gaddy, Steven D Townsend.

  Group B Streptococcus (GBS) is an opportunistic bacterium that can cause severe infection during gestation, leading to adverse pregnancy outcomes and neonatal disease. As current treatments only decrease chances of early onset neonatal disease without impacting the risk of chorioamnionitis, preterm birth, or late-onset disease, novel therapeutics are needed. Here, we demonstrate that human milk oligosaccharides (HMOs) positively modulate cocultures of GBS and Lactobacillus spp., common inhabitants of a healthy vaginal microbiome, across in vitro, ex vivo, and in vivo experiments. HMOs shift the total cell population in vitro to favor Lactobacillus, which was qualitatively visualized via scanning electron microscopy. Lactobacillus adherence to EpiVaginal tissues was also increased with HMOs during coinoculation with GBS. Using an in vivo mouse model of reproductive GBS infection, Lactobacillus crispatus and HMOs prevented ascending infection, reducing bacterial burden in both the placenta and fetus. L. crispatus alone reduced the burden in all reproductive tissues tested except the vagina. Together, these results highlight the benefit of pre- and probiotic treatment to potentially reduce GBS colonization during gestation.

Keywords:  group B Streptococcus; human milk oligosaccharides; lactobacillus; microbiome

DOI:  https://doi.org/10.1021/acsinfecdis.5c00295
Redox Biol. 2025 May 28. pii: S2213-2317(25)00216-2. [Epub ahead of print]84 103703

Histone lactylation-induced premature senescence contributes to 1-nitropyrene-Induced chronic obstructive pulmonary disease.

Rong-Rong Wang, Dan-Lei Chen, Meng Wei, Se-Ruo Li, Peng Zhou, Jing Sun, Qi-Yuan He, Jin Yang, Hui Zhao, Lin Fu.

  Our previous study revealed that mice exposed to 1-nitropyrene (1-NP) develop pulmonary fibrosis and senescent alveolar cells. However, the impacts of chronic 1-NP on chronic obstructive pulmonary disease (COPD) and the underlying mechanism are unclear. Our research suggested that chronic 1-NP evoked alveolar structure damage, inflammatory cell infiltration, and pulmonary function decline in mice. Moreover, 1-NP increased p53 and p21 expression, the number of β-galactosidase-positive cells, and cell cycle arrest in mouse lungs and MLE-12 cells. Moreover, 1-NP promoted glycolysis and upregulated lactic dehydrogenase A (LDHA) and lactate production in mouse lungs and MLE-12 cells. Elevated glycolysis provoked histone lactylation, but not histone acetylation in pulmonary epithelial cells. Mechanistically, histone H3 lysine 14 lactylation (H3K14la) was upregulated in pulmonary epithelial cells. P53 knockdown mitigated 1-NP-induced cell cycle arrest and senescence in MLE-12 cells. CUT&Tag and ChIP-qPCR experiments confirmed that increased H3K14la directly upregulated p53 transcription in pulmonary epithelial cells. As expected, LDHA knockdown alleviated 1-NP-triggered cell cycle arrest and senescence in MLE-12 cells. In addition, supplementation with oxamate, an inhibitor of LDH, attenuated 1-NP-incurred premature senescence and the COPD-like phenotype in mice. These data revealed for the first time that histone lactylation-induced the increase in p53 transcription contributes to pulmonary epithelial cell senescence during 1-NP-induced COPD progression. Our results provide a basis for repressing lactate production as a promising therapeutic strategy for COPD.

Keywords:  1-Nitropyrene; COPD; Cellular senescence; Histone lactylation; P53

DOI:  https://doi.org/10.1016/j.redox.2025.103703