bims-bac4me 2025-08-10 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–08–10
thirty-one papers selected by
Chun-Chi Chang, Lunds universitet

Probiotic peptidoglycan skeleton enhances vaccine efficacy against MRSA by inducing trained immunity via the TLR2/JAK-STAT3 pathway.
Infections as ecosystems: community metabolic interactions in microbial pathogenesis.
Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.
Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense.
Symbiotic bacteria-mediated imbalance and repair of immune homeostasis: exploring novel mechanisms of microbiome-host interactions in atopic dermatitis.
The Invisible Extinction.
Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.
Staphylococcus aureus exploits lipoic acid salvage to combat host oxidative stress.
Metabolites derived from bacterial isolates of the human skin microbiome inhibit Staphylococcus aureus biofilm formation.
Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.
Towards airway microbiome engineering for improving respiratory health.
Nasopharyngeal Staphylococcus aureus Isolation and Bacterial Culture Profiles in COVID-19 Patients: A Comparative Study Based on Lung Involvement.
GM-CSF derived from alveolar type 2 cells promotes CD301b+ cDC2 generation and allergic airway inflammation.
Emerging host-directed strategies for overcoming drug resistance and immune evasion in Staphylococcus aureus infections.
Epithelial Memory After Respiratory Viral Infection in Mice Results in Prolonged Enhancement of Antigen Presentation.
Exploring the Therapeutic Landscape of Probiotics in Enteric and Respiratory Viral Infections.
Diversity of motility gene signatures distinguishes commensal Clostridia that elicit divergent host immune responses.
Host-intrinsic and host-extrinsic factors modulate immunity to Mtb infection, reinfection, and noncanonical vaccination routes.
Epigenetic regulation of inflammation dynamics during wound healing: a subtle yet profound shift in histone modifications.
SPP1 Regulates Alveolar Type 2 Cell-Macrophage Crosstalk and Epithelial Cell Fate in Iron-Driven Lung Fibrosis.
S-Ruxolitinib: a novel JAK/STAT-targeted therapy through restoring mucosal homeostasis for chronic rhinosinusitis with nasal polyps.
CSF1R regulates monocyte subset differentiation and intracellular metabolism.
Streptococcal natural products mediate interspecies competition with Gram-positive bacterial pathogens.
Lacticaseibacillus rhamnosus P118 enhances host tolerance to Salmonella infection by promoting microbe-derived indole metabolites.
Distribution of Dendritic Cells and Macrophages in the Nose with Special Reference to Site-dependent Differences: A Cadaveric Study.
Microbiota-Host Interactions: Exploring Their Dynamics and Contributions to Human Diseases.
Biological and clinical implications of a model of surveillance immunity.
The role of epigenetics in inflammatory memory.
In vitro metabolic interaction network of a rationally designed nasal microbiota community.
Beyond Antagonism: IL-4 Exploits TNF signaling to Shape Its Gene Expression Signature in Monocytes and Macrophages.
Lactobacillus gasseri CECT 30648 shows probiotic characteristics and colonizes the vagina of healthy women after oral administration.

Front Immunol. 2025 ;16 1606626

Probiotic peptidoglycan skeleton enhances vaccine efficacy against MRSA by inducing trained immunity via the TLR2/JAK-STAT3 pathway.

Lingdi Niu, Haoyuan Duan, Jiaqing Wang, Zheng Jia, Hai Li, Junjie Guo, Shuhe Zhang, Ning Liu, Yaxin Miao, Junwei Ge, Fang Wang.

  Trained immunity refers to the ability of trained innate immune cells to generate an immune memory that produces rapid, broad-spectrum, and long-lasting protection against heterologous stimuli. Based on the rapid and broad-spectrum protection that the peptidoglycan backbone from lactic acid bacteria, bacterium-like particles (BLPs), offers, we hypothesized that BLPs enhance protection through trained immunity. Here, we found that combining BLP with a vaccine significantly improves protective efficacy against methicillin-resistant Staphylococcus aureus (MRSA) infection, accompanied by changes in trained immunity markers. We demonstrate that BLP-induced trained immunity macrophages exhibit increased cytokine secretion and phagocytic activity in vitro. In an in vivo model, BLP confers protection against S. aureus 26003 even without specific antigens. In an ex vivo model, BLP induces increased markers of trained immunity. Transcriptome analysis suggests that BLP may induce trained immunity by activating the IL-6-JAK-STAT3 pathway through TLR2 receptor activation, thereby modulating macrophage metabolic reprogramming and function. In summary, our study establishes that BLP induction of trained immunity, along with regulated metabolic reprogramming and macrophage function, may contribute to enhancing vaccine efficacy. Our findings elucidate a novel mechanism for BLP-mediated immune enhancement, critical for the application of BLP as a vaccine vector to construct a vaccine that combines specific immune response with innate immune response.

Keywords:  MRSA; bacterium-like particles; innate immunity; peptidoglycan backbone; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1606626
Infect Immun. 2025 Aug 04. e0053024

Infections as ecosystems: community metabolic interactions in microbial pathogenesis.

Aanuoluwa E Adekoya, Shannon R West, Sydney K Arriaga, Carolyn B Ibberson.

  Microbes rarely exist alone; instead, they live in dynamic multi-species communities with a range of metabolic capacities. To establish within a polymicrobial community, an organism must compete with the other members of the community for space and nutrients. In addition, microbes form complex metabolic interdependencies in polymicrobial environments, and these nutrient exchanges are central to overall community function. Interactions between microbial community members dictate key processes, including nutrient cycling, tolerance to disturbances, and disease progression, and these interactions are known to depend on the environment in which they are measured. Therefore, understanding these ecological interactions is fundamental to our understanding of community composition, function, and impacts on disease. In this mini-review, we will describe the mechanisms microbes use to exchange nutrients in host-associated environments, with a focus on the oral and respiratory tracts. We will particularly emphasize the environmental factors that influence community composition and how interactions between organisms, ranging from cooperation to competition, impact nutrient bioavailability and overall community function during infection.

Keywords:  human microbiome; metabolism; microbe-microbe interaction; microbial ecology; physiology

DOI:  https://doi.org/10.1128/iai.00530-24
PLoS Pathog. 2025 Aug;21(8): e1013291

Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.

Adriana Moldovan, Ronald S Flannagan, Marcel Rühling, Kathrin Stelzner, Clara Hans, Kerstin Paprotka, Tobias C Kunz, David E Heinrichs, Thomas Rudel, Martin J Fraunholz.

Staphylococcus aureus is a notorious human pathogen that thrives in macrophages. It resides in mature phagolysosomes, where a subset of the bacteria eventually begin to proliferate. How S. aureus acquires essential nutrients, such as amino acids, for growth in this niche is poorly understood. Using a long-term primary human macrophage infection model, we show that branched-chain amino acid (BCAA) uptake mediated by the major transporter BrnQ1 is required by S. aureus for intracellular replication in macrophages and we provide mechanistic insight into the role of BCAAs in the success of intracellular S. aureus. Loss of BrnQ1 function renders intracellular S. aureus non-replicative and non-cytotoxic. The defective intracellular growth of S. aureus brnQ1 mutants can be rescued by supplementation with BCAAs or by overexpression of the BCAA transporters BrnQ1 or BcaP. Inactivation of the CodY repressor rescues the ability of S. aureus brnQ1 mutants to proliferate intracellularly independent of endogenous BCAA synthesis but dependent on BcaP expression. Non-replicating brnQ1 mutants in primary human macrophages become metabolically quiescent and display aberrant gene expression marked by failure to respond to intraphagosomal iron starvation. The bacteria remain, however, viable for an inordinate length of time. This dormant, yet viable bacterial state is distinct from classical persisters and small colony variants.

DOI: https://doi.org/10.1371/journal.ppat.1013291
bioRxiv. 2025 Jul 26. pii: 2025.07.23.664455. [Epub ahead of print]

Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense.

Adam Krebs, Tomi Lazarov, Anthony Reynolds, Kimberly A Dill-McFarland, Abigail Xie, James Bean, Muxue Du, Olivier Levy, John Buglino, Aaron Zhong, Anna-Lena Neehus, Stephanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E Kroon, Marlo Möller, Thomas R Hawn, Ting Zhou, Lydia W S Finley, Marc Antoine Jean Juste, Dan Fitzgerald, Frederic Geissmann, Michael S Glickman.

Mycobacterium tuberculosis (Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to M. tuberculosis (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown. Here, we investigated the role of itaconate in human iPSC-derived macrophages, either induced by GM-CSF to resemble alveolar macrophages (AM-Like cells), or treated with M-CSF to generate control macrophages (MCDM cells). Both types of human macrophages produce substantially less itaconate than mouse macrophages and AM-Ls produced 4-fold less itaconate than MCDMs. Surprisingly, ACOD1 deficient AM-L macrophages, but not MCDM macrophages, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb induced inflammatory response in MCDMs, but not AM-L macrophages, affecting both the Type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to TB, with distinct roles in different macrophage subsets. These results also show that genetically tractable hiPSC-derived macrophages are a robust and versatile model to dissect cellular host pathogen interactions.

DOI: https://doi.org/10.1101/2025.07.23.664455
Front Immunol. 2025 ;16 1649857

Symbiotic bacteria-mediated imbalance and repair of immune homeostasis: exploring novel mechanisms of microbiome-host interactions in atopic dermatitis.

Xingyue Lai, Jilin Huang, Yulin Li, Liang Dong.

  The skin surface is colonised by a rich microbiome, and intricate interactions between this microenvironment and microbial communities are critical for maintaining skin homeostasis. Atopic dermatitis (AD), a chronic inflammatory skin disease characterised by skin barrier dysfunction and aberrant immune activation, exhibits a rising global incidence. While conventional therapeutic strategies offer short-term symptom control, their long-term use is limited by adverse effects including skin atrophy, metabolic disorders, and increased infection risk. Critically, these approaches fail to cure AD or reverse the underlying immune imbalance. Recent research has firmly established the skin microbiome as a central driver in AD pathogenesis. The molecular mechanisms underpinning microbiome-host interactions, including the potential for remote regulation via the gut-skin axis, are now being actively investigated. This review systematically analyses how microbial dysbiosis in AD promotes Th2/Th17 immune polarization through three key pathways: microbial metabolites, immune signalling, and barrier integrity. Building on these mechanistic insights and recent advances, we propose novel multimodal therapeutic strategies targeting the microbial-immune axis. We further elucidate the role of commensal bacteria in maintaining immune homeostasis. Ultimately, this synthesis aims to bridge fundamental research with clinical applications, providing a robust theoretical foundation for future therapeutic development and clinical studies in AD management.

Keywords:  atopic dermatitis (AD); autoimmune skin disease; immune; skin microbiome; symbiotic bacteria

DOI:  https://doi.org/10.3389/fimmu.2025.1649857
Annu Rev Microbiol. 2025 Aug 04.

The Invisible Extinction.

Martin J Blaser, Maria Gloria Dominguez-Bello.

The characterization of the human microbiome has opened a new chapter in understanding human biology and its relationship to health and disease. Yet we also have learned that our ancient coevolved microbiome has been changing across recent human generations; we have been losing a substantial amount of its diversity. This is especially concerning because the microbiota that we acquire early in life has important bearing on our developmental trajectory, especially with regard to metabolism, immunity, and cognition. Collectively, the early-life microbiota is a partner in our human developmental biology. We detail the medical, public health, and dietary phenomena bearing on the acquisition, maintenance, and loss of members of the microbiota and then consider the linkages between the altered microbiome and the diseases that have been emerging in recent years. Finally, we highlight ways to address and solve these problems associated with modernization.

DOI: https://doi.org/10.1146/annurev-micro-051024-092416
Immunity. 2025 Jul 29. pii: S1074-7613(25)00321-8. [Epub ahead of print]

Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.

Samuel E Weinberg, Navdeep S Chandel.

Mitochondria are key regulators of immune cell function, going beyond their traditional role in ATP and metabolite production to support anabolic processes and act as hubs for intracellular signaling. A key aspect of this signaling function is the production of mitochondrial reactive oxygen species (mtROS), which act as critical second messengers in both adaptive and innate immune regulation. Immune cells maintain an optimal concentration of mtROS to maintain physiological responses, and excessive or lack of mtROS production contributes to chronic inflammation, autoimmunity, and cancer. Here, we review the molecular mechanisms controlling mtROS production and detoxification, their role in shaping macrophage and T cell fate and function, and their implications for disease pathogenesis.

DOI: https://doi.org/10.1016/j.immuni.2025.07.012
Cell Rep. 2025 Jul 31. pii: S2211-1247(25)00866-6. [Epub ahead of print]44(8): 116095

Staphylococcus aureus exploits lipoic acid salvage to combat host oxidative stress.

Iván C Acosta, Andrew Albers, Liwei Fang, Gustavo Serrato, Wei Ping Teoh, David G Glanville, Francis Alonzo.

  Phagocytic leukocytes employ reactive oxygen species to defend against pathogenic microorganisms. The bacterial pathogen Staphylococcus aureus adapts to oxidative stress by producing antioxidant enzymes and small molecules to protect proteins, nucleic acids, and other essential cellular components. Here, we show that the lipoic acid carrier protein GcvH-L promotes S. aureus resistance to oxidative stress. The gene encoding GcvH-L lies within a conserved operon in several pathogenic microorganisms. The operon also encodes LplA2, a redox-responsive lipoyl ligase, and SirTM, an ADP-ribosyltransferase. We demonstrate that ADP-ribosylation of lipoyl-GcvH-L protects lipoic acid from oxidation and regulates its transfer from GcvH-L to enzyme complexes needed for central metabolism. A ΔgcvH-L mutant is attenuated during infection and is more sensitive to phagocyte respiratory burst, phenotypes that are abrogated in NADPH oxidase-deficient mice. Thus, ADP-ribosylation and lipoylation converge on GcvH-L to promote S. aureus resistance to oxidative stress.

Keywords:  ADP-ribosylation; CP: Microbiology; CP: Molecular biology; Staphylococcus aureus; lipoic acid; oxidative stress; posttranslational modifications; reactive oxygen species; respiratory burst; salvage

DOI:  https://doi.org/10.1016/j.celrep.2025.116095
Microbiol Spectr. 2025 Aug 05. e0130625

Metabolites derived from bacterial isolates of the human skin microbiome inhibit Staphylococcus aureus biofilm formation.

Viet Hoang Le, Tetyana King, Breanna Wuerzberger, Olivia R Bauer, Megan N Carver, Tiffany S Chan, Annabeth L Henson, Grace K Hubbard, Tamar Kopadze, Claire F Patterson, Sabrina M McGraw, Aidan O'Hara, Eryk J Yarkosky, Michael G LaMontagne, Eileen M Hotze, Rosana B R Ferreira.

  The human skin microbiome is a diverse ecosystem that can help prevent infections by producing biomolecules and peptides that inhibit growth and virulence of bacterial pathogens. Staphylococcus aureus is a major human pathogen responsible for diseases that range from acute skin and soft tissue infections to life-threatening septicemia. Its ability to form biofilms is a key virulence factor contributing to its success as a pathogen as well as to its increased antimicrobial resistance. Here, we investigated the ability of bacterial skin commensals to produce molecules that inhibit S. aureus biofilm formation. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identified 77 human skin microbiome bacterial isolates from Staphylococcus and Bacillus genera. Metabolites from cell-free concentrated media (CFCM) from 26 representative isolates were evaluated for their ability to inhibit biofilm formation by both methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) S. aureus strains. CFCM, derived from most of the isolates, inhibited biofilm formation to varying extents but did not inhibit planktonic growth of S. aureus. Size fractionation of the CFCM of three S. epidermidis isolates indicated that they produce different bioactive molecules. Cluster analysis, based on either MALDI-TOF mass spectra or whole-genome sequencing draft genomes, did not show clear clusters associated with levels of biofilm inhibition among S. epidermidis strains. Finally, similar biosynthetic gene clusters were detected in all S. epidermidis strains analyzed. These findings indicate that several bacterial constituents of the human skin microbiome display antibiofilm in vitro activity, warranting further investigation on their potential as novel therapeutic agents.
IMPORTANCE: The skin is constantly exposed to the environment and consequently to numerous pathogens. The bacterial community that colonizes healthy skin is thought to play an important role in protecting us against infections. S. aureus is a leading cause of death worldwide and is frequently involved in several types of infections, including skin and soft tissue infections. Its ability to adhere to surfaces and produce biofilms is considered an important virulence factor. Here, we analyzed the activity of different species of bacteria isolated from healthy skin on S. aureus biofilm formation. We found that some species of Staphylococcus and Bacillus can reduce S. aureus biofilm formation, although a generally lower level of inhibitory activity was observed compared to S. epidermidis isolates. Among S. epidermidis isolates, strength of activity was dependent on the strain. Our data highlight the importance of mining the skin microbiome for isolates that could help combat skin pathogens.

Keywords:  Bacillus; MALDI-TOF; Staphylococcus; anti-biofilm activity; biofilms; skin microbiota

DOI:  https://doi.org/10.1128/spectrum.01306-25
Front Immunol. 2025 ;16 1595162

Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.

Yi Yang, Yi Wu, Hui Chen, Zehai Xu, Ruisi Lu, Sijie Zhang, Rui Zhan, Qinghua Xi, Yunfeng Jin.

  Glucose metabolic reprogramming describes the alterations in intracellular metabolic pathways in response to variations in the body's internal environment. This metabolic reprogramming has been the subject of extensive research. The primary function is to enhance glycolysis for rapid ATP production, even with sufficient oxygen, leading to a significant accumulation of lactic acid, which subsequently affects the functions of tumor cells and immune cells within TME. Lactylation represents a newly identified post-translational modification (PTM) that occurs due to lactate accumulation and is observed in various proteins, encompassing both histone and non-histone types. Lactylation alters the spatial configuration of proteins, influences gene transcription, and thereby regulates gene expression. This modification serves as a significant epigenetic regulatory factor in numerous diseases. Glucose metabolic reprogramming and lactylation are intricately linked in the process of tumorigenesis. Glucose reprogramming activates essential enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), through transcription factors such as HIF-1α and c-Myc, thereby enhancing glycolysis and lactate accumulation. Lactate functions as a metabolite and signaling molecule, acting as a substrate for lactylation facilitated by histone acetyltransferases such as CBP/p300. This epigenetic modification inhibits antitumor immunity through the upregulation of oncogenic signaling pathways, the induction of M2-type macrophage polarization, and the dysfunction of T-cells. Glucose metabolic reprogramming not only influences lactate synthesis but also provides sufficient substrates for lactate modification. The two factors jointly affect gene expression and protein function, acidify the tumor microenvironment, regulate immune evasion, and promote carcinogenesis. This review systematically details the mechanisms of lactylation and glucose metabolic reprogramming, their impacts on immune cells within the tumor microenvironment, and their interrelations in tumor progression, immunity, and inflammation.

Keywords:  glucose metabolic reprogramming; immune cells; lactate; lactylation; macrophage; posttranslational modification; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1595162
Adv Drug Deliv Rev. 2025 Aug 06. pii: S0169-409X(25)00147-4. [Epub ahead of print]225 115662

Towards airway microbiome engineering for improving respiratory health.

Kelsey E Hern, Arthur Prindle.

  The known roles of human-associated microbes in health and disease have expanded in recent years. While the gut microbiome is the most well studied, the airway microbiome is gaining attention as an important gatekeeper of respiratory health. Compared to the gut, the airway microbiome has lower species complexity, greater niche stability, and represents an immediate point of contact with the outside world. These features make it an attractive target for improving respiratory health. As respiratory disease continues to increase among humans, it will be critical to develop novel approaches to combat new and emergent bacterial infections, viruses, and cancers for which we do not currently have treatments. This review seeks to define strategies for airway microbiome engineering-the intentional manipulation of airway associated microbes to restore species balance, enhance protective functions, or treat disease. We summarize the growing body of literature linking the airway microbiome to respiratory health and discuss both broad-spectrum and high precision technologies that hold particular promise for further development. We argue that inhaled probiotics and bacteriophage are among the most attractive technologies for clinical translation of airway microbiome engineering to improve respiratory health.

Keywords:  Bacteriophage; Microbiome engineering; Probiotics; Respiratory microbiome; Synthetic biology; Therapeutics

DOI:  https://doi.org/10.1016/j.addr.2025.115662
Cureus. 2025 Jul;17(7): e87149

Nasopharyngeal Staphylococcus aureus Isolation and Bacterial Culture Profiles in COVID-19 Patients: A Comparative Study Based on Lung Involvement.

Burcu Vural Camalan, Naciye Badir, Sumeyra Doluoglu, Onural Ozturk.

   PURPOSE: This exploratory study aimed to determine the nasopharyngeal carriage rate of Staphylococcus aureus and to characterize the distribution of other culturable bacterial species in patients with COVID-19. Additionally, we assessed whether bacterial growth patterns differed between patients with and without lung involvement.
METHODS: Nasopharyngeal samples were collected from COVID-19 patients with and without lung involvement, as assessed by thoracic CT scans. The study also included PCR-negative control patients. Sampling occurred between January and March 2021 at a state hospital outpatient clinic. A total of 65 participants were included in the study: 51 (78.5%) tested positive for COVID-19, of whom 25 (49.0%) had lung involvement and 26 (51.0%) did not. The remaining 14 (21.5%) served as PCR-negative controls.
RESULTS: S. aureus was isolated in 11 (21.6%) of COVID-19-positive patients and 5 (35.7%) of controls. Among COVID-19 patients, the isolation rate was 6 (24.0%) in those with lung involvement and 5 (19.2%) in those without. No statistically significant differences were observed in S. aureus carriage or in the overall bacterial profiles across the groups.
CONCLUSION: Nasopharyngeal S. aureus colonization and bacterial distribution showed no significant association with COVID-19 status or lung involvement. Although colonization is common, its clinical relevance in early-stage COVID-19 remains unclear and warrants further study.

Keywords:  bacterial colonization; covid-19; lung involvement; nasopharyngeal culture; staphylococcus aureus

DOI:  https://doi.org/10.7759/cureus.87149
Sci Immunol. 2025 Aug 08. 10(110): eadt0688

GM-CSF derived from alveolar type 2 cells promotes CD301b+ cDC2 generation and allergic airway inflammation.

Julia Gschwend, Antonie Lechner, Nikolaos D Sidiropoulos, Paul Maier, Tilde Andersson, Flurin Sturzenegger, Basak Corak, Nina Brander, David A Bejarano, Elina Wells, Sandra P Melo, Joana R D Martins, Maximilian Nitschké, Ari B Molofsky, Andreas Schlitzer, Isabelle C Arnold, Sarah Mundt, Burkhard Becher, Manfred Kopf, Hubert Rehrauer, Christoph Schneider.

Pulmonary conventional dendritic cells (cDCs) are functionally and phenotypically heterogeneous antigen-presenting cells essential for orchestrating adaptive immune responses in the lung. Here, we define a cell-intrinsic role for granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in the development of a CD301b+ subset of terminally differentiated cDC2s, in addition to CD103+XCR1+ cDC1s. Unbiased single-cell transcriptomic profiling of CD11c+ cells identified both immature and differentiated lung cDC populations. GM-CSF deficiency disrupted antiapoptotic Bcl2a1 up-regulation and impaired progression to the CD301b+ transcriptional state. Despite the positioning of CD301b+ cDC2s in lymphoid cell-rich adventitial cuff areas, hematopoietic GM-CSF was dispensable for their development. Instead, alveolar epithelial type 2 cell-derived GM-CSF was required for CD301b+ cDC2 formation and pulmonary type 2 immune responses, highlighting the central role of GM-CSF signaling in shaping the pulmonary myeloid landscape.

DOI: https://doi.org/10.1126/sciimmunol.adt0688
J Adv Res. 2025 Aug 05. pii: S2090-1232(25)00590-9. [Epub ahead of print]

Emerging host-directed strategies for overcoming drug resistance and immune evasion in Staphylococcus aureus infections.

Youle Zheng, Jin Feng, Qianwei Qu, Yongzheng Liu, Yadan Zheng, Yanhua Li.

   BACKGROUND: Staphylococcus aureus poses a significant global threat to both human and animal health. Bacterial-targeted therapies are limited by strong selective pressures (e.g., mecA-mediated β-lactam resistance) and the pathogen's remarkable capacity for phagocyte intracellular survival-a strategy that allows them to evade antibiotics and the immune system, ultimately leading to persistent infections. These factors highlight the urgent need for alternative strategies to combat bacterial infections.
AIM OF REVIEW: This review explores host-directed therapies (HDTs) as alternative strategies for combating S. aureus infections, aiming to overcome limitations of current treatments and contribute to the development of novel or combination therapies.
KEY SCIENTIFIC CONCEPTS OF REVIEW: HDTs offer several advantages, including a reduced risk of bacterial resistance, a broad antimicrobial spectrum, and the potential for synergy with antibiotics to shorten treatment duration and even treat persistent intracellular infections. Target-based precision drug design shows strong promise in addressing off-target effect challenges. This review provides an overview of key host factors involved in S. aureus pathogenesis, emphasizing therapeutic agents targeting these factors, their mechanisms of action, and pharmacological profiles. These recent advancements are crucial in the ongoing efforts to combat S. aureus infections.

Keywords:  Drug-target interaction; Host-directed therapy; Immune regulation; Intracellular infection; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.jare.2025.08.001
Allergy. 2025 Aug 07.

Epithelial Memory After Respiratory Viral Infection in Mice Results in Prolonged Enhancement of Antigen Presentation.

Piotr P Janas, Wouter T'Jonck, Matthew O Burgess, Maximilian Reck, Caroline Chauché, Matthieu Vermeren, Christopher D Lucas, Calum Bain, Robert Illingworth, Edward W Roberts, Henry J McSorley, Jürgen Schwarze.

   BACKGROUND: Viral lower respiratory tract infections (LRTIs) can reduce the severity of subsequent LRTIs but have also been linked to respiratory allergy development and exacerbation. Here, we show that viral LRTI can imprint lung epithelial cells (LECs), leading to prolonged phenotypic and functional changes.
METHODS: Mice were infected via intranasal administration of respiratory syncytial virus (RSV). After 28 days, LECs were isolated using cold dispase digestion followed by magnetic-activated cell sorting. Epigenetic changes were assessed using Cleavage Under Targets and Release Using Nuclease (CUT&RUN), while transcriptional changes were evaluated using NanoString and qPCR. Flow cytometry was employed to measure cell surface major histocompatibility complex (MHC) levels, antigen uptake and processing rates, and OT-I cell proliferation after antigen presentation.
RESULTS: We identified epigenetic and transcriptomic changes in murine LECs 28 days after RSV infection, especially impacting genes associated with MHC. Lasting upregulation of MHC-I and MHC-II was further increased following in vivo LPS stimulation. Importantly, MHC upregulation was associated with increased antigen uptake and processing, as well as increased antigen presentation to T cells.
CONCLUSIONS: Our data demonstrate that RSV can induce prolonged upregulation of antigen presentation by LECs, with the potential to facilitate local T cell responses to microbial antigens and allergens and to enhance immunity or in susceptible hosts respiratory allergy.

Keywords:  RSV; epigenetic imprinting; epithelial memory; lung epithelial cells; respiratory viral infection

DOI:  https://doi.org/10.1111/all.16683
Probiotics Antimicrob Proteins. 2025 Aug 02.

Exploring the Therapeutic Landscape of Probiotics in Enteric and Respiratory Viral Infections.

Yashpal Singh Malik, Aakriti Pathania, Ujjwal Kumar De, Manu M, Harsh Panwar, Jaspreet Kaur, Adarsh Mishra, Naveen Kumar, Souvik Ghosh, Varun Kumar Sarkar, Sakshi.

  In recent times, the understanding of the human microbiome and its impact on health and disease has undergone a paradigm shift, leading to ground-breaking discoveries in the field of probiotics. Probiotics, live microorganisms known for conferring health benefits when administered adequately, have garnered significant interest for their potential to modulate the immune system's response to viral infections in both humans and animals. The emergence of enteric and respiratory viruses as significant global health threats has prompted intensive research efforts to identify novel therapeutic strategies. Traditional antiviral therapies often face challenges such as drug resistance, limited efficacy and adverse effects, underscoring the urgent need for alternative approaches. In this context, probiotics have emerged as a promising avenue for the prevention and treatment of viral infections due to their ability to modulate the host immune response, enhance mucosal barrier function and exert direct antiviral effects. This review aims to provide a comprehensive overview of the therapeutic landscape of probiotics against enteric and respiratory viruses. Based on latest findings from preclinical and clinical studies, we have explored the mechanisms underlying the antiviral activity of probiotics and their potential role in mitigating viral infections. Furthermore, promising avenues for harnessing probiotics as adjunctive or standalone interventions against enteric and respiratory viral infections have been discussed here.

Keywords:  Enteric infection; Immunomodulation; Probiotics; Respiratory infection; Viral infections

DOI:  https://doi.org/10.1007/s12602-025-10683-3
bioRxiv. 2025 Jul 23. pii: 2025.07.18.665615. [Epub ahead of print]

Diversity of motility gene signatures distinguishes commensal Clostridia that elicit divergent host immune responses.

Lennard W Duck, Melissa S Jennings, Jung-Shan Hsu, Covenant F Adeboboye, E Leighann Morgan, Kiarra J Coger, Barbara J Klocke, Dave D Hill, Katie L Alexander, Alexander F Rosenberg, Goo Lee, Qing Zhao, Charles O Elson, Craig L Maynard.

Adaptive immune responses to commensal flagellins are hallmarks of Crohn's disease, but it is unclear whether flagellins themselves promote inflammation or whether flagellated commensals can also be colitogenic. Here, we show that the arrangement of motility loci and the diversity of encoded flagellins can separate flagellated gut-derived Clostridia into at least 2 functionally distinct groups. In gnotobiotic mice, both groups induce tolerogenic responses but only one group promoted tissue inflammation following barrier disruption. Accordingly, specific flagellins expressed by members of this pro-inflammatory group displayed a heightened capacity for TLR5 activation which could be altered by modification of a defined region of the flagellin D0 domain. Finally, bacteria belonging to the pro-inflammatory group were found to be elevated in Crohn's disease biopsies. Collectively, our study identified key features of specific commensal bacteria that possess colitogenic potential and revealed one mechanism whereby these organisms can potentially initiate intestinal inflammation.

DOI: https://doi.org/10.1101/2025.07.18.665615
Cell Rep Med. 2025 Aug 05. pii: S2666-3791(25)00359-3. [Epub ahead of print] 102286

Host-intrinsic and host-extrinsic factors modulate immunity to Mtb infection, reinfection, and noncanonical vaccination routes.

Joshua D Bromley, Andrew W Simonson, Alex K Shalek, JoAnne L Flynn.

  Tuberculosis (TB) disease states and outcomes are highly heterogeneous. While this makes TB difficult to diagnose, monitor, and treat, it also presents opportunities to identify correlates of protection or disease severity that can be used as biomarkers and help inform future interventions. Immunological priming due to primary Mycobacterium tuberculosis (Mtb) infection can protect against subsequent reinfection; thus, comparing primary infection with reinfection can provide insights into features associated with host control. Here, we examine paradigms of natural and vaccine-induced immunity and examine how host-intrinsic and -extrinsic factors modulate the immune response to protect against infection and reinfection. We propose that the TB granuloma is a quasi-homeostatic system, building this model on findings from Mtb reinfection and successful prophylactics, which suggest that protective immunity depends on a balance of pro- and anti-inflammatory cellular phenotypes and that this balance can mitigate pathophysiological processes at the tissue and organismal level.

Keywords:  Mtb reinfection; granuloma; homeostasis; inflammation; natural immunity

DOI:  https://doi.org/10.1016/j.xcrm.2025.102286
Curr Opin Immunol. 2025 Aug 05. pii: S0952-7915(25)00111-6. [Epub ahead of print]96 102635

Epigenetic regulation of inflammation dynamics during wound healing: a subtle yet profound shift in histone modifications.

Jingyu Xiao, Mengjiao Chen, Yamin Zhang, Juan Tao.

Wound healing represents a dynamic process centered on the temporally coordinated inflammatory, proliferative, and remodeling phases. The inflammatory response exhibits a double-edged role: a moderate response is essential for normal healing, but excessive or persistent response impedes repair processes. In normal wound healing, histone modifications precisely regulate inflammatory responses from initiation to resolution, mainly manifested through early-stage modulation of NETs and late-stage intervention in macrophage polarization. In chronic non-healing wounds such as diabetic wounds, venous ulcers, and pressure ulcers, the specific pathological microenvironment regulates the inflammatory response of immune cells through various histone modifications, resulting in a greater intensity and longer duration of the inflammation. Herein, we summarize the critical roles of histone modifications in normal and chronic non-healing wounds, highlighting the subtle alterations of histone methylation and acetylation in macrophages that lead to macrophage reprogramming and inflammation regulation, thus providing the promise of precision therapy for chronic non-healing wounds.

DOI: https://doi.org/10.1016/j.coi.2025.102635
Am J Physiol Cell Physiol. 2025 Aug 06.

SPP1 Regulates Alveolar Type 2 Cell-Macrophage Crosstalk and Epithelial Cell Fate in Iron-Driven Lung Fibrosis.

Xinqian Du, Xinyu Zhang, Zhe Wang, Dan Wang, Yunqi Li, Zengqing Liu, Qing Miao, Hanxiao Zhang, Luo Duan, Yue Hu, Muzhi Zhang, Jie Liu, Zhe Lv, Yan Chen, Wei Wang, Ying Sun, Ye Cui.

  Pulmonary fibrosis, a life-threatening respiratory condition affecting millions globally, is characterized by progressive lung scarring that severely compromises respiratory function. With few effective treatment options available, it carries a poor prognosis for those affected. Disrupted iron homeostasis is increasingly implicated in its pathogenesis, yet the precise mechanisms linking iron overload to fibrotic progression remain elusive. This study unveils a novel pathway by which iron accumulation orchestrates fibrotic remodeling via secreted phosphoprotein 1 (SPP1)-mediated reprogramming of alveolar type 2 (AT2) cells. Using an integrated approach combining analysis of public single-cell and single-nucleus RNA sequencing datasets with functional validation across multiple murine models of pulmonary fibrosis (iron-induced, bleomycin-induced, and silica-induced), we demonstrate that iron overload within AT2 cells triggers a coordinated transcriptional cascade affecting iron handling, immune cell recruitment, and cellular differentiation. Mechanistically, SPP1 emerges as a key mediator, functioning both externally as a paracrine signal for macrophage recruitment following iron-induced secretion from AT2 cells, and internally as a driver of pathological epithelial transitions, specifically fostering the development of a Krt8+ alveolar intermediate phenotype. The clinical relevance of these findings is substantiated by analysis of human idiopathic pulmonary fibrosis specimens using publicly available single-cell and spatial transcriptomic datasets. These analyses reveal conserved pathway activation and a distinctive spatial organization of SPP1-expressing AT2 cells within remodeled tissue microenvironments, notably in close proximity to macrophages. By establishing SPP1 as a critical nexus between iron dysregulation and fibrotic progression, our work identifies the SPP1 signaling axis as a compelling therapeutic target for this devastating condition.

Keywords:  Alveolar Differentiation Intermediate; Epithelial-Macrophage Crosstalk; Iron Overload; Pulmonary Fibrosis; Secreted Phosphoprotein 1

DOI:  https://doi.org/10.1152/ajpcell.00140.2025
J Allergy Clin Immunol. 2025 Aug 05. pii: S0091-6749(25)00837-1. [Epub ahead of print]

S-Ruxolitinib: a novel JAK/STAT-targeted therapy through restoring mucosal homeostasis for chronic rhinosinusitis with nasal polyps.

Mengyan Zhuang, Jian Jiao, Qinqin Zhang, Sicen Pan, Yuan Zhang, Ting He, Ying Li, Ming Zheng, Xiangdong Wang, Luo Zhang, Claus Bachert.

   BACKGROUND: The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a crucial role in regulating immune function and inflammatory responses. Dysregulation of this pathway has been implicated in numerous disorders, including chronic rhinosinusitis with nasal polyps (CRSwNP). However, the potential therapeutic efficacy of targeted JAK inhibition in CRSwNP remains underexplored and requires further investigation.
OBJECTIVE: This study aimed to evaluate the efficacy and mechanisms of S-Ruxolitinib, a selective inhibitor of JAK1/2, as a novel therapeutic strategy for CRSwNP.
METHODS: Expression of p-STAT3 and p-STAT6 was analyzed in nasal tissues from CRSwNP patients. A murine model of CRSwNP was established to evaluate S-Ruxolitinib's effects on polyp formation, sinonasal inflammation and epithelial function. Additionally, primary human nasal epithelial cells (HNECs) were cultured to assess S-Ruxolitinib's effects on Th cytokines-induced epithelial dysfunction and production of inflammatory mediators.
RESULTS: The expression of p-STAT3 and p-STAT6 was elevated in CRSwNP patients. Intranasal S-Ruxolitinib administration in CRSwNP mice significantly reduced the number of NP-like lesions, epithelial thickness, sinonasal inflammation, disrupted barrier and ciliary integrity, and goblet cell hyperplasia. In vitro, S-Ruxolitinib reversed IL-13-induced epithelial barrier disruption, ciliary dysfunction, and goblet cell hyperplasia. It also inhibited the production of ALOX15, CCL26, and POSTN. Furthermore, S-Ruxolitinib suppressed IFN-γ-induced upregulation of CXCL9, CXCL10, and CXCL11.
CONCLUSIONS: The findings of this study provide novel evidence that JAK/STAT inhibition using S-Ruxolitinib effectively attenuates sinonasal inflammation and restores mucosal homeostasis in CRSwNP. These results suggest that S-Ruxolitinib holds promise as a potential therapeutic agent for the treatment of CRSwNP.

Keywords:  Chronic rhinosinusitis with nasal polyps; JAK/STAT; S-Ruxolitinib; epithelial barrier; mucociliary; sinonasal inflammation

DOI:  https://doi.org/10.1016/j.jaci.2025.07.020
bioRxiv. 2025 Jul 21. pii: 2025.07.17.665275. [Epub ahead of print]

CSF1R regulates monocyte subset differentiation and intracellular metabolism.

Alexandre Gallerand, Johanna Merlin, Zakariya Caillot, Chloé Delaby, Elisa Bord, Jichang Han, Bastien Dolfi, Alexia Castiglione, Sacha Grenet, Maxime Franceschini, Gisèle Jarretou, Fairouz N Zair, Evy Boré, Florian Tuffin, David Dombrowicz, Rodolphe R Guinamard, Gwendalyn J Randolph, Adeline Bertola, Patrick Auberger, Arnaud Jacquel, David A Hume, Jesse W Williams, Marc Bajénoff, Jaap G Neels, Stoyan Ivanov.

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6C high ) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6C low ) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6C low monocytes in part by blunting differentiation of Ly6C high monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.

DOI: https://doi.org/10.1101/2025.07.17.665275
bioRxiv. 2025 Jul 31. pii: 2025.07.31.667707. [Epub ahead of print]

Streptococcal natural products mediate interspecies competition with Gram-positive bacterial pathogens.

Ruth Y Isenberg, Celine W Sackih, Julia L E Willett.

Polymicrobial communities where bacteria must compete with each other to persist can serve as a source of uncharacterized antibacterial compounds to develop drugs for the treatment of drug-resistant infections. This study investigates interbacterial competition between bacteria found in the oral cavity, where Streptococcus species comprise a large portion of the resident oral microbiota and Enterococcus faecalis is a pathobiont that is commonly found in root canal infections. We used co-cultures to determine whether oral Streptococci and E. faecalis compete with each other. Our experiments revealed that multiple strains of Streptococcus mutans , an important cariogenic bacterium, kill vancomycin-resistant Enterococcus and other Gram-positive bacteria, including Staphylococcus epidermidis , and methicillin-resistant Staphylococcus aureus . Further, inhibition of Gram-positive bacteria by some strains of S. mutans requires the production of the non-ribosomal cyclic lipopeptide mutanobactin, while another strain inhibits independent of mutanobactin. We determined that S. mutans mutanobactin production increases target cell membrane permeability and that killing is contact-dependent. We also determined that an E. faecalis virulence factor, the secreted protease gelatinase (GelE), is required for recovery from mutanobactin-mediated killing. Additionally, data show that S. mutans mutanobactin production prevents and kills E. faecalis biofilms. Together, this work demonstrates how natural products from a common oral bacterium contribute to competition in polymicrobial environments, which will inform future strategies to treat and prevent bacterial infections.
IMPORTANCE: Antimicrobial resistance requires new therapeutics to treat drug-resistant infections. Novel antimicrobial compounds can be discovered in polymicrobial communities, where bacterial natural products promote competitive fitness. The oral cavity hosts a microbial consortium, and we investigated interactions between oral streptococci and Enterococcus faecalis , a common root canal infection isolate. We demonstrate antibacterial activity of streptococcal mutanobactin against Gram-positive pathogens, including antibiotic-resistant isolates. We further show that the E. faecalis virulence factor gelatinase promotes recovery from mutanobactin-mediated killing, and that mutanobactin prevents and kills E. faecalis biofilms. By probing interactions between bacteria that occupy the same niche and characterizing antibacterial activity of a bacterial product, this work contributes to broader efforts to identify and develop antibiotics to treat clinically relevant drug-resistant infections.

DOI: https://doi.org/10.1101/2025.07.31.667707
Elife. 2025 Aug 07. pii: RP101198. [Epub ahead of print]13

Lacticaseibacillus rhamnosus P118 enhances host tolerance to Salmonella infection by promoting microbe-derived indole metabolites.

Baikui Wang, Xianqi Peng, Xiao Zhou, Xiuyan Jin, Abubakar Siddique, Jiayun Yao, Haiqi Zhang, Weifen Li, Yan Li, Min Yue.

  Salmonella is one of the most common foodborne pathogens, resulting in inflammatory gastroenteritis and frequently accompanied by dysbiosis. Gut commensals, such as Lactobacillus species, have been proven to exhibit broad antibacterial activities and protect hosts against pathogenic infections. Here, Lacticaseibacillus rhamnosus strain P118, screened from 290 isolates recovered from fermented yogurts and healthy piglet intestines using traditional and Caenorhabditis elegans-infection screening strategies, exerts great probiotic properties. Notably, P118 and its supernatant exhibited great antibacterial activities and attenuated C. elegans susceptibility to Salmonella infection. We found that P118 protected mice against Salmonella lethal infections by enhancing colonization resistance, reducing pathogen invasion, alleviating intestinal pro-inflammatory response, and improving microbial dysbiosis and fecal metabolite changes. Microbiota and fecal metabolome analyses suggested P118 administration significantly decreased the relative abundances of potentially harmful microbes (e.g., Salmonella, Anaeroplasma, Klebsiella) and increased the fecal levels of tryptophan and its derivatives (indole, indole-3-acrylic acid, 5-hydroxytryptophan, 5-methoxyindoleacetate). Deterministic processes determined the gut microbial community assembly of P118-pretreated mice. Integrated omics further demonstrated that P118 probiotic activities in enhancing host tolerance to Salmonella infection were mediated by microbe-derived tryptophan/indole metabolites (e.g., indole-3-acrylic acid, indole, tryptophan, 5-methoxyindoleacetic acid, and 5-hydroxytryptophan). Collective results demonstrate that L. rhamnosus P118 could enhance host tolerance to Salmonella infections via various pathways, including direct antibacterial actions, inhibiting Salmonella colonization and invasion, attenuating pro-inflammatory responses of intestinal macrophages, and modulating gut microbiota mediated by microbe-derived indole metabolites.

Keywords:  Caenorhabditis elegans; Lacticaseibacillus rhamnosus; Salmonella; gut microbiota; indole metabolite; infectious disease; microbiology; mouse

DOI:  https://doi.org/10.7554/eLife.101198
Ann Anat. 2025 Jul 31. pii: S0940-9602(25)00337-1. [Epub ahead of print] 152710

Distribution of Dendritic Cells and Macrophages in the Nose with Special Reference to Site-dependent Differences: A Cadaveric Study.

Tomohito Tanaka, Eri Miyamoto, Yuki Yoshihashi, Kei Kitamura, Ai Hirano-Kawamoto, Gen Murakami, Shin-Ichi Abe.

   BACKGROUND: Macrophages and interdigitating dendritic cells (DCs) are key professional antigen-presenting cells. However, DCs appear to be absent in healthy nasal mucosa, despite the extensive ciliated respiratory epithelium being highly exposed to various antigens.
METHODS: Using histological specimens from 20 elderly cadavers, we examined the distribution of immunoreactive cells in the nasal vestibular skin, mucocutaneous junction, and ciliated mucosa. CD1a, CD83 and DC-SIGN were used as DC markers, with the latter two being typically employed in lymphatic tissue studies.
RESULTS: Macrophages and CD8-positive lymphocytes were widely distributed throughout the subcutaneous and submucosal tissues at all epithelial depths. These cells were occasionally found embedded within both the mucocutaneous junction epithelium and basal layer of the mucosal epithelium. In contrast, CD4-positive lymphocytes were scarce across all examined sites. CD169-positive macrophages, considered the first-line gatekeepers in lymphatic tissues, were localized along deep vessels and glands. CD1a-positive DCs (Langerhans cells) were absent from both the cytokeratin 14-negative squamous epithelium and ciliary epithelium but were abundant in the basal layer of the cytokeratin 14-positive stratified squamous epithelium. CD1a-positive cells, which exhibit either a dendritic or round morphology, were occasionally scattered through the elastic fiber-rich subcutaneous tissue. A few DC-SIGN- or CD83-positive DCs were seen in glands and along deep vessels in subcutaneous and submucosal tissues CONCLUSION: Hair follicles at the nasal vestibule were likely accompanied by a cluster of CD1a-positive cells and CD8-positive lymphocytes. Macrophages, rather than DCs, were likely the primary antigen-presenting cells for CD8-positive lymphocytes in aged nasal respiratory mucosa.

Keywords:  Dendritic cells; Immunohistochemistry; Macrophages; Mucocutaneous junction; Nasal respiratory mucosa; Vestibular skin

DOI:  https://doi.org/10.1016/j.aanat.2025.152710
Microbiologyopen. 2025 Aug;14(4): e70043

Microbiota-Host Interactions: Exploring Their Dynamics and Contributions to Human Diseases.

Siau Wui Chin, Zheng Yao Low, Wei Qi Tan, Adzzie Shazleen Azman.

  Dysbiosis is the imbalance of bacterial composition, which would otherwise change the human host's metabolic activities and usual microbiota distribution. The outcomes would be as clear as day: losing beneficial bacteria in exchange for the overgrowth of potentially pathogenic bacteria, leading to diseases. It is crucial to unravel the dynamic roles of bacteria in maintaining human health to prevent and alleviate the said dysbiosis. To date, diet, lifestyle, age, and chemical exposures were cited as the leading cause of bacterial dysbiosis atop of genetic factors. This review aims to shed light on how bacterial interplays in maintaining human health and how bacteria-bacteria interaction may play a part in the surge of antimicrobial resistance. The intricate relationship of bacteria dynamics in the gut, skin and oral was detailed to understand how bacteria dysbiosis causes diseases such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), acne vulgaris (AV), atopic dermatitis (AD), periodontitis and dental caries. Besides that, current interventions and limitations of therapeutic prospects entailing the growing concepts of rebiosis, including probiotics, prebiotics, synbiotics, microbiota transplantation, and the evolving phage therapy, were also discussed to breathe new life into the development of novel therapeutics against dysbiosis.

Keywords:  Inflammatory bowel disease; antimicrobial resistance; atopic dermatitis; dysbiosis; host–pathogen interactions; tooth decay

DOI:  https://doi.org/10.1002/mbo3.70043
J Clin Invest. 2025 Aug 01. pii: e191645. [Epub ahead of print]135(15):

Biological and clinical implications of a model of surveillance immunity.

Katharina Willmann, Luis F Moita.

The immune system must identify genuine threats and avoid reacting to harmless microbes because immune responses, while critical for organismal survival, can cause severe damage and use substantial energy resources. Models for immune response initiation have mostly focused on the direct sensing of microorganisms through pattern recognition receptors. Here, we summarize key features of the leading models of immune response initiation and identify issues they fail to solve individually, including how the immune system distinguishes between pathogens and commensals. We hypothesize and argue that surveillance of disruption to organismal homeostasis and core cellular activities is central to detecting and resolving relevant threats effectively, including infection. We propose that hosts use pattern recognition receptors to identify microorganisms and use sensing of homeostasis disruption to assess the level of threat they pose. We predict that both types of information can be integrated through molecular coincidence detectors (such as inflammasomes or others not yet discovered) and used to determine whether to initiate an immune response, its quality, and its magnitude. This conceptual framework may guide the identification of novel targets and therapeutic strategies to improve the progression and outcome of infection, cancer, autoimmunity, and chronic conditions in which inflammation plays a critical role.

DOI: https://doi.org/10.1172/JCI191645
Curr Opin Immunol. 2025 Aug 01. pii: S0952-7915(25)00106-2. [Epub ahead of print]96 102630

The role of epigenetics in inflammatory memory.

Yaqin Yu, Yueqi Qiu, Ming Zhao.

Inflammatory memory refers to the ability of an organism to mount a stronger or faster response upon re-exposure to similar inflammatory stimuli. This heightened sensitivity was once thought to be a unique characteristic of immune cells. However, recent studies have challenged this traditional view, revealing that inflammatory memory is a widely prevalent phenomenon that extends beyond immune cells to include nonimmune cells. These studies indicate that the formation and maintenance of inflammatory memory largely depend on the regulation of epigenetics. Epigenetics involves heritable changes in gene expression without altering the DNA sequence, including mechanisms such as DNA methylation and histone modifications. These modifications regulate gene transcription and influence the cellular response to inflammatory stimuli. In this review, we will discuss the epigenetic mechanisms of inflammatory memory in both immune and nonimmune cells, focusing on new mechanistic insights from the past few years, and briefly discuss the unknowns and future strategies.

DOI: https://doi.org/10.1016/j.coi.2025.102630
iScience. 2025 Aug 15. 28(8): 113114

In vitro metabolic interaction network of a rationally designed nasal microbiota community.

Laura Bonillo-Lopez, Oussama Rouam-El Khatab, Pau Obregon-Gutierrez, Joana Almansa Fernandez-Villacañas, Igor Florez-Sarasa, Florencia Correa-Fiz, Marina Sibila, Virginia Aragon, Karl Kochanowski.

  Mounting evidence suggests that metabolite exchange between microbiota members is a key driver of microbiota composition. However, we still know little about the metabolic interaction networks within many microbiota. To tackle this issue, we developed the porcine nasal consortium (PNC8), which represents the most in vivo abundant genera in the nasal microbiota of healthy piglets, and used it to systematically map the in vitro metabolic interactions between its members. Spent media experiments, exometabolomics, and direct co-cultivation, revealed that most pairwise interactions between PNC8 strains are negative, with co-depletion of sugars acting as a key driver. This prevalence of negative interactions leads to a complex competition hierarchy in which only few strains are able to consistently outcompete all others. Overall, this work provides a valuable resource for studying the nasal microbiota under experimentally tractable in vitro conditions and is a key step toward mapping its metabolic interaction network.

Keywords:  metabolomics; microbiome

DOI:  https://doi.org/10.1016/j.isci.2025.113114
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667180. [Epub ahead of print]

Beyond Antagonism: IL-4 Exploits TNF signaling to Shape Its Gene Expression Signature in Monocytes and Macrophages.

Ruoxi Yuan, Chao Yang, Bikash Mishra, David Oliver, Richard Bell, Lionel B Ivashkiv.

Investigation of crosstalk between antagonistic pro- and anti-inflammatory cytokines has focused on mechanisms and functional consequences of cross-inhibition. We investigated cross-regulation between proinflammatory TNF and anti-inflammatory IL-4 in primary human monocytes and in a skin wound-healing model. Surprisingly, TNF functioned mainly as a costimulator of IL-4-induced gene expression, whereas IL-4 selectively inhibited the TNF-induced IFN response, leaving inflammatory gene expression mostly intact. TNF and IL-4 synergistically induced gene sets important for regulating inflammation and tissue repair, which were highly induced during the phase of wound healing when these cytokines are co-expressed. Crosstalk between TNF and IL-4 was mediated by epigenetic chromatin-mediated mechanisms associated with cooperation between NF-κB and STAT6 transcription factors, erasure of negative histone mark H3K27me3, and selective inhibition of IRF1. These results identify a long-sought mechanism for expansion of the IL-4 response, and highlight the complexity of crosstalk between antagonistic cytokines that includes cooperation for select gene responses important in immune response and tissue repair.

DOI: https://doi.org/10.1101/2025.07.28.667180
Microbiol Spectr. 2025 Aug 07. e0021125

Lactobacillus gasseri CECT 30648 shows probiotic characteristics and colonizes the vagina of healthy women after oral administration.

Marta Perez, Eva Armengol, Antonio Del Casale, Ilenia Campedelli, Ana Aldea-Perona, Marta Pérez Otero, Maria Rodriguez-Palmero, Jordi Espadaler-Mazo, Pol Huedo.

  Vaginal dysbiosis is linked to recurrent infections and reproductive complications. Probiotics may restore vaginal microbiota, but there is modest evidence to support vaginal colonization after oral administration. This work aimed to screen a vaginal lactobacilli collection (n = 45) and assess vaginal colonization of selected candidates. Lactobacillus gasseri CECT 30648 (Lg) and Lactobacillus crispatus CECT 30647 (Lc) showed excellent in vitro attributes, including antagonism against 10 urogenital pathogens, resistance to gastrointestinal tract and vaginal environment-including high concentrations of biogenic amines-and adhesion to vaginal epithelium. Forty-eight healthy women (18-45 years old) were randomly allocated to consume daily a capsule containing Lg (109 CFU), a combination of Lg plus Lc (1.5 × 109 CFU), or placebo for up to 18 days (between menses). Volunteers collected vaginal samples every 3 days. The primary endpoint was the presence of probiotic strains in vaginal swabs confirmed by strain-specific quantitative PCR. Secondary variables included vaginal microbiota composition and tolerability, among others. Probiotics were well tolerated. Lg but not Lc was detected in 55.9% of participants in active groups (9 in Lg and 10 in Lg + Lc) throughout the study (P = 0.005 aggregated probiotic groups vs placebo). The sum of relative abundances of non-lactobacilli genera was significantly reduced in the probiotic group after intervention (P = 0.047 vs day 0), and there was a positive transition toward lactobacilli-dominated community state types (P = 0.039 vs day 0). Overall, we show that L. gasseri CECT 30648 exerts a broad-spectrum antimicrobial activity and can colonize the vaginal tract of healthy women, thus showing potential to promote vaginal health. The trial was registered in clinicaltrials.gov (NCT05688397).IMPORTANCEThe use of probiotics to promote vaginal health is increasing because vaginal dysbiosis has been linked to numerous gynecological and reproductive complications. While vaginal administration of probiotics using devices or creams has been widely investigated, there is limited evidence supporting vaginal colonization of a probiotic administered orally. It is therefore imperative to perform extensive in vitro characterization to select a vaginal probiotic that can survive the gastrointestinal transit and effectively colonize the vaginal tract of consumers through the oral-gut-vaginal route. We have identified the strain L. gasseri CECT 30648, which shows great probiotic properties, including antagonism against several relevant urogenital pathogens, can colonize the vaginal tract of >55% of participants, and can modulate vaginal microbiota toward a lactobacillus-dominated status in a randomized controlled clinical trial in healthy premenopausal women. These results suggest that oral consumption of L. gasseri CECT 30648 might be effective in promoting vaginal health.

Keywords:  antagonism activity; clinical study; dysbiosis; vaginal colonization; vaginal lactobacilli

DOI:  https://doi.org/10.1128/spectrum.00211-25