bims-bac4me 2025-07-27 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–07–27
eighteen papers selected by
Chun-Chi Chang, Lunds universitet

Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.
The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
Differential modulation of post-antibiotic colonization resistance to Clostridioides difficile by two probiotic Lactobacillus strains.
Lactobacillus rhamnosus D3189 modulates antiviral and inflammatory responses in primary nasal epithelial cells, reducing respiratory syncytial virus shedding.
Cues of Trained Immunity in Multiple Sclerosis Macrophages.
Microbial trash to metabolic treasure.
Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
Probiotics: An Adjuvant Treatment Strategy for Chronic Respiratory Diseases.
Bioengineering approaches to trained immunity: Physiologic targets and therapeutic strategies.
Macrophage-T cell interactions promote SLAMF1 expression for enhanced TB defense.
Dynamic balance of the lung microbiome in health and respiratory diseases.
Direct interaction between Lactiplantibacillus plantarum ZJ316-derived lipoteichoic acid and TLR2 mediates anti-inflammatory and barrier-protective effects in intestinal cells.
Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
The balance between proinflammatory, "bad", and immunomodulatory, "good", lipopolysaccharide for understanding gut-derived systemic inflammation.
Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections.
IL-17A inhibitors modulate skin microbiome in psoriasis: implications for microbial homeostasis.
Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages.
Deciphering dynamic antibiotics-microbiome-metabolome interactions in preterm infants using systems biology.

Am J Physiol Cell Physiol. 2025 Aug 01. 329(2): C456-C470

Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.

Andra Grigorescu, Anca-Lelia Riza, Ioana Streata, Mihai G Netea.

  Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.

Keywords:  immune aging; inflammaging; nutrition; trained immunity

DOI:  https://doi.org/10.1152/ajpcell.00153.2025
Cells. 2025 Jul 17. pii: 1096. [Epub ahead of print]14(14):

The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.

Eun Jung Choi, Yoon Young Jang, Eun Joo Choi, Chang Joo Oh.

  Lactate, once regarded as a metabolic byproduct, is now recognized as a critical immunometabolic regulator that shapes immune responses in both physiological and pathological contexts. This review examines how lactate accumulation occurs across diverse disease settings, including cancer, sepsis, and diabetes, through mechanisms such as hypoxia, mitochondrial dysfunction, and pharmacologic intervention. We then explore how lactate modulates immunity via four integrated mechanisms: transporter-mediated flux, receptor signaling (e.g., GPR81), context-dependent metabolic rewiring, and histone/protein lactylation. Particular emphasis is placed on the dichotomous effects of endogenous versus exogenous lactate, with the former supporting glycolytic effector functions and the latter reprogramming immune cells toward regulatory phenotypes via redox shifts and epigenetic remodeling. The review also highlights how the directionality of lactate transport, and the metabolic readiness of the cell determine, whether lactate sustains inflammation or promotes resolution. After analyzing emerging data across immune cell subsets and disease contexts, we propose that lactate serves as a dynamic rheostat that integrates environmental cues with intracellular metabolic and epigenetic programming. Understanding these context-dependent mechanisms is essential for the rational design of lactate-targeted immunotherapies that aim to modulate immune responses without disrupting systemic homeostasis.

Keywords:  anti-inflammation; immunometabolism; lactate

DOI:  https://doi.org/10.3390/cells14141096
mBio. 2025 Jul 21. e0146825

Differential modulation of post-antibiotic colonization resistance to Clostridioides difficile by two probiotic Lactobacillus strains.

Matthew H Foley, Arthur S McMillan, Sarah O'Flaherty, Rajani Thanissery, Molly E Vanhoy, Mary Gracen Fuller, Rodolphe Barrangou, Casey M Theriot.

  Probiotics are often consumed after antibiotic treatment to prevent antibiotic-associated diarrheal disease, most commonly caused by Clostridioides difficile. However, the impact of probiotic bacteria on the post-antibiotic gut microbiota is undetermined and often overlooked. Here, we examined the effect of a single dose of probiotic Lactobacillus acidophilus NCFM and Lactobacillus gasseri Lg-36 on colonization resistance against C. difficile in an antibiotic-treated mouse model. We found that L. acidophilus administration increased C. difficile infection and impaired the restoration of colonization resistance. In contrast, L. gasseri decreased C. difficile and promoted the return of colonization resistance, presumably through a putative bacteriocin inhibiting C. difficile. However, L. gasseri transiently colonizes the mouse gut, and its administration impacts colonization resistance after it is no longer detectable. We analyzed the gut microbiota of mice and found that members of the understudied Muribaculaceae family were enriched after L. gasseri administration and associated with colonization resistance. Using Muribaculum intestinale and Duncaniella muris, we determined that elevated growth of these species can restrict C. difficile growth in vitro, suggesting that these bacteria may play a role in establishing colonization resistance in vivo. These findings highlight the potential pitfalls of specific probiotic strains taken after antibiotic treatment and support the need for further investigations of their influence on the gut microbiota post-antibiotic. Additionally, this work supports the role of the Muribaculaceae as beneficial gut commensals that can contribute to colonization resistance against C. difficile and illustrates the need to decipher community interactions in complex microbial consortia.IMPORTANCEProbiotic research has overwhelmingly generalized the safety of select strains perceived as beneficial, while most studies are based on individual strains to substantiate particular functional attributes. In contrast, Clostridioides difficile studies document how this complex pathogen interacts with diverse members of the gut microbiota to cause diarrheal disease. Despite their purported ability to inhibit pathogens and modulate the gut microbiota, probiotics have been used to treat C. difficile infections with little success. In this study, we examine how common probiotics can impact the recovery of the gut microbiota after antibiotics by measuring colonization resistance against C. difficile in a mouse model. We show that Lactobacillus acidophilus enhances C. difficile infection, while Lactobacillus gasseri promotes colonization resistance potentially through its expression of bacteriocins and an enrichment of Muribaculaceae. This work highlights the complexity of probiotic interactions with pathogens and the indigenous microbiota and further supports that the overlooked Muribaculaceae are capable of inhibiting C. difficile.

Keywords:  Clostridioides difficile; Lactobacillus; Muribaculaceae; colonization resistance; microbiome; probiotic

DOI:  https://doi.org/10.1128/mbio.01468-25
Front Cell Infect Microbiol. 2025 ;15 1625517

Lactobacillus rhamnosus D3189 modulates antiviral and inflammatory responses in primary nasal epithelial cells, reducing respiratory syncytial virus shedding.

Tejasri Yarlagadda, Jacob Stedman, Diane Maresco-Pennisi, Andrea Coleman, Anders Cervin, Kirsten Spann.

   Introduction: Respiratory syncytial virus (RSV) infection in the upper respiratory tract promotes disease progression and transmission, with excessive inflammation contributing to severe lower respiratory tract involvement. This study investigates the immunomodulatory effects of Lactobacillus rhamnosus D3189 on viral kinetics and innate immune responses in well-differentiated nasal epithelial cells (WD-NECs).
Methods: WD-NECs from healthy adult donors (N = 8) were cultured in vitro, treated with L. rhamnosus D3189, and then infected with RSV (strain RS4) 24 hours later. Viral replication and shedding were assessed via RT-qPCR and plaque assays. Cytotoxicity and epithelial integrity were evaluated using LDH release and transepithelial electrical resistance (TEER). Inflammatory and antiviral responses were investigated using multiplex immunoassays, AlphaLISA, and ELISA.
Results: RSV infection induced robust viral replication and shedding, disrupted epithelial barrier integrity, and triggered the release of pro-inflammatory cytokines and type I/III interferons. L. rhamnosus D3189 alone did not induce cytotoxicity or inflammation. While it had no effect on viral replication, TEER, LDH release, or IFN-λ1/3 levels, D3189 significantly enhanced IFN-β production, reduced viral shedding, and attenuated RSV-induced cytokine and chemokine responses.
Discussion: L. rhamnosus D3189 modulates the epithelial immune response to RSV, reducing inflammation and viral shedding without compromising epithelial integrity. These findings support its potential as a novel strategy to limit RSV-associated infection and transmission.

Keywords:  antiviral; inflammation; innate immunity; lactobacilli; nasal epithelium; respiratory syncytial virus

DOI:  https://doi.org/10.3389/fcimb.2025.1625517
Cells. 2025 Jul 10. pii: 1054. [Epub ahead of print]14(14):

Cues of Trained Immunity in Multiple Sclerosis Macrophages.

Elisa Popa, Hélène Cheval, Violetta Zujovic.

  Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity-a form of innate immune memory-may play a crucial role in the autoimmune component of MS. By examining key findings from immunology, neuroinflammation, and MS pathophysiology, we explore how innate immune cells, particularly monocytes and macrophages, could contribute to disease onset and progression through persistent pro-inflammatory responses. Understanding the impact of trained immunity in MS could open new avenues for therapeutic strategies targeting the innate immune system.

Keywords:  epigenetic; inflammation; macrophages; metabolism; multiple sclerosis; trained immunity

DOI:  https://doi.org/10.3390/cells14141054
Immunometabolism (Cobham). 2025 Jul;7(3): e00067

Microbial trash to metabolic treasure.

Alexander S Dowdell, Sean P Colgan.

  In a recent Nature publication, Lesbats et al uncover the molecular fate of phagocytosed bacterial contents. The authors observed incorporation of bacterial biomolecules (amino acids, metabolites) into those of the host macrophage through stable isotope labeling and mass spectrometry. Further, the authors found that the state of the phagocytosed bacteria, living or dead, dramatically alters the macrophage's metabolic program toward either a pro-inflammatory or a "recycling" direction, respectively. This commentary summarizes these findings and further discusses the implications of this work in a broader sense.

Keywords:  AMPK; autophagy; dendritic cell; mTORC1; macrophage; neutrophil; phagocytosis

DOI:  https://doi.org/10.1097/IN9.0000000000000067
Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]

Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.

Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.

  Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.

Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis

DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
Respir Med. 2025 Jul 22. pii: S0954-6111(25)00331-2. [Epub ahead of print] 108268

Probiotics: An Adjuvant Treatment Strategy for Chronic Respiratory Diseases.

Bharti Verma, Nitish Kumar, Sumel Ashique, Biplab Debnath, Ashish Garg, Neeraj Mishra, Naheed Mojgani, Monika Kaurav, Madhu Gupta, Mithun Bhowmick, Farzad Taghizadeh-Hesary.

  Chronic respiratory disease is considered by reduced airflow and heightened airway inflammation, a pattern that has progressively increased in past few decades. Currently, chronic respiratory disease is considered one of the main leading causes of death worldwide. The gut-lung axis, which connects these two organs, facilitates bidirectional communication and may be influenced by microbiome populations in the context of disease interactions. The human microbiome, particularly in the gastrointestinal tract is thought to play a pivotal role in affecting diseases and maintaining homeostasis. Dysbiosis, defined as an imbalance in the gut microbiota, is associated with an elevated risk of lung infections. Studies have shown that modifying the gut microbiota by the use of probiotics, prebiotics, and synbiotics can reduce the duration and extent of respiratory infections. Probiotics have been observed to significantly alter serum cytokine and IgE levels in allergic conditions, as well as reduce eosinophilia in individuals with asthma. However, there has been no discernible improvement in clinical symptoms, although this approach may diminish eosinophilia in chronic obstructive pulmonary disease (COPD) patients and mitigate serum cytokine and IgE levels. Several factors such as illness severity, treatment duration, patient-specific, environmental characteristics, and treatment regimen seem to influence the effectiveness of these interventions. Research indicates that direct interaction and colonization of respiratory epithelial cells by probiotic microbes can enhance the success of intranasal probiotic delivery compared to oral administration. Although allergic rhinitis is a chronic inflammatory ailment, nasal probiotics have been utilized to address acute infections and respiratory disorders, offering a promising therapeutic avenue for a range of chronic inflammatory conditions.

Keywords:  COPD; Gut-lung axis; Lung diseases; Prebiotics; Probiotics; Synbiotics

DOI:  https://doi.org/10.1016/j.rmed.2025.108268
Elife. 2025 Jul 23. pii: e106339. [Epub ahead of print]14

Bioengineering approaches to trained immunity: Physiologic targets and therapeutic strategies.

Hannah Riley Knight, Marie Kim, Nisha Kannan, Hannah Taylor, Hailey Main, Emily Azcue, Aaron Esser-Kahn.

  Trained immunity presents a unique target for modulating the immune response against infectious and non-infectious threats to human health. To address the unmet need for training-targeted therapies, we explore bioengineering methods to answer research questions and address clinical applications. Current challenges in trained immunity include self-propagating autoinflammatory disease, a lack of controllable cell and tissue specificity, and the unintentional induction of training by known drugs and diseases. The bioengineering tools discussed in this review (nanotherapeutics, biomechanical modulation, cellular engineering, and machine learning) could address these challenges by providing additional avenues to modulate and interrogate trained immunity. The preferential activation of peripheral or central training has not yet been achieved and could be accessed using nanoparticle systems. Targeted delivery of training stimuli using nanocarriers can enrich the response in various cell and organ systems, while also selectively activating peripheral training in the local tissues or central trained immunity in bone marrow progenitor cells. Beyond chemical- or pathogen-based activation of training, force-based cues, such as interaction with mechanoreceptors, can induce trained phenotypes in many cell types. Mechanotransduction influences immune cell activation, motility, and morphology and could be harnessed as a tool to modulate training states in next-generation therapies. For known genetic and epigenetic mediators of trained immunity, cellular engineering could precisely activate or deactivate programs of training. Genetic engineering could be particularly useful in generating trained cell-based therapies like chimeric antigen receptor (CAR) macrophages. Finally, machine learning models, which are rapidly transforming biomedical research, can be employed to identify signatures of trained immunity in pre-existing datasets. They can also predict protein targets for previously identified inducers of trained immunity by modeling drug-protein or protein-protein interactions in silico. By harnessing the modular techniques of bioengineering for applications in trained immunity, training-based therapies can be more efficiently translated into clinical practice.

Keywords:  bioengineering; biomechanics; cellular engineering; immunology; inflammation; machine learning; nanotherapeutics; trained immunity

DOI:  https://doi.org/10.7554/eLife.106339
Nat Commun. 2025 Jul 23. 16(1): 6794

Macrophage-T cell interactions promote SLAMF1 expression for enhanced TB defense.

G V R Krishna Prasad, Steven J Grigsby, Gideon A Erkenswick, Cynthia Portal-Celhay, Ekansh Mittal, Guozhe Yang, Samuel M Fallon, Fengyixin Chen, Thais Klevorn, Neharika Jain, Yuanyuan Li, Makedonka Mitreva, Amanda J Martinot, Joel D Ernst, Jennifer A Philips.

CD4+ T cells are crucial for protective immunity to intracellular pathogens. In addition to secreting cytokines, CD4+ T cells promote control of Mycobacterium tuberculosis infection through cognate interactions with macrophages, but the mechanism has been unclear. Here, we show that SLAMF1/CD150 is highly and uniquely induced in macrophages by antigen-specific interactions with CD4+ T cells. In macrophages, SLAMF1 enhances the generation of reactive oxygen species and restricts Mtb replication. Mtb-infection of mice promotes SLAMF1 expression specifically on infected macrophages, not uninfected bystanders. SLAMF1 expression depends on adaptive immunity and also autophagy. Moreover, Slamf1-/- mice have higher Mtb burden and more rapid disease progression than wild type mice. Using Slamf1fl/fl conditional knock-out mice, we show that in vivo Slamf1 is specifically required in macrophages to restrict mycobacterial growth and limit IL-1β production. In macaques, macrophage SLAMFI expression also correlates with T cell responses and protection. Combined, these data demonstrate that SLAMF1 is a marker of macrophage-T cells interactions, and it promotes protection against Mtb.

DOI: https://doi.org/10.1038/s41467-025-61826-7
Chin Med J (Engl). 2025 Jul 21.

Dynamic balance of the lung microbiome in health and respiratory diseases.

Xin Wang, Lingfeng Bi, Jiayi Li, Dan Liu, Weimin Li, Zhoufeng Wang.

   ABSTRACT: Recent studies have challenged the once prevalent notion that the human lungs are sterile, instead unveiling a dynamic microbial environment that interacts intricately with both the host and external factors. This review describes the distinct microbial compositions between healthy individuals and those with respiratory diseases, as well as discussing the variations in microbial composition across different disease states. We explore the crucial role of the lung microbiome in maintaining respiratory health and describe its implications in various respiratory diseases. We discuss how these microbial differences correlate with the severity and progression of respiratory diseases, including chronic obstructive pulmonary disease, cystic fibrosis, lung cancer, asthma, coronavirus disease 2019, and tuberculosis. Furthermore, we analyze the pathogenic mechanisms of the lung microbiome, as well as the associations between changes in the lung microbiome and systemic effects, including the emerging concepts of the gut-lung axis and brain-lung axis, which highlight the interconnected influence of the microbiota on lung health. This review aims to provide a comprehensive understanding of the profound impact of microbial dynamics on respiratory health and disease, suggesting new avenues for targeted diagnostic and therapeutic strategies.

Keywords:  Asthma; Chronic obstructive pulmonary disease; Cystic fibrosis; Health; Immune mechanism; Lung cancer; Lung disease; Respiratory diseases; Respiratory microbiome

DOI:  https://doi.org/10.1097/CM9.0000000000003712
Food Funct. 2025 Jul 23.

Direct interaction between Lactiplantibacillus plantarum ZJ316-derived lipoteichoic acid and TLR2 mediates anti-inflammatory and barrier-protective effects in intestinal cells.

Jiarun Han, Lina Ding, Xin Zhao, Jiaqi Liu, Jiaqi Yin, Qi Wang, Ping Li, Qing Gu.

Lipoteichoic acid (LTA), a key bioactive substance of the Gram-positive bacterial cell wall, has garnered attention for its immunomodulatory properties. Herein, we investigated the underlying molecular mechanism by which LTA derived from Lactiplantibacillus plantarum ZJ316 exerts anti-inflammatory effects through interaction with Toll-like receptor 2 (TLR2). Molecular docking, dynamics simulations, and surface plasmon resonance (SPR) indicated a strong and specific binding affinity (KD = 1.02 μM), with key residues (e.g., Lys422, Arg486, Arg508) involved in stabilizing the LTA-TLR2 complex. Using an in vitro inflammatory model of Caco-2 cells induced by macrophage supernatant, we demonstrated that LTA significantly upregulated TLR2 expression and inhibited the ERK and p38 MAPK phosphorylation, resulting in reduced secretion of pro-inflammatory cytokines (TNF-α, IL-8) and enhanced anti-inflammatory IL-10 expression. Furthermore, LTA protected intestinal epithelial barrier function by enhancing the expression of tight junction proteins (ZO-1, Occludin, and Claudin-1). These findings highlight the potential of L. plantarum ZJ316-derived LTA as a bioactive component for intestinal health and provide new insight into its regulatory mechanism via the TLR2-MAPK signaling pathway.

DOI: https://doi.org/10.1039/d5fo01925g
Adv Sci (Weinh). 2025 Jul 24. e02297

Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.

Chuyi Tan, Han Ma, Jespar Chen, Gaifeng Ma, Alok Jha, Sipin Tan, Yaxi Zhu, Meidong Liu, Ke Liu, Xianzhong Xiao, Monowar Aziz, Huan Chen, Ping Wang, Huali Zhang.

  Immune cell metabolic reprogramming toward glycolysis is vital for sepsis defense. While interleukin 1 receptor 2 (IL1R2) acts as a decoy receptor for IL1α/β, its potential impact on cell metabolism and death during sepsis remains unclear. This study observed elevated plasma soluble IL1R2 (sIL1R2) levels in septic patients and mice. In pyroptotic macrophages, reduced intracellular IL1R2 expression led to its release extracellularly. Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as the binding partner of IL1R2 in macrophages. IL1R2 suppresses ENO1 activity to inhibit glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation in macrophages. IL1R2-deficient mice exhibited heightened susceptibility to sepsis, with increased inflammation, organ injury, and mortality. Notably, ENO1 inhibition reduced inflammation, organ injury, and improved survival rates in septic mice. The study reveals that IL1R2 interacts with ENO1 to inhibit glycolysis-mediated pyroptosis and inflammation in sepsis, suggesting the IL1R2-ENO1 interaction as a promising therapeutic target of sepsis.

Keywords:  IL1R2; enolase 1; glycolysis; macrophages; pyroptosis; sepsis

DOI:  https://doi.org/10.1002/advs.202502297
Front Immunol. 2025 ;16 1588129

The balance between proinflammatory, "bad", and immunomodulatory, "good", lipopolysaccharide for understanding gut-derived systemic inflammation.

Rafael Tume, Samar El Sherbiny, Roberto Bono, Thomas Gautier, Jean Paul Pais de Barros, Tomás Meroño.

  Lipopolysaccharide (LPS) from Gram-negative bacteria has been one of the most studied pathogen-associated molecular patterns triggering rapid inflammatory reactions. However, evidence shows that not all LPS molecules are proinflammatory ("bad"), and that "good" LPS from gut commensal bacteria exert immunomodulatory actions. The Limulus amebocyte lysis test commonly used to quantify LPS in circulation, only targets "bad" LPS, when not inactivated by plasma components. Use of other methods showed healthy subjects featuring elevated levels of LPS (suggesting predominance of "good" or inactive LPS in circulation). This review aims to summarize the evidence supporting the higher abundance of "good" LPS coming from gut commensals of healthy individuals and their potential impact in human health.

Keywords:  gut microbiota; inflammation; intestinal permeability; lipopolysaccharide (endotoxin); nutrition

DOI:  https://doi.org/10.3389/fimmu.2025.1588129
Commun Biol. 2025 Jul 23. 8(1): 1096

Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections.

Kimberly Kajihara, Donghong Yan, Gretchen L Seim, Hannah Little-Hooy, Jing Kang, Cynthia Chen, Marco De Simone, Tim Delemarre, Spyros Darmanis, Haridha Shivram, Rebecca N Bauer, Carrie M Rosenberger, Sharookh B Kapadia, Min Xu, Miguel Reyes.

Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood. Here, we performed a multi-cohort analysis of single cell and bulk transcriptomic data from 1845 patients across 25 studies. Our meta-analysis revealed a conserved severity-associated gene signature pointing to emergency myelopoiesis (EM) and increased IL1R2 expression in monocytes and neutrophils from patients with bacterial sepsis, COVID-19, and influenza. Analysis of tocilizumab-treated COVID-19 patients showed that IL-6 signaling blockade partially reduces this signature and results in a compensatory increase in G-CSF. To validate the role of these cytokines in vivo, we used a mouse model of influenza infection that recapitulates severity-associated increases in IL1R2+ monocytes and IL1R2hi neutrophils, and demonstrate that combined IL-6 and G-CSF blockade inhibits their production. Our study demonstrates the cooperative role of G-CSF and IL-6 in driving the production of severity-associated IL1R2+ myeloid cells and highlights the link between myeloid dysregulation and tissue injury during severe infection.

DOI: https://doi.org/10.1038/s42003-025-08407-y
J Transl Med. 2025 Jul 24. 23(1): 817

IL-17A inhibitors modulate skin microbiome in psoriasis: implications for microbial homeostasis.

Ying Lv, Huiying Bian, Yanjia Jing, Jing Zhou.

   BACKGROUND: The IL-17A inhibitors target aberrant immune responses in psoriasis but also impacts the host's defense against infections. The effects of this treatment on skin microorganisms and microbiome-encoded metabolic pathways remain unclear.
OBJECTIVES: This was an exploratory clinical study designed to investigate whether Psoriasis is associated with skin microbiota, as well as a longitudinal cohort study aimed at revealing the effects of IL-17A inhibitor treatment on skin microbiota in Psoriasis.
METHODS: In this study, we recruited 26 patients with moderate to severe psoriasis and 15 healthy controls. We collected skin microbiome samples from both greasy and dry skin regions. All samples were analyzed using 16S rDNA gene sequencing to determine the microbial profiles.
RESULTS: Compared with healthy controls, the composition and function of skin microbiome in psoriasis patients are heterogeneous. Treatment with IL-17A inhibitors significantly increases the alpha diversity of the skin microbiota in psoriasis patients, indicating potential restoration of microbial community richness and evenness. However, this treatment does not entirely alter the taxonomic composition of the skin microbiota; rather, it shifts the relative abundance of specific microbial species, indicating that certain core microbial features remain relatively stable. Moreover, IL-17A inhibitors help adjust the functional profile of the skin microbiome in psoriasis patients, bringing it closer to that of healthy individuals.
CONCLUSIONS: Psoriasis patients exhibit significant heterogeneity in both the composition and functionality of their skin microbiota. Although IL-17A inhibitor treatment fails to fundamentally alter its taxonomic composition, this therapy effectively enhances microbial community stability by increasing alpha diversity and modulating the relative abundance of various taxa. Additionally, it adjusts the functional profile of the skin microbiota towards a healthier state, thereby contributing to the restoration of microecological balance.

Keywords:  16S rDNA gene; IL-17A inhibitor; Psoriasis; Skin microbiome stability

DOI:  https://doi.org/10.1186/s12967-025-06723-9
Immunohorizons. 2025 Jul 14. pii: vlaf028. [Epub ahead of print]9(8):

Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages.

Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther.

  Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is unclear but it is crucial to consider amino acid restoration as a tool for treating sepsis. We demonstrate that lipopolysaccharide (LPS)-mediated iNOS, ASS1, and ASL protein expression and nitric oxide generation were dependent on exogenous arginine in RAW 264.7 macrophages. Exogenous citrulline was not sufficient to restore nitric oxide generation in arginine-free conditions. Despite the induction of iNOS and ASS1 mRNA in arginine-free conditions, exogenous arginine was necessary and citrulline was not sufficient to overcome eIF2-α (elongation initiation factor 2-α)-mediated translational repression of iNOS and ASS1 protein expression. Moreover, exogenous arginine, but not citrulline, selectively modified the inflammatory cytokine and chemokine expression profile of the LPS-activated RAW 264.7 and bone marrow-derived macrophages. Our study highlights the complex, differential regulation of proinflammatory cytokine expression, and NO generation by exogenous arginine in macrophages.

Keywords:  cell activation; cytokines; endotoxin shock; monocytes/macrophages; nitric oxide

DOI:  https://doi.org/10.1093/immhor/vlaf028
iScience. 2025 Aug 15. 28(8): 113038

Deciphering dynamic antibiotics-microbiome-metabolome interactions in preterm infants using systems biology.

Seo-Young Park, Yi Qing Lee, Dongseok Kim, Dong Kyung Sung, Kyeong-Seog Kim, Jae-Seung Lee, Joo-Youn Cho, Wonsik Lee, Se In Sung, Dong-Yup Lee.

  Preterm infants are frequently administered antibiotics to prevent infections, yet their impact on the developing gut microbiota and metabolome remains complex and clinically significant. To systematically assess these effects, we analyzed longitudinal stool samples from 54 extremely- and very-low-birthweight infants by integrating clinical data, 16S rRNA-based microbiome profiling, targeted metabolomics, and community-scale metabolic modeling. Antibiotic exposure disrupted microbial diversity, depleted beneficial taxa, and altered metabolites such as short-chain fatty acids (SCFAs) and bile acids. Class-specific antibiotic effects were observed, with cephalosporins promoting Staphylococcus dominance and potentially reducing bile acid diversity. Necrotizing enterocolitis (NEC) samples showed SCFAs depletion and enrichment of antibiotic-resistant genera. In silico models further identified microbial contributors to SCFAs production and recapitulated metabolite trends. These findings demonstrate how antibiotic regimens can perturb the neonatal gut ecosystem and highlight the need for precision antibiotic stewardship to preserve microbiome-derived metabolic functions and reduce disease risk in preterm infants.

Keywords:  Metabolomics; Microbiome; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2025.113038