bims-bac4me 2025-03-16 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–03–16
forty papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

The role of m6A modification during macrophage metabolic reprogramming in human diseases and animal models.
Determining Ciliary Function and Membrane Impermeability of the Pseudostratified Lung Airway Epithelium.
Absence of c-Maf and IL-10 enables type I IFN enhancement of innate responses to LPS in alveolar macrophages.
Regulation of Ferroptosis in Cancer and Immune Cells.
Lactate: A key regulator of the immune response.
Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease.
Human Skin Microbiota-Derived Extracellular Vesicles and Their Cosmeceutical Possibilities-A Mini Review.
Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.
Role of Formyl Peptide Receptor 2 and Toll-Like Receptor 2 in Skin Barrier Function and Atopic Dermatitis.
Trained immunity using probiotics and inactivated pathogens enhances resistance to Salmonella enterica serovar Typhimurium infection by activating the cGAS-STING signal pathway in mice and chickens.
Staphylococcus aureus utilizes vimentin to internalize human keratinocytes.
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.
KLF family members control expression of genes required for tissue macrophage identities.
Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities.
Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities.
Exercise-driven gut microbiota alterations enhance colonization resistance against methicillin-resistant Staphylococcus aureus.
Genome-wide mutagenesis identifies factors involved in MRSA vaginal colonization.
Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.
The Ligand Binding Domain of the Cell Wall Protein SraP Modulates Macrophage Apoptosis and Inflammatory Responses in Staphylococcus aureus Infections.
METs, NETs, and UTIs.
Alveolar macrophages from persons with HIV mount impaired TNF signaling networks to M. tuberculosis infection.
Innate immune system signaling and intestinal dendritic cells migration to the brain underlie behavioral changes after microbial colonization in adult mice.
Analysis of cytosolic mtDNA release during Staphylococcus aureus infection.
Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets.
Genome-scale resources in the infant gut symbiont Bifidobacterium breve reveal genetic determinants of colonization and host-microbe interactions.
Dexamethasone has profound influence on the energy metabolism of porcine blood leukocytes and prevents the LPS-induced glycolytic switch.
The phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages.
The Multifaceted Role of Macrophages in Biology and Diseases.
The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.
Upper and lower airway microbiota across infancy and childhood.
Recent insights and advances in gut microbiota's influence on host antiviral immunity.
Classification of C-Type Lectins and Recognition of Pathogens.
Bacillus paralicheniformis-mediated gut microbiota promotes M2 macrophage polarization by inhibiting P38 MAPK signaling to alleviate necrotizing enterocolitis and apoptosis in mice.
Integrating multi-omics data to reveal the host-microbiota interactome in inflammatory bowel disease.
Comparison of human macrophages derived from peripheral blood and bone marrow.
Immune training enhances anti-viral responses and improves outcomes in Pax5-/+ mice susceptible to chronic infection.
Probiotic Bifidobacterium bifidum strains desialylate MUC13 and increase intestinal epithelial barrier function.
L-serine metabolic regulation and host respiratory homeostasis.
Differentiation success of reprogrammed cells is heterogeneous in vivo and modulated by somatic cell identity memory.

Front Immunol. 2025 ;16 1521196

The role of m6A modification during macrophage metabolic reprogramming in human diseases and animal models.

Huiling Wang, Peiqi Xu, Kai Yin, Shengjun Wang.

  Macrophage metabolic reprogramming refers to the process by which macrophages adjust their physiological pathways to meet survival and functional demands in different immune microenvironments. This involves a range of metabolic pathways, including glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and cholesterol transport. By modulating the expression and activity of key enzymes and molecules within these pathways, macrophages can make the transition between pro- and anti-inflammatory phenotypes, thereby linking metabolic reprogramming to inflammatory responses and the progression of several diseases, such as atherosclerosis, inflammatory bowel disease (IBD), and acute lung injury (ALI). N6-methyladenosine (m6A) modification has emerged as a critical regulatory mechanism during macrophage metabolic reprogramming, broadly affecting RNA stability, translation, and degradation. Therapeutic strategies targeting m6A modification can regulate the onset of metabolic diseases by influencing macrophage metabolic changes, for instance, small molecule inhibitors of methyltransferase-like 3 (METTL3) can affect glucose metabolism and inhibit IBD. This review systematically explores recent findings on the role and molecular mechanisms of m6A modification during macrophage metabolic reprogramming in human diseases and animal models, underscoring its potential as a therapeutic target for metabolic diseases.

Keywords:  M1/M2 macrophage reprogramming; cholesterol transport; fatty acid oxidation; glycolysis; oxidative phosphorylation; tricarboxylic acid cycle

DOI:  https://doi.org/10.3389/fimmu.2025.1521196
J Vis Exp. 2025 Feb 21.

Determining Ciliary Function and Membrane Impermeability of the Pseudostratified Lung Airway Epithelium.

Muhammad Faheem, Masfique Mehedi.

Differentiating primary lung airway epithelial cells in the air-liquid interface (ALI) is a popular technique to develop a multi-cellular pseudostratified airway epithelium that mimics the apical side of the lung airway. While the differentiation of primary lung airway cells is expected, the assessment of biophysical properties like ciliary function and membrane impermeability provides a quality assessment of the airway epithelium and ensures the reliability of the experiment. Here, we describe a straightforward protocol for the development of multi-cellular pseudostratified airway epithelium in ALI culture and assess two important biophysical properties: ciliary function and membrane impermeability. To determine ciliary function, we captured the ciliary movement of a 4-week differentiated airway epithelium using a high-speed camera attached to an inverted microscope, followed by quantifying ciliary beat frequency (CBF) using the Simon Amon Video Analysis (SAVA) system. We also measured transepithelial electrical resistance (TEER) using a volt-ohm meter to determine the epithelial barrier integrity of the airway epithelium.

DOI: https://doi.org/10.3791/67094
J Immunol. 2025 Mar 03. pii: vkae029. [Epub ahead of print]

Absence of c-Maf and IL-10 enables type I IFN enhancement of innate responses to LPS in alveolar macrophages.

Pamelia N Lim, Maritza M Cervantes, Linh K Pham, Sydney R Doherty, Ankita Tufts, Divya Dubey, Dat Mai, Alan Aderem, Alan H Diercks, Alissa C Rothchild.

  Alveolar macrophages (AMs) are lung-resident myeloid cells and airway sentinels for inhaled pathogens and environmental particles. While AMs can be highly inflammatory in response to respiratory viruses, they do not mount proinflammatory responses to all airborne pathogens. For example, we previously showed that AMs fail to mount a robust proinflammatory response to Mycobacterium tuberculosis. Here, we address this discrepancy by investigating the capacity of murine AMs for direct innate immune sensing, using LPS as a model. Use of LPS-coated fluorescent beads enabled us to distinguish between directly exposed and bystander cells to measure transcriptional responses, by RNA-sequencing after cell sorting, and cytokine responses, by flow cytometry. We find that AMs have decreased proinflammatory responses to low-dose LPS compared to other macrophage types (bone marrow-derived macrophages, peritoneal macrophages), as measured by TNF, IL-6, Ifnb, and Ifit3. The reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. We also find that AMs do not produce IL-10 in response to a variety of stimuli due to low expression of the transcription factor c-Maf, while exogenous c-Maf expression restores IL-10 production in AMs. Lastly, we show that lack of IL-10 enables type I IFN enhancement of AM responses to LPS. Overall, we demonstrate AMs have a cell-intrinsic hyporesponsiveness to LPS, which makes them uniquely tolerant to low-dose exposure. Regulation of AM innate responses by distinct CD14, c-Maf, and IL-10 expression patterns has important implications for both respiratory infections and environmental airborne exposures.

Keywords:  IL-10; alveolar macrophages; c-Maf; innate immunity; type I IFN

DOI:  https://doi.org/10.1093/jimmun/vkae029
Immune Netw. 2025 Feb;25(1): e6

Regulation of Ferroptosis in Cancer and Immune Cells.

Naeyoon Jang, Il-Kyu Kim, Dawoon Jung, Yeonseok Chung, Yun Pyo Kang.

  Ferroptosis, an iron-dependent form of regulated cell death, is driven by lipid peroxidation and shaped by metabolic and antioxidant pathways. In immune cells, ferroptosis susceptibility varies by cell types, lipid composition, and metabolic demands, influencing immune responses in cancer, infections, and autoimmune diseases. Therapeutically, targeting ferroptosis holds promise in cancer immunotherapy by enhancing antitumor immunity or inhibiting immunosuppressive cells. This review highlights the metabolic pathways underlying ferroptosis, its regulation in immune cells, its dual role in tumor progression and antitumor immunity, and its context-dependent therapeutic implications for optimizing cancer treatment.

Keywords:  Cancer; Ferroptosis; Immune system; Metabolism

DOI:  https://doi.org/10.4110/in.2025.25.e6
Immunity. 2025 Mar 11. pii: S1074-7613(25)00075-5. [Epub ahead of print]58(3): 535-554

Lactate: A key regulator of the immune response.

Alba Llibre, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Claudio Mauro.

  Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.

Keywords:  immune regulation; lactate; lactate sensing; lactate signaling; lactylation

DOI:  https://doi.org/10.1016/j.immuni.2025.02.008
Immune Netw. 2025 Feb;25(1): e3

Tissue-Specific Metabolic Reprogramming in Innate Lymphoid Cells and Its Impact on Disease.

Jongho Ham, Wooseok Yang, Hye Young Kim.

  Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

Keywords:  Fatty acid oxidation; Glycolysis; Immunometabolism; Innate lymphoid cell; Oxidative phosphorylation; Therapeutic targets; Tissue-specific immunity

DOI:  https://doi.org/10.4110/in.2025.25.e3
Exp Dermatol. 2025 Mar;34(3): e70073

Human Skin Microbiota-Derived Extracellular Vesicles and Their Cosmeceutical Possibilities-A Mini Review.

Thangavelu Soundara Rajan, Ramasamy Saiganesh, Madasamy Sivagnanavelmurugan, Francesca Diomede.

  The human skin hosts a complex ecosystem of microorganisms, collectively termed the skin microbiota. This intricate skin microbial community plays a pivotal role in human health and disease. Microbes interact with the host skin cells and immune cells through microbial products such as metabolites and secreted proteins. Research in recent years has received significant attention towards extracellular vesicles (EVs)-mediated microbe-host communication. In this concise review, we discuss the role of skin microbiota EVs in the regulation and maintenance of functional dermal tissue. The human topical microbiota is predominantly composed of bacteria, with Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes being the predominant phyla. Fungi, particularly Malassezia species, also constitute a significant component of this dermal microbial ecosystem. Nevertheless, research on EVs has primarily focused on a limited number of bacterial and fungal species pertaining to skin, including Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, Lactobacillus plantarum and Malassezia sympodialis. Particularly, EVs derived from Staphylococcus epidermidis and Lactobacillus plantarum show a promising outcome towards the management of skin inflammation and skin ageing. Given the demonstrated ability of EVs to penetrate the skin cells and deliver beneficial compounds, their application in cosmetic and cosmeceutical products remains in its early stages. Accordingly, we also address the need for extensive research, challenges and opportunities to fully harness their potential for skincare regimens.

Keywords:  cosmeceuticals; cosmetics; extracellular vesicles; human skin microbiota; skin ageing; skin diseases; skin inflammation

DOI:  https://doi.org/10.1111/exd.70073
J Immunol. 2025 Jan 01. 214(1): 85-103

Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution.

Temitayo T Bamgbose, Robert M Schilke, Oluwakemi O Igiehon, Ebubechukwu H Nkadi, Monika Binwal, David Custis, Sushma Bharrhan, Benjamin Schwarz, Eric Bohrnsen, Catharine M Bosio, Rona S Scott, Arif Yurdagul, Brian N Finck, Matthew D Woolard.

  Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function and polarization, which is crucial to the resolution of inflammation. The contribution of lipid synthesis to proinflammatory macrophage responses is well understood. However, how lipid synthesis regulates proresolving macrophage responses needs to be better understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that regulates lipid metabolism. We previously demonstrated that lipin-1 supports proresolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage proresolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis, the transport of citrate from the mitochondria, reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO mice and macrophages. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting proresolving macrophage function in response to proresolving stimuli.

Keywords:  citrate carrier; efferocytosis; fatty acid; inflammation resolution; lipin-1

DOI:  https://doi.org/10.1093/jimmun/vkae010
J Invest Dermatol. 2025 Mar 09. pii: S0022-202X(25)00100-9. [Epub ahead of print]

Role of Formyl Peptide Receptor 2 and Toll-Like Receptor 2 in Skin Barrier Function and Atopic Dermatitis.

Marco Lebtig, Andreas Peschel, Dorothee Kretschmer.

  The skin acts as a barrier against external threats and plays an important role in tissue repair. Skin cells, including keratinocytes, sense microbe-associated molecular pattern molecules released by members of the bacterial microbiome, and the cellular responses control central processes of skin homeostasis or inflammation. How the combination and amount of different microbe-associated molecular patterns modulate skin cell functions is not yet fully understood. Here, we review the current knowledge of the responses of skin cells to microbe-associated molecular patterns, focusing on Toll-like receptor 2 and formyl peptide receptor 2, two of the most important receptors for sensing the skin microbiome.

Keywords:  Atopic dermatitis; Keratinocytes; Microbiome; Skin barrier

DOI:  https://doi.org/10.1016/j.jid.2025.02.002
J Adv Res. 2025 Mar 12. pii: S2090-1232(25)00152-3. [Epub ahead of print]

Trained immunity using probiotics and inactivated pathogens enhances resistance to Salmonella enterica serovar Typhimurium infection by activating the cGAS-STING signal pathway in mice and chickens.

Junpeng Jia, Wenxin Ji, Ningna Xiong, Jian Lin, Qian Yang.

   INTRODUCTION: Concerns about antibiotic resistance have prompted interest in alternative strategies for enhancing disease resistance, particularly in livestock and poultry production.
OBJECTIVES: This study explored the role of trained immunity in enhancing resistance to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection in mice and chickens.
METHODS: We investigated the effects of probiotics and inactivated pathogenic bacterial strains on host immunity in Toll-like receptor 2-deficient mice (TLR2-/-) to assess whether these effects were related to bacterial outer membrane components such as peptidoglycan (PNG), lipoarabinomannan (LAM) and lipoteichoic acid (LTA). Bacterial genomes were evaluated for their ability to enhance the host immune system. Macrophage-depletion models were used to identify the key immune cells involved in trained immunity, with a focus on the cGAS-STING pathway.
RESULTS: Probiotics and inactivated pathogenic strains enhanced host immunity and protected against S. Typhimurium infection. As demonstrated in the TLR2-deficient mice, the effects were not dependent on bacterial outer membrane components. Instead, bacterial genomes played a significant role in activating trained immunity. Macrophages were identified as the primary cells that mediated the response with the cGAS-STING pathway playing a crucial role. The results observed using the mouse models led to investigating the potential application of trained immunity in poultry.
CONCLUSION: Trained immunity activated by probiotics and inactivated bacterial pathogens enhanced resistance against S. Typhimurium infection via macrophage activation and involved the cGAS-STING pathway. These findings highlight the potential of trained immunity as an alternative strategy for disease prevention in both livestock and poultry.

Keywords:  Bacterial genome; Macrophages; S. Typhimurium; Trained immunity; cGAS-STING pathway

DOI:  https://doi.org/10.1016/j.jare.2025.03.011
Front Cell Infect Microbiol. 2025 ;15 1543186

Staphylococcus aureus utilizes vimentin to internalize human keratinocytes.

Kyoungok Jang, Hangeun Kim, Dobin Choi, Soojin Jang, Dae-Kyun Chung.

   Introduction: Vimentin is an intermediate filamentous cytoskeletal protein involved in cell migration, adhesion, and division. Recent studies have demonstrated that several bacteria and viruses interact with vimentin to facilitate entry and trafficking within eukaryotic cells. However, the relationship between Staphylococcus aureus and vimentin remains unclear.
Methods: In the current study, we elucidated vimentin expression mechanism in human keratinocytes infected with S. aureus using Western blot (WB), Flow cytometry, Immunofluorescence (IF) staining, utilizing neutralizing antibodies, and small interference (si) RNA, and a vimentin overexpression vector. The physical interaction between vimentin and S. aureus was shown by IF on cell surface, intra- and intercellular space.
Results: HaCaT cells increased vimentin expression through physical interaction with live S. aureus, and not by heat-killed bacteria or bacterial culture supernatants. The Toll-like receptor (TLR) 2 signaling pathway, which includes interleukin 1 receptor-associated kinase (IRAK) and nuclear factor kappa B (NF-κB)/c-Jun N-terminal kinase (JNK) signaling activation, was involved in S. aureus-mediated vimentin expression. The vimentin protein induced by S. aureus was secreted extracellularly and bound to S. aureus in the culture media. The binding of vimentin to S. aureus accelerated the intracellular infection of HaCaT cells.
Discussion: Thus, these experiments elucidated the mechanism of vimentin protein expression during S. aureus infection in human skin keratinocytes and revealed the role of vimentin in this process. These findings suggest that vimentin could serve as a potential target for the prevention or treatment of S. aureus infections.

Keywords:  HaCaT cells; Staphylococcus aureus; TLR signaling; keratinocytes; skin infection; vimentin

DOI:  https://doi.org/10.3389/fcimb.2025.1543186
Elife. 2025 Mar 13. pii: RP102980. [Epub ahead of print]13

Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.

Nelson V Simwela, Eleni Jaecklein, Christopher M Sassetti, David G Russell.

  Mycobacterium tuberculosis (Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular Mtb utilize host-derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria's ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellular Mtb. Our analyses demonstrate that macrophages that cannot either import, store, or catabolize fatty acids restrict Mtb growth by both common and divergent antimicrobial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy, and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive to Mtb replication, but increased induction of the same fails to rescue Mtb growth. Our work expands our understanding of how host fatty acid homeostasis impacts Mtb growth in the macrophage.

Keywords:  infectious disease; lipid metabolism; macrophage; microbiology; mouse; mycobacterium; tuberculosis

DOI:  https://doi.org/10.7554/eLife.102980
J Exp Med. 2025 May 05. pii: e20240379. [Epub ahead of print]222(5):

KLF family members control expression of genes required for tissue macrophage identities.

Kathleen Pestal, Leianna C Slayden, Gregory M Barton.

Tissue-resident macrophages adopt distinct gene expression profiles and exhibit functional specialization based on their tissue of residence. Recent studies have begun to define the signals and transcription factors that induce these identities. Here we describe an unexpected and specific role for the broadly expressed transcription factor Krüppel-like factor 2 (KLF2) in the development of embryonically derived large cavity macrophages (LCMs) in the serous cavities. KLF2 not only directly regulates the transcription of genes previously shown to specify LCM identity, such as retinoic acid receptors and GATA6, but also is required for induction of many other transcripts that define the identity of these cells. Our results suggest that KLF4 may similarly regulate the identity of alveolar macrophages in the lung. These data demonstrate that broadly expressed transcription factors, such as group 2 KLFs, can play important roles in the specification of distinct identities of tissue-resident macrophages.

DOI: https://doi.org/10.1084/jem.20240379
Nat Rev Microbiol. 2025 Mar 10.

Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities.

Iliyan D Iliev, Ashwin N Ananthakrishnan, Chun-Jun Guo.

Perturbations in the intestinal microbiome are strongly linked to the pathogenesis of inflammatory bowel disease (IBD). Bacteria, fungi and viruses all make up part of a complex multi-kingdom community colonizing the gastrointestinal tract, often referred to as the gut microbiome. They can exert various effects on the host that can contribute to an inflammatory state. Advances in screening, multiomics and experimental approaches have revealed insights into host-microbiota interactions in IBD and have identified numerous mechanisms through which the microbiota and its metabolites can exert a major influence on the gastrointestinal tract. Looking into the future, the microbiome and microbiota-associated processes will be likely to provide unparalleled opportunities for novel diagnostic, therapeutic and diet-inspired solutions for the management of IBD through harnessing rationally designed microbial communities, powerful bacterial and fungal metabolites, individually or in combination, to foster intestinal health. In this Review, we examine the current understanding of the cross-kingdom gut microbiome in IBD, focusing on bacterial and fungal components and metabolites. We examine therapeutic and diagnostic opportunities, the microbial metabolism, immunity, neuroimmunology and microbiome-inspired interventions to link mechanisms of disease and identify novel research and therapeutic opportunities for IBD.

DOI: https://doi.org/10.1038/s41579-025-01163-0
J Innate Immun. 2025 Mar 07. 1-21

Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities.

Zihan Zhang, Yi Liu, Tian Yu, Zhen Liu.

Periodontitis stands out as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissue. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of therapeutic targeting has been established. Given that metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments. This paper has undergone meticulous review to furnish a comprehensive summary of the roles played by macrophages in periodontitis and associated comorbidities. To start with, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed. In conclusion, through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.

DOI: https://doi.org/10.1159/000542531
Cell Rep. 2025 Mar 12. pii: S2211-1247(25)00195-0. [Epub ahead of print]44(3): 115424

Exercise-driven gut microbiota alterations enhance colonization resistance against methicillin-resistant Staphylococcus aureus.

Tingting Xu, Dan Fang, Tianqi Xu, Xiuying Tao, Zhiqiang Wang, Yuan Liu.

  Gut microbiota plays a crucial role in resisting the invasion of pathogens, particularly multidrug-resistant (MDR) bacteria, which pose a significant threat to public health. While exercise offers numerous health benefits, its impact on host colonization resistance remains largely unclear. In this study, we demonstrate that moderate exercise significantly reduces gut colonization by methicillin-resistant Staphylococcus aureus (MRSA), a clinically important MDR pathogen. Moreover, we identify an understudied strain of the intestinal probiotic Dubosiella newyorkensis (L8) as a critical factor in mediating exercise-induced colonization resistance against MRSA. Mechanistically, L8 enhances the deprivation of fucose, a crucial carbon source essential for MRSA growth and pathogenicity. This process relies on the high binding affinity of pyruvate to the ILE257 site of the lactate dehydrogenase in L8. Overall, our work highlights the importance of moderate exercise in maintaining host colonization resistance and demonstrates L8 as a probiotic in protecting against MRSA colonization.

Keywords:  CP: Microbiology; D. newyorkensis; L8; MRSA; antimicrobial resistance; colonization resistance; exercise; gut microbiota; multidrug-resistant bacteria; nutrient depletion

DOI:  https://doi.org/10.1016/j.celrep.2025.115424
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00192-5. [Epub ahead of print]44(3): 115421

Genome-wide mutagenesis identifies factors involved in MRSA vaginal colonization.

Laurie M Lyon, Stephanie M Marroquin, John C Thorstenson, Luke R Joyce, Ernesto J Fuentes, Kelly S Doran, Alexander R Horswill.

  Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that colonizes various body sites, including the nares, skin, and vagina. During pregnancy,colonization can lead to dysbiosis, adverse pregnancy outcomes, and invasive disease. To identify genes contributing to MRSA vaginal fitness, we performed transposon sequencing (Tn-seq) using a murine model of vaginal colonization, identifying over 250 conditionally essential genes. Five genes were validated in our murine model, including those encoding the aerobic respiration protein QoxB, bacillithiol biosynthesis component BshB2, sialic acid catabolism enzyme NanE, and staphylococcal regulator of respiration SrrAB. RNA sequencing and comparative analysis identified over 30 SrrAB-regulated genes potentially important for fitness in vaginal-like conditions, particularly under oxygen stress. These findings highlight pathways such as aerobic respiration, bacillithiol biosynthesis, sialic acid catabolism, and transcriptional regulation that support MRSA's competitive fitness in the vaginal tract.

Keywords:  CP: Microbiology; MRSA; RNA-seq; SrrAB regulator; Staphylococcus aureus; Tn-seq; bacillithiol biosynthesis; host-pathogen interactions; murine vaginal model; sialic acid catabolism; transposon sequencing; vaginal colonization

DOI:  https://doi.org/10.1016/j.celrep.2025.115421
Immune Netw. 2025 Feb;25(1): e9

Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.

Ein Lee, Seung Geun Song, Haaun Moon, Minho Shong, Doo Hyun Chung.

  The importance of mitochondrial function in macrophages is well established. Alveolar macrophages (AMs), the tissue-resident macrophages (TRMs) of the lung, are particularly dependent on mitochondria-driven oxidative phosphorylation (OXPHOS) to support their functions and maintain homeostasis. However, the specific genes and pathways that regulate OXPHOS in AMs remain unclear. In this study, we investigated the role of CR6-interacting factor 1 (CRIF1), a mitochondrial regulator, as a key factor that specifically modulates the metabolic fitness and maintenance of AMs. Using single-cell RNA sequencing and transcriptomic analyses, we found CRIF1 to be highly expressed in AMs compared to TRMs from other tissues, correlating with enhanced OXPHOS activity. Genetic ablation of Crif1 in macrophages resulted in a marked reduction in AM populations exclusively in the lung, while other TRM populations were unaffected. CRIF1-deficient AMs exhibited an altered metabolic profile, including impaired mitochondrial function, increased glycolysis, and aberrant lipid accumulation. These findings underscore the essential role of CRIF1 in regulating mitochondrial functions and metabolic fitness in AMs, distinguishing it from broader mitochondrial regulators like mitochondrial transcription factor A, which operates across multiple TRM populations. Our study provides critical insights into the tissue-specific regulation of macrophage metabolism and suggests potential therapeutic avenues for lung diseases associated with AM dysfunction.

Keywords:  Alveolar macrophages; Homeostasis; Metabolic reprogramming; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.4110/in.2025.25.e9
Molecules. 2025 Mar 05. pii: 1168. [Epub ahead of print]30(5):

The Ligand Binding Domain of the Cell Wall Protein SraP Modulates Macrophage Apoptosis and Inflammatory Responses in Staphylococcus aureus Infections.

He Sun, Robert W Li, Thomas T Y Wang, Lin Ding.

  The Staphylococcus aureus cell wall protein serine rich adhesin for platelets (SraP) belongs to a large surface glycoprotein family of adhesins. Here, we provide experimental evidence that SraP mediates macrophage functions in a human monocyte-derived macrophage model via its N-terminal L-lectin module (LLM) in the ligand binding region. Our flow cytometry data demonstrated that macrophages infected by the LLM deletion strain profoundly impacted apoptosis, reducing the percentage of apoptotic cells by approximately 50%, whereas LLM overexpression significantly increased the percentage of early-stage apoptotic cells (p < 0.001). LLM deletion significantly enhanced phagocytosis by macrophages by increasing the number of engulfed bacteria, resulting in a significant increase in bacterial killing and leading to a notable decrease in bacterial survival within macrophages (p < 0.001). Furthermore, LLM modulated the ability of S. aureus to elicit inflammatory responses. The LLM deletion strain dampened the expression of proinflammatory factors but increased the expression of anti-inflammatory cytokines, such as IL10. Our evidence suggests that SraP likely plays a dual role in S. aureus pathogenesis, by acting as a virulence factor involved in bacterial adhesion and invasion and by mediating macrophage functions. Our future work will focus on the identification of small molecule inhibitors of LLM using molecular docking-based in silico screening and in vivo validation. Developing LLM inhibitors, alone or in combination with conventional antibiotics, may represent a novel strategy for combating S. aureus infections.

Keywords:  SraP; adhesin; antibiotics; gain-of-function; loss-of-function; methicillin-resistant Staphylococcus aureus; virulence

DOI:  https://doi.org/10.3390/molecules30051168
Cell Host Microbe. 2025 Mar 12. pii: S1931-3128(25)00062-9. [Epub ahead of print]33(3): 318-320

METs, NETs, and UTIs.

Thomas J Hannan.

The mucosal immune response of the urinary bladder to bacterial infection is complex, as immune cells must efficiently neutralize and contain the infection while preventing harmful pathology. A recent Immunity paper by Li et al. illuminates the critical role of a resident macrophage subset in preventing invasive and life-threatening disease.

DOI: https://doi.org/10.1016/j.chom.2025.02.014
Nat Commun. 2025 Mar 10. 16(1): 2397

Alveolar macrophages from persons with HIV mount impaired TNF signaling networks to M. tuberculosis infection.

Khanyisile Kgoadi, Prashant Bajpai, Chris C Ibegbu, Hedwin Kitdorlang Dkhar, Ana Beatriz Enriquez, Stanzin Dawa, Sushma K Cribbs, Jyothi Rengarajan.

People living with HIV (PLWH) have an increased risk for developing tuberculosis after M. tuberculosis infection, despite anti-retroviral therapy (ART). To delineate the underlying mechanisms, we conducted single cell transcriptomics on bronchoalveolar lavage cells from PLWH on ART and HIV uninfected healthy controls infected with M. tuberculosis ex vivo. We identify an M1-like proinflammatory alveolar macrophage subset that sequentially acquires TNF signaling capacity in controls but not in PLWH. Cell-cell communication analyses reveal interactions between M1-like macrophages and effector memory T cells within TNF superfamily, chemokine, and costimulatory networks in the airways of controls. These interaction networks were lacking in PLWH infected with M. tuberculosis, where anti-inflammatory M2-like alveolar macrophages and T regulatory cells dominated along with dysregulated T cell signatures. Our data support a model in which impaired TNF-TNFR signaling, M2-like alveolar macrophages and aberrant macrophage-T cell crosstalk, lead to ineffective immunity to M. tuberculosis in PLWH on ART.

DOI: https://doi.org/10.1038/s41467-025-57668-y
Brain Behav Immun. 2025 Mar 09. pii: S0889-1591(25)00098-4. [Epub ahead of print]

Innate immune system signaling and intestinal dendritic cells migration to the brain underlie behavioral changes after microbial colonization in adult mice.

Vivek Philip, Narjis Kraimi, Hailong Zhang, Jun Lu, Giada De Palma, Chiko Shimbori, Kathy D McCoy, Siegfried Hapfelmeier, Olivier P Schären, Andrew J Macpherson, Fernando Chirdo, Michael G Surette, Elena F Verdu, Fang Liu, Stephen M Collins, Premysl Bercik.

   BACKGROUND AND AIMS: Accumulating evidence suggests the microbiota is a key factor in Disorders of Gut-Brain Interaction (DGBI), by affecting host immune and neural systems. However, the underlying mechanisms remain elusive due to their complexity and clinical heterogeneity of patients with DGBIs. We aimed to identify neuroimmune pathways that are critical in microbiota-gut-brain communication during de novo gut colonization.
METHODS: We employed a combination of gnotobiotic and state-of-the-art microbial tools, behavioral analysis, immune and pharmacological approaches. Germ-free wild type, TLR signaling-deficient MyD88-/- Ticam1-/- and lymphocyte-deficient SCID mice were studied before and after colonization with specific pathogen-free microbiota, Altered Schaedler Flora, E. coli or S. typhimurium (permanent or transient colonizers). TLR agonists and antagonists, CCR7 antagonist or immunomodulators were used to study immune pathways. We assessed brain c-Fos, brain-derived neurotrophic factor, and dendritic and glial cells by immunofluorescence, expression of neuroimmune genes by NanoString and performed brain proteomics.
RESULTS: Bacterial monocolonization, conventionalization or administration of microbial products to germ-free mice altered mouse behavior similarly, acting through Toll-like receptor or nucleotide-binding oligomerization domain signaling. The process required CD11b+CD11c+CD103+ dendritic cell activation and migration into the brain. The change in behavior did not require the continued presence of bacteria and was associated with activation of multiple neuro-immune networks in the gut and the brain.
CONCLUSIONS: Changes in neural plasticity occur rapidly upon initial gut microbial colonization and involve innate immune signaling to the brain, mediated by CD11b+CD11c+CD103+ dendritic cell migration. The results identify a new target with therapeutic potential for DGBIs developing in context of increased gut and blood-brain barrier permeability.

Keywords:  Behavior; Brain; Dendritic cells; Immunity; Microbiota

DOI:  https://doi.org/10.1016/j.bbi.2025.03.012
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00208-5. [Epub ahead of print]194 93-107

Analysis of cytosolic mtDNA release during Staphylococcus aureus infection.

Caterina Licini, Gloria D'Achille, Nada Dhaouadi, Ilaria Nunzi, Fabio Marcheggiani, Matteo Fabbri, Monica Mattioli-Belmonte, Gianluca Morroni, Saverio Marchi.

  Methicillin-resistant Staphylococcus aureus (MRSA) is one of the principal human pathogens, causing severe infections in skin wounds. MRSA infection triggers a cell response mainly by mitochondrial-mediated pathway, resulting in mitochondrial outer membrane permeabilization, extrusion of the mitochondrial inner membrane into the cytoplasm, and then spillage of mitochondrial DNA (mtDNA) into the cytoplasm. The cell recognizes the discharged cytosolic mtDNA (cmtDNA) as "not-itself" because of mtDNA properties and triggers cascade events, such as the activation of inflammasomes. Here, we detail a method to detect and measure the mtDNA release into the cytoplasm in immortalized keratinocytes (HaCaT cells), after the infection with MRSA at different time points after the infection.

Keywords:  Inflammation; MOMP; Mitochondria; Staphylococcus aureus; mtDNA

DOI:  https://doi.org/10.1016/bs.mcb.2024.09.003
Immune Netw. 2025 Feb;25(1): e10

Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication.

Hyun-Ki Shin, Ye-Ji Bang.

  Aromatic amino acid (AAA) metabolites, derived from tryptophan, phenylalanine, and tyrosine through coordinated host and microbial metabolism, have emerged as critical modulators of immune function. We examine the complex journey of AAAs from dietary intake through intestinal absorption and metabolic transformation, highlighting the crucial role of host-microbe metabolic networks in generating diverse immunomodulatory compounds. This review provides a unique integrative perspective by mapping the molecular mechanisms through which these metabolites orchestrate immune responses. Through detailed analysis of metabolite-receptor and metabolite-transporter interactions, we reveal how specific molecular recognition drives cell type-specific immune responses. Our comprehensive examination of signaling networks-from membrane receptor engagement to nuclear receptor activation to post-translational modifications- demonstrates how the same metabolite can elicit distinct functional outcomes in different immune cell populations. The context-dependent nature of these molecular interactions presents both challenges and opportunities for therapeutic development, particularly in inflammatory conditions where metabolite signaling pathways are dysregulated. Understanding the complexity of these regulatory networks and remaining knowledge gaps is fundamental for advancing metabolite-based therapeutic strategies in immune-mediated disorders.

Keywords:  Aromatic amino acids; Gut microbiome; Host-microbe interactions; Immunometabolism; Immunomodulation; Molecular mechanisms

DOI:  https://doi.org/10.4110/in.2025.25.e10
Signal Transduct Target Ther. 2025 Mar 07. 10(1): 93

Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets.

Fan Guan, Ruixuan Wang, Zhenjie Yi, Peng Luo, Wanyao Liu, Yao Xie, Zaoqu Liu, Zhiwei Xia, Hao Zhang, Quan Cheng.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

DOI: https://doi.org/10.1038/s41392-025-02124-y
Cell. 2025 Mar 07. pii: S0092-8674(25)00195-3. [Epub ahead of print]

Genome-scale resources in the infant gut symbiont Bifidobacterium breve reveal genetic determinants of colonization and host-microbe interactions.

Anthony L Shiver, Jiawei Sun, Rebecca Culver, Arvie Violette, Char Wynter, Marta Nieckarz, Samara Paula Mattiello, Prabhjot Kaur Sekhon, Francesca Bottacini, Lisa Friess, Hans K Carlson, Daniel P G H Wong, Steven Higginbottom, Meredith Weglarz, Weigao Wang, Benjamin D Knapp, Emma Guiberson, Juan Sanchez, Po-Hsun Huang, Paulo A Garcia, Cullen R Buie, Benjamin H Good, Brian DeFelice, Felipe Cava, Joy Scaria, Justin L Sonnenburg, Douwe Van Sinderen, Adam M Deutschbauer, Kerwyn Casey Huang.

  Bifidobacteria represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest in bifidobacteria as a live biotic therapy, our understanding of colonization, host-microbe interactions, and the health-promoting effects of bifidobacteria is limited. To address these major knowledge gaps, we used a large-scale genetic approach to create a mutant fitness compendium in Bifidobacterium breve. First, we generated a high-density randomly barcoded transposon insertion pool and used it to determine fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. Second, to enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1,462 genes. We leveraged these tools to reveal community- and diet-specific requirements for colonization and to connect the production of immunomodulatory molecules to growth benefits. These resources will catalyze future investigations of this important beneficial microbe.

Keywords:  RB-TnSeq; bifidobacteria; functional genomics; genome-scale metabolic reconstruction; genome-scale ordered mutant collection; glucose-phosphate stress; indole-3-lactic acid; infant microbiome; metabolomics; microbiome assembly

DOI:  https://doi.org/10.1016/j.cell.2025.02.010
Front Immunol. 2025 ;16 1514061

Dexamethasone has profound influence on the energy metabolism of porcine blood leukocytes and prevents the LPS-induced glycolytic switch.

Wenjuan Ma, Julia Brenmoehl, Nares Trakooljul, Klaus Wimmers, Eduard Murani.

  In farm animals, little is known about the relationship between energy metabolism of immune cells and their activation state. Moreover, there has recently been evidence that dexamethasone, a powerful glucocorticoid-based drug, can exert its anti-inflammatory effects by interfering with the energy metabolism of immune cells, but the mechanisms are not yet fully understood. To address these knowledge gaps, we explored the connection between the energy metabolism of porcine peripheral blood mononuclear cells (PBMCs) and their response to pro- and anti-inflammatory stimulation with lipopolysaccharide (LPS) and dexamethasone (DEX) in vitro. Interventions in the metabolism of PBMCs with the glycolysis inhibitor 2-deoxy-D-glucose or the HIF-1α inhibitor KC7F2 reduced the LPS-induced TNF-α production, but the mitochondrial ATP synthesis inhibitor oligomycin showed no significant effect. The anti-inflammatory action of DEX was not affected by any of the inhibitors. To investigate the metabolic actions of LPS and DEX in PBMCs, we evaluated glycolysis and mitochondrial respiration following 24 hours stimulation using the Seahorse XFe96 flux analyzer. Our results revealed significantly higher glycolysis in LPS-treated PBMCs, but provided no evidence for a change in mitochondrial respiration. In contrast, DEX reduced LPS-induced glycolysis and, especially when administered alone, significantly lowered mitochondrial respiration. Pretreatment with KC7F2 counteracted the effects of LPS and DEX on glycolysis, and reduced mitochondrial respiration regardless of the inflammatory state of the PBMCs. Gene expression analysis identified the glucose transporter SLC2A3, and the tricarboxylic acid cycle genes IDH1 and SDHB as the main switches for the antagonistic metabolic actions of LPS and DEX, which are closely associated with the inflammatory state of PBMCs.

Keywords:  GLUT3; PBMC; dexamethasone; glucocorticoid receptor; immunometabolism; inflammation; lipopolysaccharide (LPS)

DOI:  https://doi.org/10.3389/fimmu.2025.1514061
bioRxiv. 2025 Mar 02. pii: 2025.02.27.640612. [Epub ahead of print]

The phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages.

Henry Yi Cheng, Jiachen Chu, Nathachit Limjunyawong, Jianan Chen, Yingzhi Ye, Kevin Hong Chen, Nicholas Koylass, Shuying Sun, Xinzhong Dong, Zhaozhu Qiu.

  Phagosome degradation is an evolutionally conserved and highly effective innate immune response against pathogen infections. The success of this process relies on the ability of phagocytes to regulate the maturation of phagosomes. However, the underlying molecular mechanisms and its roles in shaping downstream immune activation remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon peritoneal Escherichia coli infection in mice. Surprisingly, phagosome bacterial degradation also stimulated STING-IRF3-interferon responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation and pyroptosis induced an unexpected release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and overall peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages. It also highlights the potential of targeting the PAC channel as a therapeutic strategy for treating bacterial infections.

Keywords:  Phagosome maturation; STING-IRF3 signaling; TMEM206; gasdermin D; inflammasome activation; interferon responses; large peritoneal macrophages; phagosomal acidification; proton-activated chloride channel

DOI:  https://doi.org/10.1101/2025.02.27.640612
Int J Mol Sci. 2025 Feb 27. pii: 2107. [Epub ahead of print]26(5):

The Multifaceted Role of Macrophages in Biology and Diseases.

Jan Brancewicz, Natalia Wójcik, Zuzanna Sarnowska, Julia Robak, Magdalena Król.

  Macrophages are highly adaptable immune cells capable of responding dynamically to diverse environmental cues. They are pivotal in maintaining homeostasis, orchestrating immune responses, facilitating tissue repair, and, under certain conditions, contributing to disease pathogenesis. This review delves into the complex biology of macrophages, highlighting their polarization states, roles in autoimmune and inflammatory diseases, involvement in cancer progression, and potential as therapeutic targets. By understanding the context-dependent functional plasticity of macrophages, we can better appreciate their contributions to health and disease, paving the way for innovative therapeutic strategies.

Keywords:  autoimmune disease; cancer; macrophages

DOI:  https://doi.org/10.3390/ijms26052107
Clin Rev Allergy Immunol. 2025 Mar 13. 68(1): 28

The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.

Xinxin Wu, Changya Liu, Caiyun Zhang, Le Kuai, Sheng Hu, Ning Jia, Jiankun Song, Wencheng Jiang, Qilong Chen, Bin Li.

  Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms.

Keywords:  Lactate; Lactylation; Psoriasis

DOI:  https://doi.org/10.1007/s12016-025-09037-2
Pediatr Res. 2025 Mar 12.

Upper and lower airway microbiota across infancy and childhood.

Ariel J Hernandez-Leyva, Anne L Rosen, Christopher P Tomera, Elaina E Lin, Elikplim H Akaho, Allison M Blatz, William R Otto, Joey Logan, Lisa R Young, Rebecca M Harris, Samantha A Whiteside, Andrew L Kau, Audrey R Odom John.

BACKGROUND: The upper and lower respiratory tracts feature distinct environments and responses affecting microbial colonization but investigating the relationship between them is technically challenging. We aimed to identify relationships between taxa colonizing the nasopharynx and trachea across childhood.
METHODS: We employed V4 16S rRNA gene sequencing to profile nasopharyngeal swabs and tracheal aspirates collected from 172 subjects between 20 weeks and 18 years of age. These samples were collected prior to elective procedures over the course of 20 weeks in 2020 from subjects enrolled in a cross-sectional study. After extraction, sequencing, and quality control, we studied the remaining 147 of 172 nasopharyngeal swabs and 95 of 172 tracheal aspirates, including 80 subject-matched pairs of samples.
RESULTS: Sequencing data revealed that the nasopharynx is colonized by few, often highly abundant taxa, while the tracheal aspirates feature greater diversity. The patterns of colonization identified in the nasopharynx correlate with subject age across childhood.
CONCLUSION: Our data suggests that there are relatively few species that colonize both the nasopharyngeal tract and the trachea. Furthermore, we observe a pattern of change in the nasopharyngeal microbiota that is correlated with age, suggesting a possible developmental progression of the nasopharyngeal microbiota across childhood.
IMPACT: The airway microbiota in childhood plays important roles in respiratory health and immune development. In this work, we report on paired nasopharyngeal swab and tracheal aspirate samples from a cross-sectional cohort of children from infancy to 18 years. We find that the upper and lower airway microbiota are unlikely to share taxa and do not correlate in terms of diversity. We show that the composition of the upper airway microbiota is strongly correlated with age, with a stereotypic developmental trajectory during childhood and adolescence. Our results inform our understanding of airway microbiota assembly and may be used to predict airway disease in young children.

DOI: https://doi.org/10.1038/s41390-025-03942-0
Front Microbiol. 2025 ;16 1536778

Recent insights and advances in gut microbiota's influence on host antiviral immunity.

Ying Liu, Danying Yan, Ran Chen, Yingying Zhang, Chuwen Wang, Guoqing Qian.

  A diverse array of microbial organisms colonizes the human body, collectively known as symbiotic microbial communities. Among the various pathogen infections that hosts encounter, viral infections represent one of the most significant public health challenges worldwide. The gut microbiota is considered an important biological barrier against viral infections and may serve as a promising target for adjuvant antiviral therapy. However, the potential impact of symbiotic microbiota on viral infection remains relatively understudied. In this review, we discuss the specific regulatory mechanisms of gut microbiota in antiviral immunity, highlighting recent advances in how gut microbiota regulate the host immune response, produce immune-related molecules, and enhance the host's defense against viruses. Finally, we also discuss the antiviral potential of oral probiotics.

Keywords:  antiviral immunity; gut microbiota; metabolites; microbiome; virome

DOI:  https://doi.org/10.3389/fmicb.2025.1536778
Microbiol Immunol. 2025 Mar 12.

Classification of C-Type Lectins and Recognition of Pathogens.

Yasunobu Miyake.

  C-type lectins are calcium-dependent glycan-binding proteins that play key roles in the innate immune response by recognizing pathogens. Soluble C-type lectins agglutinate and neutralize pathogens, activate the complement system, and promote pathogen clearance via opsonization. Membrane-bound C-type lectins, also known as C-type lectin receptors (CLRs), internalize pathogens and induce their degradation in lysosomes, presenting pathogen-derived antigens to MHC-II molecules to activate adaptive immunity. CLRs also have signaling capabilities. Some contain the immunoreceptor tyrosine-based activation motif (ITAM), which induces inflammatory responses by activating transcription factors, such as NF-κB and NFAT. Others contain the immunoreceptor tyrosine-based inhibitory motif (ITIM), which suppresses activating signals by activating phosphatases, such as SHP-1. This creates a balance between activation and inhibition. C-type lectins are classified into 17 groups based on their structural domains, with Groups II and V members being particularly important for pathogen recognition. In this review, we present the accumulated and recent information on pathogen recognition by C-type lectins, along with their classification and basic functions.

Keywords:  C‐type lectin; glycan; host immunity; immune evasion; pathogen recognition

DOI:  https://doi.org/10.1111/1348-0421.13211
Microbiol Res. 2025 Mar 05. pii: S0944-5013(25)00092-8. [Epub ahead of print]296 128136

Bacillus paralicheniformis-mediated gut microbiota promotes M2 macrophage polarization by inhibiting P38 MAPK signaling to alleviate necrotizing enterocolitis and apoptosis in mice.

Shumin Yang, Huachun Pan, Tingyang Wang, Xinxin Zhou, Lele Fan, Hongde Xiao, Zutao Zhou, Yuncai Xiao, Deshi Shi.

  Clostridial necrotizing enterocolitis is a severe gastrointestinal disease induced by Clostridium, strongly associated with intestinal dysbiosis. Fecal microbiota transplantation (FMT) has proven effective in treating gastrointestinal diseases by remodeling intestinal microbial homeostasis. However, it remains unclear whether FMT from donors with beneficial microbiota can improve the recipient's intestinal function more efficiently. This study found that probiotic Bacillus paralicheniformis SN-6-mediated gut microbiota effectively prevent Clostridial necrotizing enteritis and explored the underlying molecular mechanisms. Data demonstrated that SN-6 altered gut microbiota composition, ameliorated Clostridium perfringens-induced intestinal microbiota dysbiosis and metabolic reprogramming, particularly enhancing tryptophan metabolism. This led to a marked reduction in intestinal barrier damage and inflammation. FMT from SN-6-treated mice reduced jejunal inflammation in Clostridium perfringens-infected mice, strengthened jejunal barrier and enriched beneficial bacteria, such as Lactobacillus, Blautia, Akkermansia. Furthermore, 3-indoleacetic acid (IAA), a metabolite enriched by SN-6, activated aryl hydrocarbon receptor (AhR), suppressed the P38 mitogen-activated protein kinase (P38 MAPK) signaling, and drove macrophage polarization from M0 to M2-type, thereby reducing apoptosis and excessive inflammation. This study highlights Bacillus paralicheniformis SN-6 as a key modulator of intestinal immunomodulation via the gut microbiota-IAA-AhR-P38 MAPK axis, offering a potential therapeutic target for preventing and controlling clostridial necrotizing enteritis.

Keywords:  3-indoleacetic acid; Clostridial enteritis; Fecal microbiota transplantation; Gut microbiota; M1/M2 balance; SN-6

DOI:  https://doi.org/10.1016/j.micres.2025.128136
Gut Microbes. 2025 Dec;17(1): 2476570

Integrating multi-omics data to reveal the host-microbiota interactome in inflammatory bowel disease.

Fengyuan Su, Meng Su, Wenting Wei, Jiayun Wu, Leyan Chen, Xiqiao Sun, Moyan Liu, Shiqiang Sun, Ren Mao, Arno R Bourgonje, Shixian Hu.

  Numerous studies have accelerated the knowledge expansion on the role of gut microbiota in inflammatory bowel disease (IBD). However, the precise mechanisms behind host-microbe cross-talk remain largely undefined, due to the complexity of the human intestinal ecosystem and multiple external factors. In this review, we introduce the interactome concept to systematically summarize how intestinal dysbiosis is involved in IBD pathogenesis in terms of microbial composition, functionality, genomic structure, transcriptional activity, and downstream proteins and metabolites. Meanwhile, this review also aims to present an updated overview of the relevant mechanisms, high-throughput multi-omics methodologies, different types of multi-omics cohort resources, and computational methods used to understand host-microbiota interactions in the context of IBD. Finally, we discuss the challenges pertaining to the integration of multi-omics data in order to reveal host-microbiota cross-talk and offer insights into relevant future research directions.

Keywords:  IBD; gut microbiome; host-microbiota interactome; methodologies; multi-omics

DOI:  https://doi.org/10.1080/19490976.2025.2476570
J Immunol. 2025 Mar 05. pii: vkae032. [Epub ahead of print]

Comparison of human macrophages derived from peripheral blood and bone marrow.

Hannah L Smith, Russell B Foxall, Patrick J Duriez, Emma L Teal, Adam D Hoppe, Janos M Kanczler, Juliet C Gray, Stephen A Beers.

  Macrophage differentiation, phenotype, and function have been assessed extensively in vitro by predominantly deriving human macrophages from peripheral blood. It is accepted that there are differences between macrophages isolated from different human tissues; however, the importance of anatomical source for in vitro differentiation and characterization is less clear. Here, phenotype and function were evaluated between human macrophages derived from bone marrow or peripheral blood. Macrophages were differentiated by adherence of heterogenous cell populations or CD14 isolation and polarized with IFNγ and LPS or IL-4 and IL-13 for 48 hours before evaluation of phenotype and phagocytic capacity. The presence of stromal cells in bone marrow heterogenous cultures resulted in a reduction in macrophage purity compared to peripheral blood, which was negated after CD14 isolation. Phenotypically, monocyte-derived macrophages (MDMs) derived from peripheral blood and bone marrow resulted in similar expression of classical and polarized macrophages markers, including CD14, HLA-DR, CD38, and CD40 (increased after IFNγ/LPS), and CD11b and CD206 (elevated after IL-4/IL-13). Functionally, these cells also showed similar levels of Fc-independent and Fc-dependent phagocytosis, although there was a nonsignificant reduction of Fc-dependent phagocytosis in the bone marrow derived macrophages after IFNγ/LPS stimulation. In summary, we have identified that human MDMs differentiated from peripheral blood and bone marrow showed similar characteristics and functionality, suggesting that isolating cells from different anatomical niches does not affect macrophage differentiation after CD14 isolation. Consequently, due to high yield and ready availability peripheral blood derived macrophages are still the most suitable source.

Keywords:  ADCP; PBMCs; bone marrow; macrophages; phagocytosis

DOI:  https://doi.org/10.1093/jimmun/vkae032
EMBO Mol Med. 2025 Mar 13.

Immune training enhances anti-viral responses and improves outcomes in Pax5-/+ mice susceptible to chronic infection.

Zhe Lu, Olivia Stencel, Wei Liu, Eleni Vasileiou, Haifeng C Xu, Piyush Pandey, Paweł Stachura, Abdelrahman Elwy, Anastassia Tsombal, Ann-Sophie Mai, Franziska Auer, Mina N F Morcos, Maximilian Seidl, Sarah Koziel, Peter-Martin Bruch, Sascha Dietrich, Sarah Elitzur, Gunther Hartmann, Karl S Lang, Stefan Janssen, Ute Fischer, Sanil Bhatia, Philipp A Lang, Arndt Borkhardt, Julia Hauer, Aleksandra A Pandyra.

  Viral infections pose a significant global burden. Host susceptibility to pathogens is determined by many factors including genetic variation that can lead to immunodeficient or dysregulated antiviral immune responses. Pax5 heterozygosity (Pax5-/+), resulting in reduced PAX5 levels in mice, mimics germline or somatic PAX5 dysregulation contributing to diseases such as childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). In contrast to the well-characterized roles of PAX5 during early B-cell development, little is known about how Pax5 heterozygosity impacts antiviral responses. We infected Pax5-/+ mice with the noncytopathic Lymphocytic Choriomeningitis Virus (LCMV) and found that infection with the chronic Docile strain resulted in decreased survival of Pax5-/+ mice. While early adaptive CD8+ T-cell (CTL) immunity was robust in Pax5-/+ mice, LCMV-specific neutralizing antibody production was compromised leading to impaired long-term viral clearance and a pro-inflammatory milieu in the bone marrow (BM). Here we show that survival outcomes were improved upon prophylactic treatment with the β-glucan immune trainer through induction of heterologous protection against chronic infection. β-Glucan enhanced viral clearance, CTL immunity, neutralizing antibody production and reduced monocyte immunosuppression in multiple LCMV-resident host organs. New insight from this study will help design effective prophylactic treatment strategies against chronic viral infections, particularly in genetically predisposed susceptible hosts.

Keywords:  Chronic Infection; LCMV; PAX5; Trained Immunity; β-glucan

DOI:  https://doi.org/10.1038/s44321-025-00208-4
Sci Rep. 2025 Mar 13. 15(1): 8778

Probiotic Bifidobacterium bifidum strains desialylate MUC13 and increase intestinal epithelial barrier function.

Celia Segui-Perez, Liane Z X Huang, Fernanda L Paganelli, Elke Lievens, Karin Strijbis.

  Probiotic bacteria including Bifidobacterial species have the capacity to improve intestinal health, but the underlying molecular mechanisms are often not understood. Bifidobacteria are considered keystone species but have a relatively low abundance in the adult intestinal tract. Bifidobacterium colonization depends on degradation of host-derived carbohydrates, including human milk oligosaccharides and mucin-associated oligosaccharides. Specific Bifidobacterium strains can enhance intestinal barrier integrity and improve symptoms of gastrointestinal disorders. We previously reported that the transmembrane mucin MUC13 localizes to the apical and lateral membrane and regulates epithelial tight junction strength. Here, we screened probiotic bacterial strains for their capacity to modulate MUC13 and enhance intestinal barrier function. Of these probiotic bacteria, a Bifidobacterium bifidum strain uniquely degraded the MUC13 O-glycosylated extracellular domain. Further characterization of two probiotic B. bifidum strains (W23 and W28) and the type strain 20456 demonstrated that the W23 and W28 strains adhered strongly to the apical surface, had high sialidase activity, penetrated the mucus layer, and enhanced epithelial barrier integrity. These results underscore the strain-specific properties of these specific B. bifidum strains that most likely contribute to their probiotic effects in the intestinal tract.

Keywords:   Bifidobacterium bifidum ; Lactiplantibacillus plantarum ; Lactobacillus plantarum ; Intestinal barrier function; MUC13; Neuraminidase; Probiotics; Sialic acids; Soluble mucus layer; Tight junctions

DOI:  https://doi.org/10.1038/s41598-025-92125-2
Front Cell Infect Microbiol. 2025 ;15 1518659

L-serine metabolic regulation and host respiratory homeostasis.

Pan Li, Xiaoyan Wu, Yanlan Huang, Ruijing Qin, Pan Xiong, Yangyang Qiu.

  L-Serine, a non-essential amino acid (NEAA), can be obtained through diet or in situ synthesis. Functionally, L-serine not only serves as the precursor of other amino acids, lipids, and nucleotides, but also participates in the folate/methionine cycle. An increasing number of studies have demonstrated that L-serine is widely used in the adjuvant therapy of many diseases (e.g., inflammation, infections, fibrosis, and tumors). Here, we summarize the synthesis and metabolism of serine followed by its functions in health and disease. Moreover, we delineate the potential mechanisms whereby L-serine is involved in the occurrence and progression of respiratory diseases. This review aims to summarize the research progress of serine in diseases, propose the problems that need to be solved in the future, and provide guidance for subsequent research and development.

Keywords:  PHGDH; infection; inflammation; respiratory diseases; serine

DOI:  https://doi.org/10.3389/fcimb.2025.1518659
Stem Cell Reports. 2025 Mar 12. pii: S2213-6711(25)00051-7. [Epub ahead of print] 102447

Differentiation success of reprogrammed cells is heterogeneous in vivo and modulated by somatic cell identity memory.

Tomas Zikmund, Jonathan Fiorentino, Chris Penfold, Marco Stock, Polina Shpudeiko, Gaurav Agarwal, Larissa Langfeld, Kseniya Petrova, Leonid Peshkin, Stephan Hamperl, Antonio Scialdone, Eva Hoermanseder.

  Nuclear reprogramming can change cellular fates. Yet, reprogramming efficiency is low, and the resulting cell types are often not functional. Here, we used nuclear transfer to eggs to follow single cells during reprogramming in vivo. We show that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. We find subsets of reprogramming-resistant cells that fail to form functional cell types, undergo cell death, or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. Thus, our work demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming.

Keywords:  Xenopus; early embryonic development; in vivo reprogramming; mucocilliary epithelium; nuclear transfer; single cell RNAseq

DOI:  https://doi.org/10.1016/j.stemcr.2025.102447