bims-bac4me 2025-01-26 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–01–26
35 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow.
Recognition of Staphylococcus aureus by the pattern recognition molecules langerin, mannan-binding lectin, and surfactant protein D: the influence of capsular polysaccharides and wall teichoic acid.
Activation and evasion of inflammasomes during viral and microbial infection.
Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome.
Metabolic tug-of-war: Microbial metabolism shapes colonization resistance against enteric pathogens.
The neonate respiratory microbiome.
TSST-1 promotes colonization of Staphylococcus aureus within the vaginal tract by activation of CD8+ T cells.
Dual RNA sequencing of a co-culture model of Pseudomonas aeruginosa and human 2D upper airway organoids.
Extracellular HSP70 facilitated β-glucan induced trained immunity in macrophages to suppress sepsis via TLR2-NF-κB axis.
Lactic acid in the vaginal milieu modulates the Candida-host interaction.
Apigenin inhibits NLRP3 inflammasome activation in monocytes and macrophages independently of CD38.
Antibiotic-mediated dysbiosis leads to activation of inflammatory pathways.
Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine.
Microbial molecules, metabolites, and malignancy.
Circadian metabolic adaptations to infections.
Extracellular peroxiredoxin 6 released from alveolar epithelial cells as a DAMP drives macrophage activation and inflammatory exacerbation in acute lung injury.
Building Spatiotemporal Understanding of Mycobacterium tuberculosis-Host Interactions.
Patterns of Klebsiella pneumoniae bacteremic dissemination from the lung.
New opportunities in mechanistic and functional microbiome studies.
Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease.
Interkingdom signaling between gastrointestinal hormones and the gut microbiome.
Protocol for predicting host-microbe interactions and their downstream effect on host cells using MicrobioLink.
Limosilactobacillus reuteri - a probiotic gut commensal with contextual impact on immunity.
Novel vaccine strategies to induce respiratory mucosal immunity: advances and implications.
A mechanistic understanding of the effect of Staphylococcus aureus VraS histidine kinase single point mutation on antibiotic resistance.
Dissecting S-itaconation at host-pathogen interactions with chemical proteomics tools.
Mucosal immunity elicited by a human-Fcγ receptor-I targeted intranasal vaccine platform enhances resistance against nasopharyngeal colonization of Streptococcus pneumoniae and induces broadly protective immunity against respiratory pathogens.
Sialidase fusion protein protects against influenza infection in a cigarette smoke-induced model of COPD.
Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
Establishment of a 3D-Printed Tissue-on-a-Chip Model for Live Imaging of Bacterial Infections.
Epigenetic phase variation in the gut microbiome enhances bacterial adaptation.
Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
Protocol for identifying Mycobacterium tuberculosis infection status through airway microbiome profiling.
Integration of 168,000 samples reveals global patterns of the human gut microbiome.
Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.

Immunity. 2025 Jan 16. pii: S1074-7613(24)00577-6. [Epub ahead of print]

Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow.

Iñaki Robles-Vera, Aitor Jarit-Cabanillas, Paola Brandi, María Martínez-López, Sarai Martínez-Cano, Manuel Rodrigo-Tapias, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Vanesa Nuñez, Cristina González-Correa, Javier Moleón, Juan Duarte, Laura Conejero, Pablo Mata-Martínez, Carmen María Díez-Rivero, Marta Bergón-Gutiérrez, Iván Fernández-López, Manuel J Gómez, Ana Quintas, Ana Dopazo, Fátima Sánchez-Cabo, Esther Pariente, Carlos Del Fresno, José Luis Subiza, Salvador Iborra, David Sancho.

  Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that Enterococcus faecalis translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed E. faecalis reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses in vitro and in vivo and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (Clec4e) was essential for E. faecalis-induced TI in BMPs. Clec4e-/- mice showed impaired TI upon E. faecalis administration and reduced pathology following DSS treatment. Thus, Mincle sensing of E. faecalis induces TI that may have long-term effects on pathologies associated with increased gut permeability.

Keywords:  Mincle receptor; bone marrow progenitors; gut bacterial translocation; inflammation; macrophages; trained immunity

DOI:  https://doi.org/10.1016/j.immuni.2024.12.012
Front Immunol. 2024 ;15 1504886

Recognition of Staphylococcus aureus by the pattern recognition molecules langerin, mannan-binding lectin, and surfactant protein D: the influence of capsular polysaccharides and wall teichoic acid.

Kirstine Mejlstrup Hymøller, Stig Hill Christiansen, Anders Grønnegaard Schlosser, Uffe B Skov Sørensen, Jean C Lee, Steffen Thiel.

  The innate immune system plays a critical role in the rapid recognition and elimination of pathogens through pattern recognition receptors (PRRs). Among these PRRs are the C-type lectins (CTLs) langerin, mannan-binding lectin (MBL), and surfactant protein D (SP-D), which recognize carbohydrate patterns on pathogens. Each represents proteins from different compartments of the body and employs separate effector mechanisms. We have investigated their interaction with the Gram-positive opportunistic pathogen Staphylococcus aureus, a bacterium whose cell wall contains two key glycopolymers: capsular polysaccharide (CP) and wall teichoic acid (WTA). Using a langerin-expressing cell line and recombinant langerin, MBL, and SP-D, we demonstrated that langerin, MBL, and SP-D all recognize nonencapsulated S. aureus. However, the bacterium may produce CP that effectively shields S. aureus from recognition by all three CTLs. Experiments utilizing mutant S. aureus strains confirmed that WTA is a ligand for MBL, but that langerin likely interacts with an additional unknown ligand. A competition assay revealed that MBL and SP-D inhibit langerin's interaction with S. aureus, highlighting the intricate redundancy and cooperation within the innate immune system. This study highlights the dynamic interplay of langerin, MBL, and SP-D in recognizing specific surface structures on S. aureus and provides insight into how this pathogen evades innate immune recognition.

Keywords:  C-type lectins; S. aureus; capsular polysaccharides; innate immunity; langerin; mannan-binding lectin; surfactant protein D; wall teichoic acid

DOI:  https://doi.org/10.3389/fimmu.2024.1504886
Cell Mol Life Sci. 2025 Jan 21. 82(1): 56

Activation and evasion of inflammasomes during viral and microbial infection.

Dan Ren, Xiaoou Ye, Ruiming Chen, Xiuzhi Jia, Xianhong He, Jinhui Tao, Tengchuan Jin, Songquan Wu, Hongliang Zhang.

  The inflammasome is a cytoplasmic multiprotein complex that induces the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) or pyroptosis by activating caspases, which play critical roles in regulating inflammation, cell death, and various cellular processes. Multiple studies have shown that the inflammasome is a key regulator of the host defence response against pathogen infections. During the process of pathogenic microbe invasion into host cells, the host's innate immune system recognizes these microbes by activating inflammasomes, triggering inflammatory responses to clear the microbes and initiate immune responses. Moreover, microbial pathogens have evolved various mechanisms to inhibit or evade the activation of inflammasomes. Therefore, we review the interactions between viruses and microbes with inflammasomes during the invasion process, highlight the molecular mechanisms of inflammasome activation induced by microbial pathogen infection, and highlight the corresponding strategies that pathogens employ to evade inflammasome activity. Finally, we also discuss potential therapeutic strategies for the treatment of pathogenic microbial infections via the targeting of inflammasomes and their products.

Keywords:  AIM2; Evasion; Inflammasome; Microbe; NLRP3; Viral

DOI:  https://doi.org/10.1007/s00018-025-05575-2
Cell Chem Biol. 2025 Jan 16. pii: S2451-9456(24)00517-8. [Epub ahead of print]32(1): 111-125.e6

Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome.

Aayushi Uberoi, Sofía M Murga-Garrido, Preeti Bhanap, Amy E Campbell, Simon A B Knight, Monica Wei, Anya Chan, Taylor Senay, Saba Tegegne, Ellen K White, Carrie Hayes Sutter, Clementina Mesaros, Thomas R Sutter, Elizabeth A Grice.

  The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites in vivo, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders.

Keywords:  aryl hydrocarbon receptor; keratinocytes; skin barrier; skin microbiota; tryptophan

DOI:  https://doi.org/10.1016/j.chembiol.2024.12.007
Cell Chem Biol. 2025 Jan 16. pii: S2451-9456(24)00515-4. [Epub ahead of print]32(1): 46-60

Metabolic tug-of-war: Microbial metabolism shapes colonization resistance against enteric pathogens.

Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss.

A widely recognized benefit of gut microbiota is that it provides colonization resistance against enteric pathogens. The gut microbiota and their products can protect the host from invading microbes directly via microbe-pathogen interactions and indirectly by host-microbiota interactions, which regulate immune system function. In contrast, enteric pathogens have evolved mechanisms to utilize microbiota-derived metabolites to overcome colonization resistance and increase their pathogenic potential. This review will focus on recent studies of metabolism-mediated mechanisms of colonization resistance and virulence strategies enteric pathogens use to overcome them, along with how induction of inflammation by pathogenic bacteria changes the landscape of the gut and enables alternative metabolic pathways. We will focus on how intestinal pathogens counteract the protective effects of microbiota-derived metabolites to illustrate the growing appreciation of how metabolic factors may serve as crucial virulence determinants and overcome colonization resistance.

DOI: https://doi.org/10.1016/j.chembiol.2024.12.005
Acta Physiol (Oxf). 2025 Feb;241(2): e14266

The neonate respiratory microbiome.

Sabine Pirr, Maike Willers, Dorothee Viemann.

  Over the past two decades, it has become clear that against earlier assumptions, the respiratory tract is regularly populated by a variety of microbiota even down to the lowest parts of the lungs. New methods and technologies revealed distinct microbiome compositions and developmental trajectories in the differing parts of the respiratory tract of neonates and infants. In this review, we describe the current understanding of respiratory microbiota development in human neonates and highlight multiple factors that have been identified to impact human respiratory microbiome development including gestational age, mode of delivery, diet, antibiotic treatment, and early infections. Moreover, we discuss to date revealed respiratory microbiome-disease associations in infants and children that may indicate a potentially imprinting cross talk between microbial communities and the host immune system in the respiratory tract. It becomes obvious how insufficient our knowledge still is regarding the exact mechanisms underlying such cross talk in humans. Lastly, we highlight strong findings that emphasize the important role of the gut-lung axis in educating and driving pulmonary immunity. Further research is needed to better understand the host - respiratory microbiome interaction in order to enable the translation into microbiome-based strategies to protect and improve human respiratory health from early childhood.

Keywords:  gut–lung axis; host–immunity interaction; microbiome development; microbiota; neonate; respiratory disease; respiratory tract

DOI:  https://doi.org/10.1111/apha.14266
Infect Immun. 2025 Jan 22. e0043924

TSST-1 promotes colonization of Staphylococcus aureus within the vaginal tract by activation of CD8+ T cells.

Karine Dufresne, Kait F Al, Heather C Craig, Charlotte E M Coleman, Katherine J Kasper, Jeremy P Burton, John K McCormick.

  Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus and is the determinant of menstrual toxic shock syndrome (mTSS); however, the impact of TSST-1 on the vaginal environment beyond mTSS is not understood. Herein, we assessed how TSST-1 affects vaginal colonization by S. aureus, host inflammatory responses, and changes in microbial communities within the murine vagina. We demonstrated that TSST-1 induced a CD8+ T-cell-dependent inflammatory response in 24 h that correlated with S. aureus persistence within the vaginal tract. This increase was due to superantigen-dependent T-cell activation that triggered a change in microbial composition within the vaginal tract. Altogether, this study demonstrates that within the vaginal tract, TSST-1 modulates the vaginal microbiota to favor the survival of S. aureus in the absence of mTSS.IMPORTANCEToxic shock syndrome toxin-1 (TSST-1) is a superantigen toxin produced from Staphylococcus aureus that causes the menstrual form of toxic shock syndrome. This research demonstrates that TSST-1 also has a wider function within the vaginal tract than previously expected. We show that TSST-1, by activating CD8+ T cells, induces an inflammatory environment that modifies the vaginal microbiota to favor colonization by S. aureus. These are important findings as S. aureus can colonize the human vaginal tract efficiently and subsequently trigger dysbiosis within the microbial communities leading to several adverse outcomes such as decreased fertility, increased risks for sexually transmitted diseases, and issues related to pregnancy and birth.

Keywords:  Staphylococcus aureus; T cells; TSST-1; superantigen; vaginal environment

DOI:  https://doi.org/10.1128/iai.00439-24
Sci Rep. 2025 Jan 17. 15(1): 2222

Dual RNA sequencing of a co-culture model of Pseudomonas aeruginosa and human 2D upper airway organoids.

Cayetano Pleguezuelos-Manzano, Wouter A G Beenker, Gijs J F van Son, Harry Begthel, Gimano D Amatngalim, Jeffrey M Beekman, Hans Clevers, Jeroen den Hertog.

  Pseudomonas aeruginosa is a Gram-negative bacterium that is notorious for airway infections in cystic fibrosis (CF) subjects. Bacterial quorum sensing (QS) coordinates virulence factor expression and biofilm formation at population level. Better understanding of QS in the bacterium-host interaction is required. Here, we set up a new P. aeruginosa infection model, using 2D upper airway nasal organoids that were derived from 3D organoids. Using dual RNA-sequencing, we dissected the interaction between organoid epithelial cells and WT or QS-mutant P. aeruginosa strains. Since only a single healthy individual and a single CF subject were used as donors for the organoids, conclusions about CF-specific effects could not be deduced. However, P. aeruginosa induced epithelial inflammation, whereas QS signaling did not affect the epithelial airway cells. Conversely, the epithelium influenced infection-related processes of P. aeruginosa, including QS-mediated regulation. Comparison of our model with samples from the airways of CF subjects indicated that our model recapitulates important aspects of infection in vivo. Hence, the 2D airway organoid infection model is relevant and may help to reduce the future burden of P. aeruginosa infections in CF.

Keywords:   Pseudomonas aeruginosa ; 2D co-culture; Airway organoids; Dual RNA-sequencing; Infection model; Quorum sensing

DOI:  https://doi.org/10.1038/s41598-024-82500-w
Cytokine. 2025 Jan 16. pii: S1043-4666(25)00008-0. [Epub ahead of print]187 156861

Extracellular HSP70 facilitated β-glucan induced trained immunity in macrophages to suppress sepsis via TLR2-NF-κB axis.

Ran Qi, Xin Cheng, Shan Chen, Jinjun Fan.

  Sepsis is a common systemic infectious disease followed by extremely high incidence and mortality with no effective treatment and clinical drugs. As a key mediator involved in infection and immunity, it has been reported that sepsis patients are accompanied by increased heat shock protein 70 (HSP70). Trained immunity is a novel innate immunity approach that can be activated by β-glucan to fight against sepsis. The mechanism of HSP70 activating trained macrophages against sepsis needs further elucidation. Trained immunity and sepsis models were established by β-glucan and LPS individually both in vivo and in vitro. We demonstrated that HSP70 was significantly upregulated in septic mice serum, and HSP70 could protect mice from sepsis by activating β-glucan-trained macrophages as an ideal secondary inducer via TLR2-NF-κB pathway. Additionally, the sepsis resistant effects of HSP70 could be blocked by its antibody. In summary, more than a molecular chaperone to maintain homeostasis, HSP70 could be an important trained immunity inducer to help the body fighting against sepsis, which provided new stimuli for trained immunity and novel therapeutic solutions for sepsis.

Keywords:  HSP70; Macrophages; Sepsis; TLR2; Trained immunity

DOI:  https://doi.org/10.1016/j.cyto.2025.156861
Virulence. 2025 Dec;16(1): 2451165

Lactic acid in the vaginal milieu modulates the Candida-host interaction.

Diletta Rosati, Marisa Valentine, Mariolina Bruno, Arnab Pradhan, Axel Dietschmann, Martin Jaeger, Ian Leaves, Frank L van de Veerdonk, Leo A B Joosten, Sumita Roy, Mark H T Stappers, Neil A R Gow, Bernhard Hube, Alistair J P Brown, Mark S Gresnigt, Mihai G Netea.

  Vulvovaginal candidiasis (VVC) is one of the most common infections caused by Candida albicans. VVC is characterized by an inadequate hyperinflammatory response and clinical symptoms associated with Candida colonization of the vaginal mucosa. Compared to other host niches in which C. albicans can cause infection, the vaginal environment is extremely rich in lactic acid that is produced by the vaginal microbiota. We examined how lactic acid abundance in the vaginal niche impacts the interaction between C. albicans and the human immune system using an in vitro culture in vaginal simulative medium (VSM). The presence of lactic acid in VSM (VSM+LA) increased C. albicans proliferation, hyphal length, and its ability to cause damage during subsequent infection of vaginal epithelial cells. The cell wall of C. albicans cells grown in VSM+LA displayed a robust mannan fibrillar structure, β-glucan exposure, and low chitin content. These cell wall changes were associated with altered immune responses and an increased ability of the fungus to induce trained immunity. Neutrophils were compromised in clearing C. albicans grown in VSM+LA conditions, despite mounting stronger oxidative responses. Collectively, we found that fungal adaptation to lactic acid in a vaginal simulative context increases its immunogenicity favouring a pro-inflammatory state. This potentially contributes to the immune response dysregulation and neutrophil recruitment observed during recurrent VVC.

Keywords:  Vulvovaginal candidiasis; candida albicans; host response; lactic acid; vaginal simulative medium

DOI:  https://doi.org/10.1080/21505594.2025.2451165
Front Immunol. 2024 ;15 1497984

Apigenin inhibits NLRP3 inflammasome activation in monocytes and macrophages independently of CD38.

Knut Husø Lauritzen, Kuan Yang, Michael Frisk, Mieke C Louwe, Maria Belland Olsen, Mathias Ziegler, William E Louch, Bente Halvorsen, Pål Aukrust, Arne Yndestad, Øystein Sandanger.

   Introduction: CD38, a regulator of intracellular calcium signalling, is highly expressed in immune cells. Mice lacking CD38 are very susceptible to acute bacterial infections, implicating CD38 in innate immune responses. The effects of CD38 inhibition on NLRP3 inflammasome activation in human primary monocytes and monocyte-derived macrophages have not been investigated. Apigenin is a naturally occurring flavonoid known to inhibit CD38. However, apigenin has also been proposed to inhibit the extracellular ATP receptor P2XR7, an upstream activator of NLRP3. In this study we aimed to investigate whether apigenin attenuates NLRP3 inflammasome activation in human monocytes and monocyte-derived macrophages through CD38 inhibition.
Methods: LPS-primed human monocytes and monocyte-derived macrophages were treated with apigenin, the CD38 inhibitor 78c, antagonists of CD38 second messengers (8-br-ADPR and 8-br-cADPR) or the ATP hydrolase, apyrase, prior to NLRP3 activation with ATP, monosodium urate crystals (MSU) or nigericin. IL-1β and TNF secretion and mRNA expression, as well as N-terminal gasdermin-D formation were quantified. Ca2+ mobilization was determined by live confocal microscopy. NLRP3 activity was also compared in WT and CD38-/- mouse bone marrow-derived macrophages (BMDMs) with and without CD38 inhibitors.
Results: Apigenin significantly inhibited IL-1β release from LPS-primed monocytes and macrophages activated with ATP, MSU, or nigericin. CD38 inhibition with 78c also attenuated NLRP3-dependent IL-1β release. Apigenin was a potent inhibitor of Ca2+ flux from the endoplasmic reticulum to the cytosol in human monocyte-derived macrophages. Apyrase attenuated IL-1β release induced by ATP or MSU, but not by nigericin. However, the NLRP3 inflammasome is not compromised in CD38-/- bone marrow-derived macrophages compared to corresponding WT cells, and apigenin moderated IL-1β release in both genotypes.
Discussion: Our data support that apigenin attenuates NLRP3 activation independently of CD38. Our results also suggest that MSU crystals activate NLRP3 through autocrine or paracrine ATP signalling.

Keywords:  CD38; NLRP3; apigenin; inflammasome; macrophage; monocyte

DOI:  https://doi.org/10.3389/fimmu.2024.1497984
Front Immunol. 2024 ;15 1493991

Antibiotic-mediated dysbiosis leads to activation of inflammatory pathways.

Jemma J Taitz, Jian Tan, Duan Ni, Camille Potier-Villette, Georges Grau, Ralph Nanan, Laurence Macia.

   Introduction: The gut microbiota plays a pivotal role in influencing host health, through the production of metabolites and other key signalling molecules. While the impact of specific metabolites or taxa on host cells is well-documented, the broader impact of a disrupted microbiota on immune homeostasis is less understood, which is particularly important in the context of the increasing overuse of antibiotics.
Methods: Female C57BL/6 mice were gavaged twice daily for four weeks with Vancomycin, Polymyxin B, or PBS (control). Caecal microbiota composition was assessed via 16S rRNA sequencing and caecal metabolites were quantified with NMR spectroscopy. Immune profiles of spleen and mesenteric lymph nodes (MLNs) were assessed by flow cytometry, and splenocytes assessed for ex vivo cytokine production. A generalised additive model approach was used to examine the relationship between global antibiotic consumption and IBD incidence.
Results: Antibiotics significantly altered gut microbiota composition, reducing alpha-diversity. Acetate and butyrate were significantly reduced in antibiotic groups, while propionate and succinate increased in Vancomycin and PmB-treated mice, respectively. The MLNs and spleen showed changes only to DC numbers. Splenocytes from antibiotic-treated mice stimulated ex vivo exhibited increased production of TNF. Epidemiological analysis revealed a positive correlation between global antibiotic consumption and IBD incidence.
Discussion: Our findings demonstrate that antibiotic-mediated dysbiosis results in significantly altered short-chain fatty acid levels but immune homeostasis in spleen and MLNs at steady state is mostly preserved. Non-specific activation of splenocytes ex vivo, however, revealed mice with perturbed microbiota had significantly elevated production of TNF. Thus, this highlights antibiotic-mediated disruption of the gut microbiota may program the host towards dysregulated immune responses, predisposing to the development of TNF-associated autoimmune or chronic inflammatory disease.

Keywords:  IBD; Polymyxin B; TNF; antibiotics; autoimmunity; dysbiosis; gut microbiota; vancomycin

DOI:  https://doi.org/10.3389/fimmu.2024.1493991
Nat Commun. 2025 Jan 21. 16(1): 877

Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine.

Yanfei Ma, Yifan Zhong, Wenjie Tang, Teresa G Valencak, Jingliang Liu, Zhaoxi Deng, Jiangdi Mao, Daren Liu, Shanshan Wang, Yuhao Wang, Haifeng Wang.

Metabolic syndrome (MetS) is a difficult-to-manage disease that poses a significant risk to human health. Here, we show that the supplementation of Lactobacillus reuteri ZJ617 ameliorates symptoms of MetS in mice induced by the high-fat diet. L. reuteri ZJ617 modulates host metabolism by interacting with the microbiome, resulting in the production of spermidine synthesized by the microbiota. L. reuteri ZJ617 serves as a source of substrates for the microbiota to synthesize spermidine, hence preventing the decline of bacteria responsible for spermidine production. Spermidine treatment mimics the metabolic effects of L. reuteri ZJ617, whereas pharmacological inhibition of spermidine biosynthesis in mice abolishes these benefits. Our findings reveal the mechanism by which L. reuteri ZJ617 alleviates MetS symptoms and provide support for its potential use as a probiotic for promoting metabolic health.

DOI: https://doi.org/10.1038/s41467-025-56105-4
Neoplasia. 2025 Jan 18. pii: S1476-5586(25)00007-7. [Epub ahead of print]60 101128

Microbial molecules, metabolites, and malignancy.

Ryan M Thomas.

  Research elucidating the role of the microbiome in carcinogenesis has grown exponentially over the past decade. Initially isolated to associative studies on colon cancer development, the field has expanded to encompass nearly every solid and liquid malignancy that may afflict the human body. Investigations are rapidly progressing from association to causation and one particular area of causal effect relates to microbial metabolites and how they influence cancer development, progression, and treatment response. These metabolites can be produced de novo from individual members of the microbiome, whether that be bacteria, fungi, archaea, or other microbial organisms, or they can be through metabolic processing of dietary compounds or even host-derived molecules. In this review, contemporary research elucidating mechanisms whereby microbial-derived molecules and metabolites impact carcinogenesis and cancer treatment efficacy will be presented. While many of the examples focus on bacterial metabolites in colon carcinogenesis, this simply illustrates the accelerated nature of these investigations that occurred early in microbiome research but provides an opportunity for growth in other cancer areas. Indeed, research into the interaction of microbiome-derived metabolites in other malignancies is growing as well as investigations that involve non-bacterial metabolites. This review will provide the reader a framework to expand their knowledge regarding this complex and exciting field of cancer research.

Keywords:  Cancer; Immunity; Metabolites; Microbiome; Microbiota

DOI:  https://doi.org/10.1016/j.neo.2025.101128
Philos Trans R Soc Lond B Biol Sci. 2025 Jan 23. 380(1918): 20230473

Circadian metabolic adaptations to infections.

Claudio Costantini, Stefano Brancorsini, Francesco Grignani, Luigina Romani, Marina Maria Bellet.

  Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host-microbiota-pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Keywords:  circadian clock; immune response; metabolism; microbiota; pathogen

DOI:  https://doi.org/10.1098/rstb.2023.0473
Int Immunopharmacol. 2025 Jan 16. pii: S1567-5769(25)00012-8. [Epub ahead of print]148 114023

Extracellular peroxiredoxin 6 released from alveolar epithelial cells as a DAMP drives macrophage activation and inflammatory exacerbation in acute lung injury.

Ke Lang, Xiaocen Wang, Tingting Wei, Xinyi Ning, Shuyang Chen, Yuqiao Luo, Hongru Li, Yifan Xu, Dong Yang, Yuanlin Song.

  Acute respiratory distress syndrome (ARDS) is featured with acute lung inflammatory injury. Our prospective study found that higher levels of peroxiredoxin 6(PRDX6) were detected in bronchoalveolar lavage (BAL) fluid from ARDS patients. Elevated PRDX6 was also correlated with monocytic activation and poor prognosis in ARDS patients. To investigate the origin of extracellular PRDX6, we conducted in vitro and in vivo experiments, demonstrating that PRDX6 can be actively released from alveolar epithelial cells under stress conditions. Our study demonstrated that it could be released from injured lung epithelial cells into the bronchoalveolar interstitial space in mice with acute lung injury and in vitro experiments. Moreover, exogenous PRDX6 was shown to activate the TLR4/NF-κB signalling pathway and induce M1 polarization of macrophages. Notably, the inflammatory effects of PRDX6 were mitigated by specific inhibition of the TLR4 (Toll-like receptor 4)-MD2 (Myeloid differentiation factor 2) complex. Using molecular docking simulations and in vitro binding assays, we confirmed a direct interaction between PRDX6 and MD2, further supporting its role as a damage-associated molecular patterns (DAMP) in ARDS. Our findings suggest that extracellular PRDX6 in bronchoalveolar lavage fluid could be a new DAMP factor in ALI, providing new insights into the pathogenesis of secondary hit in ALI/ARDS and highlighting PRDX6 as a potential therapeutic target for mitigating lung inflammation.

Keywords:  Acute lung injury; Damage-associated molecular pattern (DAMP); Macrophages; Peroxiredoxin 6; TLR4-MD2 complex

DOI:  https://doi.org/10.1016/j.intimp.2025.114023
ACS Infect Dis. 2025 Jan 23.

Building Spatiotemporal Understanding of Mycobacterium tuberculosis-Host Interactions.

Anna-Lisa E Lawrence, Shumin Tan.

  Heterogeneity during Mycobacterium tuberculosis (Mtb) infection greatly impacts disease outcome and complicates treatment. This heterogeneity encompasses many facets, spanning local differences in the host immune response to Mtb and the environment experienced by the bacterium, to nonuniformity in Mtb replication state. All of these facets are interlinked and each can affect Mtb susceptibility to antibiotic treatment. In-depth spatiotemporal understanding of Mtb-host interactions is thus critical to both fundamental comprehension of Mtb infection biology and for the development of effective therapeutic regimens. Such spatiotemporal understanding dictates the need for analysis at the single bacterium/cell level in the context of intact tissue architecture, which has been a significant technical challenge. Excitingly, innovations in spatial single cell methodology have opened the door to such studies, beginning to illuminate aspects ranging from intergranuloma differences in cellular composition and phenotype, to sublocation differences in Mtb physiology and replication state. In this perspective, we discuss recent studies that demonstrate the potential of these methodological advancements to reveal critical spatiotemporal insight into Mtb-host interactions, and highlight future avenues of research made possible by these advances.

Keywords:  C3HeB/FeJ; fluorescence in situ hybridization; nonhuman primate; spatiotemporal heterogeneity

DOI:  https://doi.org/10.1021/acsinfecdis.4c00840
Nat Commun. 2025 Jan 17. 16(1): 785

Patterns of Klebsiella pneumoniae bacteremic dissemination from the lung.

Caitlyn L Holmes, Katherine G Dailey, Karthik Hullahalli, Alexis E Wilcox, Sophia Mason, Bridget S Moricz, Lavinia V Unverdorben, George I Balazs, Matthew K Waldor, Michael A Bachman.

Bacteremia, a leading cause of death, generally arises after bacteria establish infection in a particular tissue and transit to secondary sites. Studying dissemination from primary sites by solely measuring bacterial burdens does not capture the movement of individual clones. By barcoding Klebsiella pneumoniae, a leading cause of bacteremia, we track pathogen dissemination following pneumonia. Variability in organ bacterial burdens is attributable to two distinct dissemination patterns distinguished by the degree of similarity between the lung and systemic sites. In metastatic dissemination, lung bacterial clones undergo heterogeneous expansion and the dominant clones spread to secondary organs, leading to greater similarity between sites. In direct dissemination, bacterial clones exit the lungs without clonal expansion, leading to lower burdens in systemic sites and more dissimilarity from the lung. We uncover bacterial and host factors that influence the dynamics of clonal sharing and expansion. Here, our data reveal unexpected heterogeneity in Klebsiella bacteremia dynamics and define a framework for understanding within-host bacterial dissemination.

DOI: https://doi.org/10.1038/s41467-025-56095-3
Cell Chem Biol. 2025 Jan 16. pii: S2451-9456(24)00524-5. [Epub ahead of print]32(1): 5-8

New opportunities in mechanistic and functional microbiome studies.

Judith Behnsen, Kerwyn Casey Huang, Matthew T Sorbara, Meng C Wang, Jun Yu, Melody Y Zeng.

The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this "chemical biology of the microbiome" focus issue from Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.

DOI: https://doi.org/10.1016/j.chembiol.2024.12.012
MedComm (2020). 2025 Feb;6(2): e70063

Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease.

Weifeng He, Lingfeng Yan, Dongxue Hu, Jianlei Hao, Yih-Cherng Liou, Gaoxing Luo.

  Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.

Keywords:  neutrophil functions; neutrophil heterogeneity; neutrophil plasticity; neutrophil signaling pathways; neutrophil‐targeted therapies

DOI:  https://doi.org/10.1002/mco2.70063
Gut Microbes. 2025 Dec;17(1): 2456592

Interkingdom signaling between gastrointestinal hormones and the gut microbiome.

Xinyu Zhao, Ye Qiu, Lanfan Liang, Xiangsheng Fu.

  The interplay between the gut microbiota and gastrointestinal hormones plays a pivotal role in the health of the host and the development of diseases. As a vital component of the intestinal microecosystem, the gut microbiota influences the synthesis and release of many gastrointestinal hormones through mechanisms such as modulating the intestinal environment, producing metabolites, impacting mucosal barriers, generating immune and inflammatory responses, and releasing neurotransmitters. Conversely, gastrointestinal hormones exert feedback regulation on the gut microbiota by modulating the intestinal environment, nutrient absorption and utilization, and the bacterial biological behavior and composition. The distributions of the gut microbiota and gastrointestinal hormones are anatomically intertwined, and close interactions between the gut microbiota and gastrointestinal hormones are crucial for maintaining gastrointestinal homeostasis. Interventions leveraging the interplay between the gut microbiota and gastrointestinal hormones have been employed in the clinical management of metabolic diseases and inflammatory bowel diseases, such as bariatric surgery and fecal microbiota transplantation, offering promising targets for the treatment of dysbiosis-related diseases.

Keywords:  Gastrointestinal hormones; dysbiosis; gut microbiota; interkingdom signaling; metabolic disease

DOI:  https://doi.org/10.1080/19490976.2025.2456592
STAR Protoc. 2025 Jan 16. pii: S2666-1667(24)00735-4. [Epub ahead of print]6(1): 103570

Protocol for predicting host-microbe interactions and their downstream effect on host cells using MicrobioLink.

Lejla Gul, Anna Julia Elias, Tanvi Tambaku, Marton Olbei, Emily Watters, Balazs Bohar, Dezso Modos, Matthew Madgwick, Tamas Korcsmaros.

  Analyzing host-microbe interactions is essential for understanding how microbiota changes disrupt host homeostasis. Here, we present a protocol for predicting host-microbe protein-protein interactions and their downstream effects using MicrobioLink. We describe steps for setting up the environment, installing software, and preparing human transcriptomic and bacterial proteomic data. The protocol outlines procedures for predicting protein-protein interactions through domain-motif interactions, integrating multi-omic datasets to map downstream effects, performing network analyses to identify key regulatory pathways, and visualizing multi-layered networks for systems-level data interpretation. For complete details on the use and execution of this protocol, please refer to Gul et al.1 and Poletti et al.2.

Keywords:  Bioinformatics; Cell Biology; Microbiology; Systems biology

DOI:  https://doi.org/10.1016/j.xpro.2024.103570
Gut Microbes. 2025 Dec;17(1): 2451088

Limosilactobacillus reuteri - a probiotic gut commensal with contextual impact on immunity.

Amanda H Lee, Daphne Michelle Rodriguez Jimenez, Marlies Meisel.

  The gut microbiome plays a key role in human health, influencing various biological processes and disease outcomes. The historical roots of probiotics are traced back to Nobel Laureate Élie Metchnikoff, who linked the longevity of Bulgarian villagers to their consumption of sour milk fermented by Lactobacilli. His pioneering work led to the global recognition of probiotics as beneficial supplements, now a multibillion-dollar industry. Modern probiotics have been extensively studied for their immunomodulatory effects. Limosilactobacillus reuteri (L. reuteri), a widely used probiotic, has garnered significant attention for its systemic immune-regulatory properties, particularly in relation to autoimmunity and cancer. This review delves into the role of L. reuteri in modulating immune responses, with a focus on its impact on systemic diseases.

Keywords:  Autoimmunity; Limosilactobacillus reuteri; cancer; immune system; probiotic; systemic disease

DOI:  https://doi.org/10.1080/19490976.2025.2451088
MedComm (2020). 2025 Feb;6(2): e70056

Novel vaccine strategies to induce respiratory mucosal immunity: advances and implications.

Ming Zhou, Haiqin Xiao, Xinyi Yang, Tong Cheng, Lunzhi Yuan, Ningshao Xia.

  Rapid advances in vaccine technology are becoming increasingly important in tackling global health crises caused by respiratory virus infections. While traditional vaccines, primarily administered by intramuscular injection, have proven effective, they often fail to provide the broad upper respiratory tract mucosal immunity, which is urgently needed for first-line control of respiratory viral infections. Furthermore, traditional intramuscular vaccines may not adequately address the immune escape of emerging virus variants. In contrast, respiratory mucosal vaccines developed using the body's mucosal immune response mechanism can simultaneously establish both systemic and mucosal immunity. This dual action effectively allows the respiratory mucosal immune system to function as the first line of defense, preventing infections at the entry points. This review highlights the efficacy of respiratory mucosal vaccines, including innovative delivery methods such as nasal and oral formulations, in enhancing local and systemic immune barriers. Notably, respiratory mucosal vaccines offer potential advantages in protecting against emerging virus variants and maintaining long-term and multidimensional immune memory in the upper respiratory tract. In addition, a combination of intramuscular and respiratory mucosal delivery of vaccines largely improves their coverage and effectiveness, providing valuable insights for future vaccine development and public inoculation strategies.

Keywords:  multidimensional immune protection; respiratory mucosal vaccines; respiratory virus infection

DOI:  https://doi.org/10.1002/mco2.70056
bioRxiv. 2025 Jan 06. pii: 2025.01.06.631495. [Epub ahead of print]

A mechanistic understanding of the effect of Staphylococcus aureus VraS histidine kinase single point mutation on antibiotic resistance.

Liaqat Ali, Salima Karki, Gunavanthi D Boorgula, Amir Mekakda, Brittnee Cagle-White, Shrijan Bhattarai, Robert Beaudoin, Aryanna Blakeney, Sanjay Singh, Shashikant Srivastava, May H Abdelaziz.

Bacterial genomic mutations in Staphylococcus aureus (S. aureus) have been detected in isolated resistant clinical strains, yet their mechanistic effect on the development of antimicrobial resistance remains unclear. The resistance-associated regulatory systems acquire adaptive mutations under stress conditions that may lead to a gain of function effect and contribute to the resistance phenotype. Here, we investigate the effect of a single-point mutation (T331I) in VraS histidine kinase, part of the VraSR two-component system in S. aureus. VraSR senses and responds to environmental stress signals by upregulating gene expression for cell wall synthesis. A combination of enzyme kinetics, microbiological, and transcriptomic analysis revealed the mechanistic effect of the mutation on VraS and S. aureus . Michaelis Menten's kinetics show that the VraS mutation caused an increase in the autophosphorylation rate of VraS and enhanced its catalytic efficiency. The introduction of the mutation through recombineering coupled with CRISPR-Cas9 counterselection to the Newman strain wild-type (WT) genome doubled the minimum inhibitory concentration of three cell wall-targeting antibiotics. The mutation caused an enhanced S. aureus growth rate at sub-lethal doses of the antibiotics, confirming the causative effect of mutation on bacterial persistence. Transcriptomic analysis showed a genome-wide alteration in gene expression levels and protein-protein interaction network of the mutant compared to the WT strain after exposure to vancomycin. The results suggest that vraS mutation causes several mechanistic changes at the protein and cellular levels that favor bacterial survival under antibiotic stress and cause the mutation-harboring strains to become the dominant population during infection.
Importance: Rising antimicrobial resistance (AMR) is a global health problem. Mutations in the two- component system have been linked to drug- resistance in Staphylococcus aureus , yet the exact mechanism through which these mutations work is understudied. We investigated the T331I mutation in the vraS gene linked to sensing and responding to cell wall stress. The mutation caused changes at the protein level by increasing the catalytic efficiency of VraS kinase activity. Introducing the mutation to the genome of an S. aureus strain resulted in changes in the phenotypic antibiotic susceptibility, growth kinetics, and genome-wide transcriptomic alterations. By a combination of enzyme kinetics, microbiological, and transcriptomic approaches, we highlight how small genetic changes can significantly impact bacterial physiology and survival under antibiotic stress. Understanding the mechanistic basis of antibiotic resistance is crucial to guide the development of novel therapeutic agents to combat AMR.

DOI: https://doi.org/10.1101/2025.01.06.631495
Curr Opin Microbiol. 2025 Jan 21. pii: S1369-5274(25)00001-3. [Epub ahead of print]83 102579

Dissecting S-itaconation at host-pathogen interactions with chemical proteomics tools.

Zihua Liu, Chu Wang.

The molecular essence of the battle between host and pathogens lies in the protein-protein or protein-metabolite interactions. Itaconate is one of the most upregulated immunometabolites, regulating immune responses through either noncovalent binding or covalent modification in the host. We herein briefly review recent progresses in the discoveries of physiological and pathological roles of itaconate and applications of chemical proteomic technologies in exploring itaconate modifications on cysteines (S-itaconation) at the interface of host-pathogen interactions. Key challenges are also proposed as future outlook.

DOI: https://doi.org/10.1016/j.mib.2025.102579
Vaccine. 2025 Jan 16. pii: S0264-410X(25)00026-X. [Epub ahead of print]48 126729

Mucosal immunity elicited by a human-Fcγ receptor-I targeted intranasal vaccine platform enhances resistance against nasopharyngeal colonization of Streptococcus pneumoniae and induces broadly protective immunity against respiratory pathogens.

Sudeep Kumar, Karsten Hazlett, Guangchun Bai.

  The development of safe and effective mucosal vaccines are hampered by safety concerns associated with adjuvants or live attenuated microbes. We previously demonstrated that targeting antigens to the human-Fc-gamma-receptor-I (hFcγRI) eliminates the need for adjuvants, thereby mitigating safety concerns associated with the mucosal delivery of adjuvant formulated vaccines. Here we evaluated the role of the route of immunization in the mucosal immunity elicited by the hFcγRI-targeted vaccine approach. To enable Ag targeting, PspA from Streptococcus pneumoniae (Sp) was genetically fused with the hFcγRI-targeting antibody (α-hFcγRI) to generate PspA-FP. Intranasal (IN) immunization with the PspA-FP induced significantly higher IgA, IgG, and memory T cell response in the lung mucosa compared to that of the intramuscular (IM) route, while both routes exhibited similar increase in the systemic IgG response. The IN immunization elicited better resistance against nasal colonization (NC) of Sp compared to the IM immunization. Additionally, the resistance to NC with the IN administered PspA-FP was higher than the PspA-Alum formulation administered by the IM route. While the protection form lethal pulmonary Sp infection correlated with the systemic Ab response, the resistance from NC (of Sp) correlated with the mucosal immune response. Similar to the pneumococcal pneumoniae model, the hFcγRI-targeted vaccine (based on HA as Ag) was equally protective against pulmonary Influenza virus infection via both routes. However, the IN route promoted better protection compared to the IM route against a lethal pulmonary infection with Francisella tularensis (Ft). The enhanced protection against Ft correlated with the superior mucosal immune response elicited by the IN route compared to the IM route. These observations showed a differential requirement for mucosal delivery for protection depending on the type of pathogen. Moreover, this study revealed that the hFcγRI-targeted vaccine platform is broadly-effective as an adjuvant-free mucosal vaccine platform against respiratory pathogens.

Keywords:  Adjuvant; Antigen presenting cell; FcγRI-targeting; Francisella tularensis; Influenza a virus; Mucosal vaccine; Streptococcus pneumoniae

DOI:  https://doi.org/10.1016/j.vaccine.2025.126729
Mucosal Immunol. 2025 Jan 19. pii: S1933-0219(25)00004-2. [Epub ahead of print]

Sialidase fusion protein protects against influenza infection in a cigarette smoke-induced model of COPD.

Cheng-Yen Chang, Dominique Armstrong, John M Knight, Trevor V Gale, Stephen Hawley, Max Wang, Nancy Chang, David B Corry, Farrah Kheradmand.

  First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker CD169, and downregulated inhibitory Siglec-F and Siglec-H molecules. Upon reinfection, mice treated with DAS181 showed activated and protective memory response in the lungs. Collectively, we show that this sialidase fusion protein promotes a beneficial immunomodulatory reaction in the lungs, supporting a new IFV-A therapeutic option for at-risk smokers.

Keywords:  Alveolar macrophage; Inflammation; Influenza infection; Sialidase fusion protein; Siglec

DOI:  https://doi.org/10.1016/j.mucimm.2025.01.004
Sci Adv. 2025 Jan 24. 11(4): eadq9301

Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.

Jing Wu, Komudi Singh, Vivian Shing, Anand Gupta, Brett C Arenberg, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

DOI: https://doi.org/10.1126/sciadv.adq9301
Adv Exp Med Biol. 2025 Jan 18.

Establishment of a 3D-Printed Tissue-on-a-Chip Model for Live Imaging of Bacterial Infections.

Albert Fuglsang-Madsen, Janus Anders Juul Haagensen, Charlotte De Rudder, Filipa Bica Simões, Søren Molin, Helle Krogh Johansen.

  Despite advances in healthcare, bacterial pathogens remain a severe global health threat, exacerbated by rising antibiotic resistance. Lower respiratory tract infections, with their high death toll, are of particular concern. Accurately replicating host-pathogen interactions in laboratory models is crucial for understanding these diseases and evaluating new therapies. In this communication, we briefly present existing in vivo models for cystic fibrosis and their limitations in replicating human respiratory infections. We then present a novel, 3D-printed, cytocompatible microfluidic lung-on-a-chip device, designed to simulate the human lung environment, and with possible use in recapitulating general infectious diseases.Our device enables the colonisation of fully differentiated lung epithelia at an air-liquid interface with Pseudomonas aeruginosa, a key pathogen in many severe infections. By incorporating dynamic flow, we replicate the clearance of bacterial toxins and planktonic cells, simulating both acute and chronic infections. This platform supports real-time monitoring of therapeutic interventions, mimics repeated drug administrations as in clinical settings, and facilitates the analysis of colony-forming units and cytokine secretion over time. Our findings indicate that this lung-on-a-chip device has significant potential for advancing infectious disease research, in optimizing treatment strategies against infections and in developing novel treatments.

Keywords:  Bacterial infections; Infection models; Microfluidics; Organ on a chip; Pseudomonas aeruginosa

DOI:  https://doi.org/10.1007/5584_2024_829
bioRxiv. 2025 Jan 11. pii: 2025.01.11.632565. [Epub ahead of print]

Epigenetic phase variation in the gut microbiome enhances bacterial adaptation.

Mi Ni, Yu Fan, Yujie Liu, Yangmei Li, Wanjin Qiao, Lauren E Davey, Xue-Song Zhang, Magdalena Ksiezarek, Edward Mead, Alan Touracheau, Wenyan Jiang, Martin J Blaser, Raphael H Valdivia, Gang Fang.

The human gut microbiome within the gastrointestinal tract continuously adapts to variations in diet, medications, and host physiology. A central strategy for genetic adaptation is epigenetic phase variation (ePV) mediated by bacterial DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, and enable a single bacterial strain to exhibit variable phenotypic states. Genome-wide and site-specific ePV have been well characterized in human pathogens' antigenic variation and virulence factor production. However, the role of ePV in facilitating adaptation within the human microbiome remains poorly understood. Here, we comprehensively cataloged genome-wide and site-specific ePV in human infant and adult gut microbiomes. First, using long-read metagenomic sequencing, we detected genome-wide ePV mediated by complex structural variations of DNA methyltransferases, highlighting the ones associated with antibiotics or fecal microbiota transplantation. Second, we analyzed an extensive collection of public short-read metagenomic sequencing datasets, uncovering a greater prevalence of genome-wide ePV in the human gut microbiome. Third, we quantitatively detected site-specific ePVs using single-molecule methylation analysis to identify dynamic variations associated with antibiotic treatment or probiotic engraftment. Finally, we performed an in-depth assessment of an Akkermansia muciniphila isolate from an infant, highlighting that ePV can regulate gene expression and enhance the bacterial adaptive capacity by employing a bet-hedging strategy to increase tolerance to differing antibiotics. Our findings indicate that epigenetic modifications are a common and broad strategy used by bacteria in the human gut to adapt to their environment.

DOI: https://doi.org/10.1101/2025.01.11.632565
Sci Adv. 2025 Jan 24. 11(4): eadu4369

Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.

Joshua S Stoolman, Rogan A Grant, Leah K Billingham, Taylor A Poor, Samuel E Weinberg, Madeline C Harding, Ziyan Lu, Jason Miska, Marten Szibor, Gr Scott Budinger, Navdeep S Chandel.

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.

DOI: https://doi.org/10.1126/sciadv.adu4369
STAR Protoc. 2025 Jan 16. pii: S2666-1667(24)00739-1. [Epub ahead of print]6(1): 103574

Protocol for identifying Mycobacterium tuberculosis infection status through airway microbiome profiling.

Geoffrey Olweny, Moses Levi Ntayi, Edward Kyalo, Alex Kayongo.

  This protocol describes the steps to determine an airway microbiome signature for identifying Mycobacterium tuberculosis infection status. We outline procedures for processing microbiome data, calculating diversity measures, and fitting Dirichlet multinomial mixture models. Additionally, we provide steps for analyzing taxonomic relative and differential abundances, as well as identifying potential biomarkers associated with infection status. For complete details on the use and execution of this protocol, please refer to Kayongo et al.1.

Keywords:  bioinformatics; immunology; microbiology

DOI:  https://doi.org/10.1016/j.xpro.2024.103574
Cell. 2025 Jan 16. pii: S0092-8674(24)01430-2. [Epub ahead of print]

Integration of 168,000 samples reveals global patterns of the human gut microbiome.

Richard J Abdill, Samantha P Graham, Vincent Rubinetti, Mansooreh Ahmadian, Parker Hicks, Ashwin Chetty, Daniel McDonald, Pamela Ferretti, Elizabeth Gibbons, Marco Rossi, Arjun Krishnan, Frank W Albert, Casey S Greene, Sean Davis, Ran Blekhman.

  The factors shaping human microbiome variation are a major focus of biomedical research. While other fields have used large sequencing compendia to extract insights requiring otherwise impractical sample sizes, the microbiome field has lacked a comparably sized resource for the 16S rRNA gene amplicon sequencing commonly used to quantify microbiome composition. To address this gap, we processed 168,464 publicly available human gut microbiome samples with a uniform pipeline. We use this compendium to evaluate geographic and technical effects on microbiome variation. We find that regions such as Central and Southern Asia differ significantly from the more thoroughly characterized microbiomes of Europe and Northern America and that composition alone can be used to predict a sample's region of origin. We also find strong associations between microbiome variation and technical factors such as primers and DNA extraction. We anticipate this growing work, the Human Microbiome Compendium, will enable advanced applied and methodological research.

Keywords:  16S rRNA amplicon sequencing; atlas; compendium; global variation; gut microbiome

DOI:  https://doi.org/10.1016/j.cell.2024.12.017
Mol Cancer. 2025 Jan 17. 24(1): 23

Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.

Peng Zhao, Shuangshuang Yin, Yuling Qiu, Changgang Sun, Haiyang Yu.

  Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.

Keywords:  Autophagy; CMA; Drug resistance; Ferritinophagy; Ferroptosis; Inflammation; LMP; Mitophagy; Pyroptosis; cGAS-STING

DOI:  https://doi.org/10.1186/s12943-024-02217-2