bims-bac4me 2023-05-28 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2023‒05‒28
29 papers selected by
Chun-Chi Chang
University Hospital Zurich

Regulation of short-chain fatty acids in the immune system.
Ursolic Acid Promotes Autophagy by Inhibiting Akt/mTOR and TNF-α/TNFR1 Signaling Pathways to Alleviate Pyroptosis and Necroptosis in Mycobacterium tuberculosis-Infected Macrophages.
Microbiota and epigenetics: Health impact.
Impact of the host microbiota on fungal infections: New possibilities for intervention?
Symbiotic microbiome Staphylococcus epidermidis restricts IL-33 production in allergic nasal epithelium via limiting the cellular necroptosis.
The development and function of human monocyte-derived dendritic cells regulated by metabolic reprogramming.
Co-infection of the respiratory epithelium, scene of complex functional interactions between viral, bacterial, and human neuraminidases.
Human oral lectin ZG16B acts as a cell wall polysaccharide probe to decode host-microbe interactions with oral commensals.
Macrophages in immunoregulation and therapeutics.
Epigenetic regulation of pulmonary inflammation.
Conditioning of the immune system by the microbiome.
Staphylococcus aureus persisters are associated with reduced clearance in a catheter-associated biofilm infection.
Gasdermin splicing.
β-Glucan Induces Training Immunity to Promote Antiviral Activity by Activating TBK1.
β-glucans: a potential source for maintaining gut microbiota and the immune system.
Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.
Discovery of phosphorylated lantibiotics with proimmune activity that regulate the oral microbiome.
Gene Expression Profiling of Classically Activated Macrophages in Leishmania infantum Infection: Response to Metabolic Pre-Stimulus with Itaconic Acid.
Future Modulation of Gut Microbiota: From Eubiotics to FMT, Engineered Bacteria, and Phage Therapy.
Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages.
Activation, Amplification, and Ablation as Dynamic Mechanisms of Dendritic Cell Maturation.
Modelling Microglial Innate Immune Memory In Vitro: Understanding the Role of Aerobic Glycolysis in Innate Immune Memory.
The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential.
The Influence of Gut Microbiota on Oxidative Stress and the Immune System.
Engineering bacteria to modulate host metabolism.
Monocyte Differentiation and Heterogeneity: Inter-Subset and Interindividual Differences.
Host protection by two memory-like MAIT subsets.
Magnetic-activated cell sorting identifies a unique lung microbiome community.
Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation.

Front Immunol. 2023 ;14 1186892

Regulation of short-chain fatty acids in the immune system.

Xiao-Feng Liu, Jia-Hao Shao, Yi-Tao Liao, Li-Ning Wang, Yuan Jia, Peng-Jun Dong, Zhi-Zhong Liu, Dan-Dan He, Chao Li, Xian Zhang.

  A growing body of research suggests that short-chain fatty acids (SCFAs), metabolites produced by intestinal symbiotic bacteria that ferment dietary fibers (DFs), play a crucial role in the health status of symbiotes. SCFAs act on a variety of cell types to regulate important biological processes, including host metabolism, intestinal function, and immune function. SCFAs also affect the function and fate of immune cells. This finding provides a new concept in immune metabolism and a better understanding of the regulatory role of SCFAs in the immune system, which impacts the prevention and treatment of disease. The mechanism by which SCFAs induce or regulate the immune response is becoming increasingly clear. This review summarizes the different mechanisms through which SCFAs act in cells. According to the latest research, the regulatory role of SCFAs in the innate immune system, including in NLRP3 inflammasomes, receptors of TLR family members, neutrophils, macrophages, natural killer cells, eosinophils, basophils and innate lymphocyte subsets, is emphasized. The regulatory role of SCFAs in the adaptive immune system, including in T-cell subsets, B cells, and plasma cells, is also highlighted. In addition, we discuss the role that SCFAs play in regulating allergic airway inflammation, colitis, and osteoporosis by influencing the immune system. These findings provide evidence for determining treatment options based on metabolic regulation.

Keywords:  G-protein-coupled receptor; adaptive immunity; histone deacetylase; innate immunity; short-chain fatty acid

DOI:  https://doi.org/10.3389/fimmu.2023.1186892
Inflammation. 2023 May 22.

Ursolic Acid Promotes Autophagy by Inhibiting Akt/mTOR and TNF-α/TNFR1 Signaling Pathways to Alleviate Pyroptosis and Necroptosis in Mycobacterium tuberculosis-Infected Macrophages.

Jingjing Shen, Yan Fu, Fanglin Liu, Bangzuo Ning, Xin Jiang.

  As a lethal infectious disease, tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Its complex pathophysiological process limits the effectiveness of many clinical treatments. By regulating host cell death, Mtb manipulates macrophages, the first line of defense against invading pathogens, to evade host immunity and promote the spread of bacteria and intracellular inflammatory substances to neighboring cells, resulting in widespread chronic inflammation and persistent lung damage. Autophagy, a metabolic pathway by which cells protect themselves, has been shown to fight intracellular microorganisms, such as Mtb, and they also play a crucial role in regulating cell survival and death. Therefore, host-directed therapy (HDT) based on antimicrobial and anti-inflammatory interventions is a pivotal adjunct to current TB treatment, enhancing anti-TB efficacy. In the present study, we showed that a secondary plant metabolite, ursolic acid (UA), inhibited Mtb-induced pyroptosis and necroptosis of macrophages. In addition, UA induced macrophage autophagy and enhanced intracellular killing of Mtb. To investigate the underlying molecular mechanisms, we explored the signaling pathways associated with autophagy as well as cell death. The results showed that UA could synergistically inhibit the Akt/mTOR and TNF-α/TNFR1 signaling pathways and promote autophagy, thus achieving its regulatory effects on pyroptosis and necroptosis of macrophages. Collectively, UA could be a potential adjuvant drug for host-targeted anti-TB therapy, as it could effectively inhibit pyroptosis and necroptosis of macrophages and counteract the excessive inflammatory response caused by Mtb-infected macrophages via modulating the host immune response, potentially improving clinical outcomes.

Keywords:  autophagy; host-directed therapy; mycobacterium tuberculosis; necroptosis; pyroptosis; ursolic acid

DOI:  https://doi.org/10.1007/s10753-023-01839-w
Prog Mol Biol Transl Sci. 2023 ;pii: S1877-1173(23)00077-7. [Epub ahead of print]198 93-117

Microbiota and epigenetics: Health impact.

Taruna Ahrodia, Bharti Kandiyal, Bhabatosh Das.

  Epigenetic changes associated with disease development and progressions are of increasing importance because of their potential diagnostic and therapeutic applications. Several epigenetic changes associated with chronic metabolic disorders have been studied in various diseases. Epigenetic changes are mostly modulated by environmental factors, including the human microbiota living in different parts of our bodies. The microbial structural components and the microbially derived metabolites directly interact with host cells, thereby maintaining homeostasis. Microbiome dysbiosis, on the other hand, is known to produce elevated levels of disease-linked metabolites, which may directly affect a host metabolic pathway or induce epigenetic changes that can lead to disease development. Despite their important role in host physiology and signal transduction, there has been little research into the mechanics and pathways associated with epigenetic modifications. This chapter focuses on the relationship between microbes and their epigenetic effects in diseased pathology, as well as on the regulation and metabolism of the dietary options available to the microbes. Furthermore, this chapter also provides a prospective link between these two important phenomena, termed "Microbiome and Epigenetics."

Keywords:  Cancer; Epigenetics; Metabolism; Microbiome; Non-coding RNAs; Regulation; Short-chain fatty acid (SCFAs)

DOI:  https://doi.org/10.1016/bs.pmbts.2023.03.018
Adv Drug Deliv Rev. 2023 May 19. pii: S0169-409X(23)00211-9. [Epub ahead of print]198 114896

Impact of the host microbiota on fungal infections: New possibilities for intervention?

Eve W L Chow, Li Mei Pang, Yue Wang.

  Many human fungal pathogens are opportunistic. They are primarily benign residents of the human body and only become infectious when the host's immunity and microbiome are compromised. Bacteria dominate the human microbiome, playing an essential role in keeping fungi harmless and acting as the first line of defense against fungal infection. The Human Microbiome Project, launched by NIH in 2007, has stimulated extensive investigation and significantly advanced our understanding of the molecular mechanisms governing the interaction between bacteria and fungi, providing valuable insights for developing future antifungal strategies by exploiting the interaction. This review summarizes recent progress in this field and discusses new possibilities and challenges. We must seize the opportunities presented by researching bacterial-fungal interplay in the human microbiome to address the global spread of drug-resistant fungal pathogens and the drying pipelines of effective antifungal drugs.

Keywords:  Antifungal therapy; Bacteria; Candida; Microbiome; Peptidoglycan; Quorum sensing molecules

DOI:  https://doi.org/10.1016/j.addr.2023.114896
BMC Microbiol. 2023 May 26. 23(1): 154

Symbiotic microbiome Staphylococcus epidermidis restricts IL-33 production in allergic nasal epithelium via limiting the cellular necroptosis.

Yung Jin Jeon, Chan Hee Gil, Jina Won, Ara Jo, Hyun Jik Kim.

  BACKGROUND: Allergic rhinitis (AR) is characterized by airway inflammation in nasal mucosa from inhaled allergens and interleukin (IL)-33 is the potent inducer of Th2 inflammation in allergic nasal epithelium. Staphylococcus epidermidis is one of the most abundant colonizers of the healthy human nasal mucosa and might impact the allergen-induced inflammatory responses in the nasal epithelium. Thus, we sought to characterize the mechanism of S. epidermidis regulating Th2 inflammation and IL-33 production in AR nasal mucosa.RESULTS: The AR symptoms were alleviated and eosinophilic infiltration, serum IgE levels, and Th2 cytokines were significantly decreased in OVA-sensitized AR mice in response to human nasal commensal S. epidermidis. The inoculation of S. epidermidis to normal human nasal epithelial cells reduced IL-33 and GATA3 transcriptions and also reduced IL-33 and GATA3 expression in AR nasal epithelial (ARNE) cells and the nasal mucosa of AR mice. Our data exhibited that the cellular necroptosis of ARNE cells might be involved in IL-33 production and inoculation of S. epidermidis decreased the phosphorylation of necroptosis enzymes in ARNE cells, which was related to the reduction of IL-33 production.
CONCLUSIONS: We present that human nasal commensal S. epidermidis reduces allergic inflammation by suppressing IL-33 production in nasal epithelium. Our findings indicate that S. epidermidis serves a role in blocking allergen-induced cellular necroptosis in allergic nasal epithelium which might be a key mechanism of reduction of IL-33 and Th2 inflammation.

Keywords:  Allergic rhinitis; Interleukin-33; Nasal epithelium; Necroptosis; Staphylococcus epidermidis

DOI:  https://doi.org/10.1186/s12866-023-02898-7
J Leukoc Biol. 2023 May 26. pii: qiad062. [Epub ahead of print]

The development and function of human monocyte-derived dendritic cells regulated by metabolic reprogramming.

Ying Zhao, Cuie Gao, Lu Liu, Li Wang, Zhiqiang Song.

  Human monocyte-derived dendritic cells (moDCs) develop from monocytes play a key role in innate inflammatory responses as well as T-cell priming. Steady-state moDCs regulate immunogenicity and tolerogenicity by changing metabolic patterns to participate in the body's immune response. Increased glycolytic (Gly) metabolism after danger signal induction may strengthen moDCs' immunogenicity, whereas high levels of mitochondrial oxidative phosphorylation (OXPHOS) were associated with the immaturity and tolerogenicity of moDCs. In this review, we will discuss what is currently known about differential metabolic reprogramming of human moDCs development and distinct functional properties.

Keywords:  glycolysis; immunogenicity; metabolism; moDCs; oxidative phosphorylation; tolerogenicity

DOI:  https://doi.org/10.1093/jleuko/qiad062
Front Microbiol. 2023 ;14 1137336

Co-infection of the respiratory epithelium, scene of complex functional interactions between viral, bacterial, and human neuraminidases.

Vanessa Escuret, Olivier Terrier.

  The activity of sialic acids, known to play critical roles in biology and many pathological processes, is finely regulated by a class of enzymes called sialidases, also known as neuraminidases. These are present in mammals and many other biological systems, such as viruses and bacteria. This review focuses on the very particular situation of co-infections of the respiratory epithelium, the scene of complex functional interactions between viral, bacterial, and human neuraminidases. This intrinsically multidisciplinary topic combining structural biology, biochemistry, physiology, and the study of host-pathogen interactions, opens up exciting research perspectives that could lead to a better understanding of the mechanisms underlying virus-bacteria co-infections and their contribution to the aggravation of respiratory pathology, notably in the context of pre-existing pathological contexts. Strategies that mimic or inhibit the activity of the neuraminidases could constitute interesting treatment options for viral and bacterial infections.

Keywords:  bacterial superinfections; co-infection; host-pathogen interactions; influenza viruses; neuraminidase (NA); paramyxoviruses; respiratory epithelium; sialic acids

DOI:  https://doi.org/10.3389/fmicb.2023.1137336
Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2216304120

Human oral lectin ZG16B acts as a cell wall polysaccharide probe to decode host-microbe interactions with oral commensals.

Soumi Ghosh, Christian P Ahearn, Christine R Isabella, Victoria M Marando, Gregory J Dodge, Helen Bartlett, Robert L McPherson, Amanda E Dugan, Shikha Jain, Lubov Neznanova, Hervé Tettelin, Rachel Putnik, Catherine L Grimes, Stefan Ruhl, Laura L Kiessling, Barbara Imperiali.

  The oral microbiome is critical to human health and disease, yet the role that host salivary proteins play in maintaining oral health is unclear. A highly expressed gene in human salivary glands encodes the lectin zymogen granule protein 16 homolog B (ZG16B). Despite the abundance of this protein, its interaction partners in the oral microbiome are unknown. ZG16B possesses a lectin fold, but whether it binds carbohydrates is unclear. We postulated that ZG16B would bind microbial glycans to mediate recognition of oral microbes. To this end, we developed a microbial glycan analysis probe (mGAP) strategy based on conjugating the recombinant protein to fluorescent or biotin reporter functionality. Applying the ZG16B-mGAP to dental plaque isolates revealed that ZG16B predominantly binds to a limited set of oral microbes, including Streptococcus mitis, Gemella haemolysans, and, most prominently, Streptococcus vestibularis. S. vestibularis is a commensal bacterium widely distributed in healthy individuals. ZG16B binds to S. vestibularis through the cell wall polysaccharides attached to the peptidoglycan, indicating that the protein is a lectin. ZG16B slows the growth of S. vestibularis with no cytotoxicity, suggesting that it regulates S. vestibularis abundance. The mGAP probes also revealed that ZG16B interacts with the salivary mucin MUC7. Analysis of S. vestibularis and MUC7 with ZG16B using super-resolution microscopy supports ternary complex formation that can promote microbe clustering. Together, our data suggest that ZG16B influences the compositional balance of the oral microbiome by capturing commensal microbes and regulating their growth using a mucin-assisted clearance mechanism.

Keywords:  cell wall polysaccharides; glycan analysis probe; human soluble lectins; microbial glycans; oral microbiota

DOI:  https://doi.org/10.1073/pnas.2216304120
Signal Transduct Target Ther. 2023 May 22. 8(1): 207

Macrophages in immunoregulation and therapeutics.

Shanze Chen, Abdullah F U H Saeed, Quan Liu, Qiong Jiang, Haizhao Xu, Gary Guishan Xiao, Lang Rao, Yanhong Duo.

Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

DOI: https://doi.org/10.1038/s41392-023-01452-1
Semin Cell Dev Biol. 2023 May 23. pii: S1084-9521(23)00112-X. [Epub ahead of print]

Epigenetic regulation of pulmonary inflammation.

Shama Ahmad, Xiao Lu Zhang, Aftab Ahmad.

  Pulmonary disease such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and pulmonary hypertension are the leading cause of deaths. More importantly, lung diseases are on the rise and environmental factors induced epigenetic modifications are major players on this increased prevalence. It has been reported that dysregulation of genes involved in epigenetic regulation such as the histone deacetylase (HDACs) and histone acetyltransferase (HATs) play important role in lung health and pulmonary disease pathogenesis. Inflammation is an essential component of respiratory diseases. Injury and inflammation trigger release of extracellular vesicles that can act as epigenetic modifiers through transfer of epigenetic regulators such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins and lipids, from one cell to another. The immune dysregulations caused by the cargo contents are important contributors of respiratory disease pathogenesis. N6 methylation of RNA is also emerging to be a critical mechanism of epigenetic alteration and upregulation of immune responses to environmental stressors. Epigenetic changes such as DNA methylation are stable and often long term and cause onset of chronic lung conditions. These epigenetic pathways are also being utilized for therapeutic intervention in several lung conditions.

Keywords:  Epigenetics; Exosomes; Lung; Pulmonary disease; Therapies

DOI:  https://doi.org/10.1016/j.semcdb.2023.05.003
Trends Immunol. 2023 May 24. pii: S1471-4906(23)00083-2. [Epub ahead of print]

Conditioning of the immune system by the microbiome.

Daniel B Graham, Ramnik J Xavier.

The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. Thus, it is an opportune time to conceive a common framework for microbiome-mediated regulation of immune function. We propose the term conditioned immunity to describe the multifaceted mechanisms by which the microbiome modulates immunity. In this regard, microbial colonization is a conditioning exposure that has durable effects on immune function through the action of secondary metabolites, foreign molecular patterns, and antigens. Here, we discuss how spatial niches impact host exposure to microbial products at the level of dose and timing, which elicit diverse conditioned responses.

DOI: https://doi.org/10.1016/j.it.2023.05.002
Front Cell Infect Microbiol. 2023 ;13 1178526

Staphylococcus aureus persisters are associated with reduced clearance in a catheter-associated biofilm infection.

Trenten J Theis, Trevor A Daubert, Kennedy E Kluthe, Kenan L Brodd, Austin S Nuxoll.

  Background: Staphylococcus aureus causes a wide variety of infections, many of which are chronic or relapsing in nature. Antibiotic therapy is often ineffective against S. aureus biofilm-mediated infections. Biofilms are difficult to treat partly due to their tolerance to antibiotics, however the underlying mechanism responsible for this remains unknown. One possible explanation is the presence of persister cells-dormant-like cells that exhibit tolerance to antibiotics. Recent studies have shown a connection between a fumC (fumarase C, a gene in the tricarboxylic acid cycle) knockout strain and increased survival to antibiotics, antimicrobial peptides, and in a Drosophila melanogaster model.Objective: It remained unclear whether a S. aureus high persister strain would have a survival advantage in the presence of innate and adaptive immunity. To further investigate this, a fumC knockout and wild type strains were examined in a murine catheter-associated biofilm model.
Results: Interestingly, mice struggled to clear both S. aureus wild type and the fumC knockout strains. We reasoned both biofilm-mediated infections predominantly consisted of persister cells. To determine the persister cell population within biofilms, expression of a persister cell marker (Pcap5A::dsRED) in a biofilm was examined. Cell sorting of biofilms challenged with antibiotics revealed cells with intermediate and high expression of cap5A had 5.9-and 4.5-fold higher percent survival compared to cells with low cap5A expression. Based on previous findings that persisters are associated with reduced membrane potential, flow cytometry analysis was used to examine the metabolic state of cells within a biofilm. We confirmed cells within biofilms had reduced membrane potential compared to both stationary phase cultures (2.5-fold) and exponential phase cultures (22.4-fold). Supporting these findings, cells within a biofilm still exhibited tolerance to antibiotic challenge following dispersal of the matrix through proteinase K.
Conclusion: Collectively, these data show that biofilms are largely comprised of persister cells, and this may explain why biofilm infections are often chronic and/or relapsing in clinical settings.

Keywords:  Staphylococcus aureus; TCA cycle; antibiotic tolerance; biofilm; persister

DOI:  https://doi.org/10.3389/fcimb.2023.1178526
Nat Immunol. 2023 May 22.

Gasdermin splicing.

Nicholas J Bernard.

DOI: https://doi.org/10.1038/s41590-023-01533-x
Viruses. 2023 May 19. pii: 1204. [Epub ahead of print]15(5):

β-Glucan Induces Training Immunity to Promote Antiviral Activity by Activating TBK1.

Guolei Wang, Zhiqiang Li, Mingfu Tian, Xianghua Cui, Jun'e Ma, Siyu Liu, Chenglin Ye, Li Yuan, Muhammad Suhaib Qudus, Uzair Afaq, Kailang Wu, Xinghui Liu, Chengliang Zhu.

  Many studies have shown that β-glucan induces a trained immune phenotype in innate immune cells to defend against bacterial and fungal infections. The specific mechanism involves cellular metabolism and epigenetic reprogramming. However, it is unclear whether β-glucan plays a role in antiviral infection. Therefore, this study investigated the role of trained immunity induced by Candida albicans and β-glucan in antiviral innate immunity. It showed that C. albicans and β-glucan promoted the expression of interferon-β (IFN-β) and interleukin-6 (IL-6) in mouse macrophages triggered by viral infection. In addition, β-glucan pretreatment attenuated the pathological damage induced by the virus in mouse lungs and promoted the expression of IFN-β. Mechanistically, β-glucan could promote the phosphorylation and ubiquitination of TANK Binding Kinase 1 (TBK1), a key protein of the innate immune pathway. These results suggest that β-glucan can promote innate antiviral immunity, and this bioactive material may be a potential therapeutic target for antiviral treatment.

Keywords:  TBK1; innate immunity; trained immunity; ubiquitination

DOI:  https://doi.org/10.3390/v15051204
Front Nutr. 2023 ;10 1143682

β-glucans: a potential source for maintaining gut microbiota and the immune system.

Ravindra Pal Singh, Aditi Bhardwaj.

  The human gastrointestinal (GI) tract holds a complex and dynamic population of microbial communities, which exerts a marked influence on the host physiology during homeostasis and disease conditions. Diet is considered one of the main factors in structuring the gut microbiota across a lifespan. Intestinal microbial communities play a vital role in sustaining immune and metabolic homeostasis as well as protecting against pathogens. The negatively altered gut bacterial composition has related to many inflammatory diseases and infections. β-glucans are a heterogeneous assemblage of glucose polymers with a typical structure comprising a leading chain of β-(1,4) and/or β-(1,3)-glucopyranosyl units with various branches and lengths as a side chain. β-glucans bind to specific receptors on immune cells and initiate immune responses. However, β-glucans from different sources differ in their structures, conformation, physical properties, and binding affinity to receptors. How these properties modulate biological functions in terms of molecular mechanisms is not known in many examples. This review provides a critical understanding of the structures of β-glucans and their functions for modulating the gut microbiota and immune system.

Keywords:  Bacteroides; Bifidobacterium; gut microbiota; immune system; β-glucans

DOI:  https://doi.org/10.3389/fnut.2023.1143682
Front Immunol. 2023 ;14 1125984

Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.

Lidia Feo-Lucas, Cristina Godio, María Minguito de la Escalera, Natalia Alvarez-Ladrón, Laura H Villarrubia, Adrián Vega-Pérez, Leticia González-Cintado, Jorge Domínguez-Andrés, Belén García-Fojeda, Carlos Montero-Fernández, Cristina Casals, Chiara Autilio, Jesús Pérez-Gil, Georgiana Crainiciuc, Andrés Hidalgo, María López-Bravo, Carlos Ardavín.

  Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

Keywords:  airway allergy inflammation; allergic asthma; alveolar dysfunction; alveolar macrophages (AM); monocytes; pneumocyte hypertrophy; surfactant dysfunction

DOI:  https://doi.org/10.3389/fimmu.2023.1125984
Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2219392120

Discovery of phosphorylated lantibiotics with proimmune activity that regulate the oral microbiome.

Abdelahhad Barbour, Leif Smith, Morvarid Oveisi, McKinley Williams, Ruo Chen Huang, Cara Marks, Noah Fine, Chunxiang Sun, Fereshteh Younesi, Sina Zargaran, Ravi Orugunty, Thomas D Horvath, Sigmund J Haidacher, Anthony M Haag, Amarpreet Sabharwal, Boris Hinz, Michael Glogauer.

  Lantibiotics are ribosomally synthesized and posttranslationally modified peptides (RiPPs) that are produced by bacteria. Interest in this group of natural products is increasing rapidly as alternatives to conventional antibiotics. Some human microbiome-derived commensals produce lantibiotics to impair pathogens' colonization and promote healthy microbiomes. Streptococcus salivarius is one of the first commensal microbes to colonize the human oral cavity and gastrointestinal tract, and its biosynthesis of RiPPs, called salivaricins, has been shown to inhibit the growth of oral pathogens. Herein, we report on a phosphorylated class of three related RiPPs, collectively referred to as salivaricin 10, that exhibit proimmune activity and targeted antimicrobial properties against known oral pathogens and multispecies biofilms. Strikingly, the immunomodulatory activities observed include upregulation of neutrophil-mediated phagocytosis, promotion of antiinflammatory M2 macrophage polarization, and stimulation of neutrophil chemotaxis-these activities have been attributed to the phosphorylation site identified on the N-terminal region of the peptides. Salivaricin 10 peptides were determined to be produced by S. salivarius strains found in healthy human subjects, and their dual bactericidal/antibiofilm and immunoregulatory activity may provide new means to effectively target infectious pathogens while maintaining important oral microbiota.

Keywords:  antibiofilm; immunomodulation; lantibiotics; oral microbiome; phosphorylated lanthipeptides

DOI:  https://doi.org/10.1073/pnas.2219392120
Trop Med Infect Dis. 2023 May 03. pii: 264. [Epub ahead of print]8(5):

Gene Expression Profiling of Classically Activated Macrophages in Leishmania infantum Infection: Response to Metabolic Pre-Stimulus with Itaconic Acid.

Génesis Palacios, Elva Vega-García, Basilio Valladares, José Antonio Pérez, Roberto Dorta-Guerra, Emma Carmelo.

  Leishmania infection of phagocytic cells, such as macrophages, induces the differentiation of infected cells into different phenotypes according to their surrounding microenvironments. The classical activation of macrophages involves metabolic reprogramming, in which several metabolites such as succinate, fumarate and itaconate are accumulated. The immunoregulatory functions of itaconate in the context of Leishmania infection were investigated in this paper. Ex vivo bone marrow-derived macrophages were differentiated into classically activated macrophages through IFNG activation and infection with Leishmania infantum. A high-throughput real-time qPCR experiment was designed for the analyses of 223 genes involved in immune response and metabolism. The transcriptional profile of classically activated macrophages revealed the enrichment of the IFNG response pathways and the upregulation of genes such as Cxcl9, Irf1, Acod1, Il12b, Il12rb1, Nos2 or Stat1. In vitro pre-stimulation with itaconate induced a loss of the parasite control and the upregulation of genes related to local acute inflammatory response. Our results reveal that itaconate accumulation dampened classically activated macrophage antiparasitic activity, and this is reflected by the differential expression of the Il12b, Icosl and Mki67 genes. The possibility of inducing parasite-killing responses in the host through metabolic reprograming is an interesting approach for the treatment of Leishmania infections that will undoubtedly attract increasing attention in the coming years.

Keywords:  Leishmania infantum; classically activated macrophages; gene expression profiling; itaconate; macrophage activation; metabolic stimulus

DOI:  https://doi.org/10.3390/tropicalmed8050264
Antibiotics (Basel). 2023 May 08. pii: 868. [Epub ahead of print]12(5):

Future Modulation of Gut Microbiota: From Eubiotics to FMT, Engineered Bacteria, and Phage Therapy.

Carlo Airola, Andrea Severino, Serena Porcari, William Fusco, Benjamin H Mullish, Antonio Gasbarrini, Giovanni Cammarota, Francesca Romana Ponziani, Gianluca Ianiro.

  The human gut is inhabited by a multitude of bacteria, yeasts, and viruses. A dynamic balance among these microorganisms is associated with the well-being of the human being, and a large body of evidence supports a role of dysbiosis in the pathogenesis of several diseases. Given the importance of the gut microbiota in the preservation of human health, probiotics, prebiotics, synbiotics, and postbiotics have been classically used as strategies to modulate the gut microbiota and achieve beneficial effects for the host. Nonetheless, several molecules not typically included in these categories have demonstrated a role in restoring the equilibrium among the components of the gut microbiota. Among these, rifaximin, as well as other antimicrobial drugs, such as triclosan, or natural compounds (including evodiamine and polyphenols) have common pleiotropic characteristics. On one hand, they suppress the growth of dangerous bacteria while promoting beneficial bacteria in the gut microbiota. On the other hand, they contribute to the regulation of the immune response in the case of dysbiosis by directly influencing the immune system and epithelial cells or by inducing the gut bacteria to produce immune-modulatory compounds, such as short-chain fatty acids. Fecal microbiota transplantation (FMT) has also been investigated as a procedure to restore the equilibrium of the gut microbiota and has shown benefits in many diseases, including inflammatory bowel disease, chronic liver disorders, and extraintestinal autoimmune conditions. One of the most significant limits of the current techniques used to modulate the gut microbiota is the lack of tools that can precisely modulate specific members of complex microbial communities. Novel approaches, including the use of engineered probiotic bacteria or bacteriophage-based therapy, have recently appeared as promising strategies to provide targeted and tailored therapeutic modulation of the gut microbiota, but their role in clinical practice has yet to be clarified. The aim of this review is to discuss the most recently introduced innovations in the field of therapeutic microbiome modulation.

Keywords:  dysbiosis; eubiotics; fecal microbiota transplant; microbiota; phage therapy; rifaximin

DOI:  https://doi.org/10.3390/antibiotics12050868
Biomolecules. 2023 Apr 29. pii: 770. [Epub ahead of print]13(5):

Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages.

Alex Cornwell, Hubert Ziółkowski, Alireza Badiei.

  This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using siRNA to knock down Glut1 reduces the expression of various pro-inflammatory cytokines and markers, such as IL-6, iNOS, MHC II/CD40, reactive oxygen species, and the hydrogen sulfide (H2S)-producing enzyme cystathionine γ-lyase (CSE). Glut1 activates a pro-inflammatory profile through a nuclear factor (NF)-κB, while silencing Glut1 can prevent lipopolysaccharide (LPS)-induced IκB degradation, blocking NF-κB activation. Glut1's role in autophagy, an essential process for macrophage functions such as antigen presentation, phagocytosis, and cytokine secretion, was also measured. The findings show that LPS stimulation decreases autophagosome formation, but Glut1 knockdown reverses this effect, increasing autophagy beyond control levels. The study highlights Glut1's importance in macrophage immune responses and its regulation of apoptosis during LPS stimulation. Knocking down Glut1 negatively impacts cell viability and mitochondrial intrinsic pathway signaling. These findings collectively suggest that targeting macrophage glucose metabolism through Glut1 could potentially serve as a target for controlling inflammation.

Keywords:  Glut 1; autophagy; hydrogen sulfide; inflammation; macrophage

DOI:  https://doi.org/10.3390/biom13050770
Biology (Basel). 2023 May 14. pii: 716. [Epub ahead of print]12(5):

Activation, Amplification, and Ablation as Dynamic Mechanisms of Dendritic Cell Maturation.

Jessica Bourque, Daniel Hawiger.

  T cell responses to cognate antigens crucially depend on the specific functionality of dendritic cells (DCs) activated in a process referred to as maturation. Maturation was initially described as alterations of the functional status of DCs in direct response to multiple extrinsic innate signals derived from foreign organisms. More recent studies, conducted mainly in mice, revealed an intricate network of intrinsic signals dependent on cytokines and various immunomodulatory pathways facilitating communication between individual DCs and other cells for the orchestration of specific maturation outcomes. These signals selectively amplify the initial activation of DCs mediated by innate factors and dynamically shape DC functionalities by ablating DCs with specific functions. Here, we discuss the effects of the initial activation of DCs that crucially includes the production of cytokine intermediaries to collectively achieve amplification of the maturation process and further precise sculpting of the functional landscapes among DCs. By emphasizing the interconnectedness of the intracellular and intercellular mechanisms, we reveal activation, amplification, and ablation as the mechanistically integrated components of the DC maturation process.

Keywords:  dendritic cells; immunity; maturation; tolerance

DOI:  https://doi.org/10.3390/biology12050716
Int J Mol Sci. 2023 May 18. pii: 8967. [Epub ahead of print]24(10):

Modelling Microglial Innate Immune Memory In Vitro: Understanding the Role of Aerobic Glycolysis in Innate Immune Memory.

Morgan Towriss, Brian MacVicar, Annie Vogel Ciernia.

  Microglia, the resident macrophages of the central nervous system, play important roles in maintaining brain homeostasis and facilitating the brain's innate immune responses. Following immune challenges microglia also retain immune memories, which can alter responses to secondary inflammatory challenges. Microglia have two main memory states, training and tolerance, which are associated with increased and attenuated expression of inflammatory cytokines, respectively. However, the mechanisms differentiating these two distinct states are not well understood. We investigated mechanisms underlying training versus tolerance memory paradigms in vitro in BV2 cells using B-cell-activating factor (BAFF) or bacterial lipopolysaccharide (LPS) as a priming stimulus followed by LPS as a second stimulus. BAFF followed by LPS showed enhanced responses indicative of priming, whereas LPS followed by LPS as the second stimulus caused reduced responses suggestive of tolerance. The main difference between the BAFF versus the LPS stimulus was the induction of aerobic glycolysis by LPS. Inhibiting aerobic glycolysis during the priming stimulus using sodium oxamate prevented the establishment of the tolerized memory state. In addition, tolerized microglia were unable to induce aerobic glycolysis upon LPS restimulus. Therefore, we conclude that aerobic glycolysis triggered by the first LPS stimulus was a critical step in the induction of innate immune tolerance.

Keywords:  BV2; DOHaD; innate immune memory; metabolism; microglia; tolerance; training

DOI:  https://doi.org/10.3390/ijms24108967
Curr Issues Mol Biol. 2023 May 11. 45(5): 4228-4245

The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential.

Mohammed Ghiboub, Matthew Bell, Dovile Sinkeviciute, Rab K Prinjha, Menno P J de Winther, Nicola R Harker, David F Tough, Wouter J de Jonge.

  SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.

Keywords:  GSK761; SP140; dendritic cells; maturation; tolerogenic potential

DOI:  https://doi.org/10.3390/cimb45050269
Biomedicines. 2023 May 08. pii: 1388. [Epub ahead of print]11(5):

The Influence of Gut Microbiota on Oxidative Stress and the Immune System.

Claudia Kunst, Stephan Schmid, Marlen Michalski, Deniz Tümen, Jonas Buttenschön, Martina Müller, Karsten Gülow.

  The human gastrointestinal tract is home to a complex microbial community that plays an important role in the general well-being of the entire organism. The gut microbiota generates a variety of metabolites and thereby regulates many biological processes, such as the regulation of the immune system. In the gut, bacteria are in direct contact with the host. The major challenge here is to prevent unwanted inflammatory reactions on one hand and on the other hand to ensure that the immune system can be activated when pathogens invade. Here the REDOX equilibrium is of utmost importance. This REDOX equilibrium is controlled by the microbiota either directly or indirectly via bacterial-derived metabolites. A balanced microbiome sorts for a stable REDOX balance, whereas dysbiosis destabilizes this equilibrium. An imbalanced REDOX status directly affects the immune system by disrupting intracellular signaling and promoting inflammatory responses. Here we (i) focus on the most common reactive oxygen species (ROS) and (ii) define the transition from a balanced REDOX state to oxidative stress. Further, we (iii) describe the role of ROS in regulating the immune system and inflammatory responses. Thereafter, we (iv) examine the influence of microbiota on REDOX homeostasis and how shifts in pro- and anti-oxidative cellular conditions can suppress or promote immune responses or inflammation.

Keywords:  REDOX; dysbiosis; inflammation; intestine; microbiome; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/biomedicines11051388
Acta Physiol (Oxf). 2023 May 24. e14001

Engineering bacteria to modulate host metabolism.

Dragos Ciocan, Eran Elinav.

  The microbial community of the gut, collectively termed the gut microbiota, modulates both host metabolism and disease development in a variety of clinical contexts. The microbiota can have detrimental effects and be involved in disease development and progression, but it can also offer benefits to the host. This has led in the last years to the development of different therapeutic strategies targeting the microbiota. In this review we will focus on one of these strategies that involves the use of engineered bacteria to modulate gut microbiota in the treatment of metabolic disorders. We will discuss the recent developments and challenges in the use of these bacterial strains with an emphasis on their use for the treatment of metabolic diseases.

Keywords:  engineered bacteria; metabolic diseases; synthetic biology; synthetic live therapy

DOI:  https://doi.org/10.1111/apha.14001
Int J Mol Sci. 2023 May 15. pii: 8757. [Epub ahead of print]24(10):

Monocyte Differentiation and Heterogeneity: Inter-Subset and Interindividual Differences.

Helen Williams, Corinne Mack, Rana Baraz, Rekha Marimuthu, Sravanthi Naralashetty, Stephen Li, Heather Medbury.

  The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies have revealed that monocyte heterogeneity is multi-dimensional. In addition, that their phenotype and function differ between subsets is well established. However, it is becoming evident that heterogeneity also exists within each subset, between health and disease (current or past) states, and even between individuals. This realisation casts long shadows, impacting how we identify and classify the subsets, the functions we assign to them, and how they are examined for alterations in disease. Perhaps the most fascinating is evidence that, even in relative health, interindividual differences in monocyte subsets exist. It is proposed that the individual's microenvironment could cause long-lasting or irreversible changes to monocyte precursors that echo to monocytes and through to their derived macrophages. Here, we will discuss the types of heterogeneity recognised in monocytes, the implications of these for monocyte research, and most importantly, the relevance of this heterogeneity for health and disease.

Keywords:  differentiation; heterogeneity; inflammation; lipid; monocyte; monocyte subsets; trained immunity

DOI:  https://doi.org/10.3390/ijms24108757
Nat Cell Biol. 2023 May 25.

Host protection by two memory-like MAIT subsets.

Margarita Dominguez-Villar.

DOI: https://doi.org/10.1038/s41556-023-01149-1
Microbiome. 2023 05 25. 11(1): 117

Magnetic-activated cell sorting identifies a unique lung microbiome community.

Daniel G Dunlap, Libing Yang, Shulin Qin, Kelvin Li, Adam Fitch, Laurence Huang, Bryan J McVerry, Timothy W Hand, Barbara A Methé, Alison Morris.

  BACKGROUND: The advent of culture-independent, next-generation DNA sequencing has led to the discovery of distinct lung bacterial communities. Studies of lung microbiome taxonomy often reveal only subtle differences between health and disease, but host recognition and response may distinguish the members of similar bacterial communities in different populations. Magnetic-activated cell sorting has been applied to the gut microbiome to identify the numbers and types of bacteria eliciting a humoral response. We adapted this technique to examine the populations of immunoglobulin-bound bacteria in the lung.METHODS: Sixty-four individuals underwent bronchoalveolar lavage (BAL). We separated immunoglobulin G-bound bacteria using magnetic-activated cell sorting and sequenced the 16S rRNA gene on the Illumina MiSeq platform. We compared microbial sequencing data in IgG-bound bacterial communities compared to raw BAL then examined the differences in individuals with and without HIV as a representative disease state.
RESULTS: Immunoglobulin G-bound bacteria were identified in all individuals. The community structure differed when compared to raw BAL, and there was a greater abundance of Pseudomonas and fewer oral bacteria in IgG-bound BAL. Examination of IgG-bound communities in individuals with HIV demonstrated the differences in Ig-bound bacteria by HIV status that were not seen in a comparison of raw BAL, and greater numbers of immunoglobulin-bound bacteria were associated with higher pulmonary cytokine levels.
CONCLUSIONS: We report a novel application of magnetic-activated cell sorting to identify immunoglobulin G-bound bacteria in the lung. This technique identified distinct bacterial communities which differed in composition from raw bronchoalveolar lavage, revealing the differences not detected by traditional analyses. Cytokine response was also associated with differential immunoglobulin binding of lung bacteria, suggesting the functional importance of these communities. Video Abstract.

Keywords:  Host response; Immunoglobulin; Microbiome

DOI:  https://doi.org/10.1186/s40168-022-01434-5
J Autoimmun. 2023 May 20. pii: S0896-8411(23)00057-4. [Epub ahead of print]138 103048

Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation.

Xiaomin Zhang, Juan Liu, Yujie Cheng, Kun Chen, Yali Chen, Ha Zhu, Zhiqing Li, Shuxun Liu, Xuetao Cao.

  Metabolic reprogramming plays a pivotal role in the differentiation and function of immune cells including dendritic cells (DCs). Regulatory DCs can be generated in regional tissue niches like splenic stroma and act as an important part of stromal control of immune response for the maintenance of immune tolerance. However, the metabolic alterations during splenic stroma-driven regulatory DCs differentiation and the metabolic enzyme involved in regulatory DCs function remain poorly understood. By combining metabolomic, transcriptomic, and functional investigations of mature DCs (maDCs) and diffDCs (regulatory DCs differentiated from activated mature DCs through coculturing with splenic stroma), here we identified succinate-CoA ligase subunit beta Suclg2 as a key metabolic enzyme that reprograms the proinflammatory status of mature DCs into a tolerogenic phenotype via preventing NF-κB signaling activation. diffDCs downregulate succinic acid levels and increase the Suclg2 expression along with their differentiation from mature DCs. Suclg2-interference impaired the tolerogenic function of diffDCs in inducing T cell apoptosis and enhanced activation of NF-κB signaling and expression of inflammatory genes CD40, Ccl5, and Il12b in diffDCs. Furthermore, we identified Lactb as a new positive regulator of NF-κB signaling in diffDCs whose succinylation at the lysine 288 residue was inhibited by Suclg2. Our study reveals that the metabolic enzyme Suclg2 is required to maintain the immunoregulatory function of diffDCs, adding mechanistic insights into the metabolic regulation of DC-based immunity and tolerance.

Keywords:  Lactb; Metabolic reprogramming; Regulatory dendritic cells; Succinic acid; Succinylation; Suclg2; T cell apoptosis; diffDCs

DOI:  https://doi.org/10.1016/j.jaut.2023.103048