bims-bac4me 2024-06-16 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒06‒16
27 papers selected by
Chun-Chi Chang, University Hospital Zurich

Heart failure affects innate immune memory.
The human lung microbiome-A hidden link between microbes and human health and diseases.
Contributions of the microbiota to the systemic inflammatory response.
Commensal E. coli limits Salmonella gut invasion during inflammation by producing toxin-bound siderophores in a tonB-dependent manner.
Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics.
Saccharomyces cerevisiae β-glucan improves the response of trained macrophages to severe P. aeruginosa infections.
Primary infection enhances neutrophil-mediated host defense by educating HSPCs.
Nutrient acquisition strategies by gut microbes.
Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.
Immunocompetent Intestine-on-Chip Model for Analyzing Gut Mucosal Immune Responses.
Mechanisms of bacterial immunity, protection, and survival during interbacterial warfare.
Regulatory mechanisms of amino acids in ferroptosis.
Bacterial esterases reverse lipopolysaccharide ubiquitylation to block host immunity.
Exploring the interaction and impact of probiotic and commensal bacteria on vitamins, minerals and short chain fatty acids metabolism.
Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms.
SIRT3-mediated OPA1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization.
The role of HMGB1 on SiC NPs-induced inflammation response in lung epithelial-macrophage co-culture system.
Editorial: Reviews in microbiome in health & disease.
The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway.
Metabolomics analysis of bronchoalveolar lavage fluid predicts unique features of the lower airway in pediatric cystic fibrosis.
Nemo mRNA vaccination improves airway barrier function in mice with airway allergy.
Fine-tuning of mononuclear phagocytes for improved inflammatory responses: role of soybean-derived immunomodulatory compounds.
A Lactobacillus Combination Ameliorates Lung Inflammation in an Elastase/LPS-induced Mouse Model of Chronic Obstructive Pulmonary Disease.
Understanding Staphylococcus aureus in hyperglycaemia: A review of virulence factor and metabolic adaptations.
Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.
ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.

Nat Rev Immunol. 2024 Jun 11.

Heart failure affects innate immune memory.

Alexandra Flemming.

DOI: https://doi.org/10.1038/s41577-024-01054-0
Imeta. 2022 Sep;1(3): e33

The human lung microbiome-A hidden link between microbes and human health and diseases.

Xinzhu Yi, Jingyuan Gao, Zhang Wang.

  Once thought to be sterile, the human lung is now well recognized to harbor a consortium of microorganisms collectively known as the lung microbiome. The lung microbiome is altered in an array of lung diseases, including chronic lung diseases such as chronic obstructive pulmonary disease, asthma, and bronchiectasis, acute lung diseases caused by pneumonia, sepsis, and COVID-19, and other lung complications such as those related to lung transplantation, lung cancer, and human immunodeficiency virus. The effects of lung microbiome in modulating host immunity and inflammation in the lung and distal organs are being elucidated. However, the precise mechanism by which members of microbiota produce structural ligands that interact with host genes and pathways remains largely uncharacterized. Multiple unique challenges, both technically and biologically, exist in the field of lung microbiome, necessitating the development of tailored experimental and analytical approaches to overcome the bottlenecks. In this review, we first provide an overview of the principles and methodologies in studying the lung microbiome. We next review current knowledge of the roles of lung microbiome in human diseases, highlighting mechanistic insights. We finally discuss critical challenges in the field and share our thoughts on broad topics for future investigation.

Keywords:  gut–lung axis; lung microbiome; microbiome–host interaction; respiratory diseases

DOI:  https://doi.org/10.1002/imt2.33
Microbiota Host. 2023 Feb;pii: e230018. [Epub ahead of print]1(1):

Contributions of the microbiota to the systemic inflammatory response.

Josey Muske, Kathryn Knoop.

The health of the intestinal microbiota impacts tolerance at homeostasis and the strength of the inflammation response during acute bloodstream infections. A complete understanding of the feedback loop between systemic inflammation and dysregulation of the gut microbiota is necessary for inflammation management. Here we will review the many ways in which the microbiota can influence the systemic pro-inflammatory response. Short-chain fatty acids, produced through the microbial metabolism of dietary fibers, can suppress inflammation systemically; in the absence of a balanced diet or disruption of the microbiota through antibiotics, there is disrupted metabolite production, leading to systemic inflammation. Dysbiosis or inflammation in the intestines can lead to a breakdown of the sturdy intestinal-epithelial barrier. When this barrier is perturbed, immunogenic lipopolysaccharides or extracellular vesicles enter the bloodstream and induce excessive inflammation. Necessary clinical treatments, such as antifungals or antibacterials, induce microbiota dysregulation and thus increased risk of endotoxemia; though probiotics may aid in improving the microbiota health and have been shown to deflate inflammation during sepsis. Within this complicated relationship: What is in control, the dysbiotic microbiota or the systemic inflammation?

DOI: https://doi.org/10.1530/mah-23-0018
PLoS Biol. 2024 Jun;22(6): e3002616

Commensal E. coli limits Salmonella gut invasion during inflammation by producing toxin-bound siderophores in a tonB-dependent manner.

Yassine Cherrak, Miguel Angel Salazar, Koray Yilmaz, Markus Kreuzer, Wolf-Dietrich Hardt.

The gastrointestinal tract is densely colonized by a polymicrobial community known as the microbiota which serves as primary line of defence against pathogen invasion. The microbiota can limit gut-luminal pathogen growth at different stages of infection. This can be traced to specific commensal strains exhibiting direct or indirect protective functions. Although these mechanisms hold the potential to develop new approaches to combat enteric pathogens, they remain far from being completely described. In this study, we investigated how a mouse commensal Escherichia coli can outcompete Salmonella enterica serovar Typhimurium (S. Tm). Using a salmonellosis mouse model, we found that the commensal E. coli 8178 strain relies on a trojan horse trap strategy to limit S. Tm expansion in the inflamed gut. Combining mutants and reporter tools, we demonstrated that inflammation triggers the expression of the E. coli 8178 antimicrobial microcin H47 toxin which, when fused to salmochelin siderophores, can specifically alter S. Tm growth. This protective function was compromised upon disruption of the E. coli 8178 tonB-dependent catecholate siderophore uptake system, highlighting a previously unappreciated crosstalk between iron intake and microcin H47 activity. By identifying the genetic determinants mediating S. Tm competition, our work not only provides a better mechanistic understanding of the protective function displayed by members of the gut microbiota but also further expands the general contribution of microcins in bacterial antagonistic relationships. Ultimately, such insights can open new avenues for developing microbiota-based approaches to better control intestinal infections.

DOI: https://doi.org/10.1371/journal.pbio.3002616
Cell Host Microbe. 2024 Jun 12. pii: S1931-3128(24)00139-2. [Epub ahead of print]32(6): 852-862

Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics.

Sophie Helaine, Brian P Conlon, Kimberly M Davis, David G Russell.

Antibiotic resistance, typically associated with genetic changes within a bacterial population, is a frequent contributor to antibiotic treatment failures. Antibiotic persistence and tolerance, which we collectively term recalcitrance, represent transient phenotypic changes in the bacterial population that prolong survival in the presence of typically lethal concentrations of antibiotics. Antibiotic recalcitrance is challenging to detect and investigate-traditionally studied under in vitro conditions, our understanding during infection and its contribution to antibiotic failure is limited. Recently, significant progress has been made in the study of antibiotic-recalcitrant populations in pathogenic species, including Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica, and Yersiniae, in the context of the host environment. Despite the diversity of these pathogens and infection models, shared signals and responses promote recalcitrance, and common features and vulnerabilities of persisters and tolerant bacteria have emerged. These will be discussed here, along with progress toward developing therapeutic interventions to better treat recalcitrant pathogens.

DOI: https://doi.org/10.1016/j.chom.2024.04.019
Inflamm Res. 2024 Jun 08.

Saccharomyces cerevisiae β-glucan improves the response of trained macrophages to severe P. aeruginosa infections.

Marta Ciszek-Lenda, Bernadeta Nowak, Grzegorz Majka, Maciej Suski, Maria Walczewska, Angelika Fedor, Edyta Golińska, Sabina Górska, Andrzej Gamian, Rafał Olszanecki, Magdalena Strus, Janusz Marcinkiewicz.

  OBJECTIVE P. AERUGINOSA: (PA), the major pathogen of lung cystic fibrosis (CF), polarizes macrophages into hyperinflammatory tissue damaging phenotype. The main aim of this study was to verify whether training of macrophages with β-glucan might improve their response to P. aeruginosa infections.METHODS: To perform this task C57BL/6 mice sensitive to infections with P. aeruginosa were used. Peritoneal macrophages were trained with Saccharomyces cerevisiae β-glucan and exposed to PA57, the strong biofilm-forming bacterial strain isolated from the patient with severe lung CF. The release of cytokines and the expression of macrophage phenotypic markers were measured. A quantitative proteomic approach was used for the characterization of proteome-wide changes in macrophages. The effect of in vivo β-glucan-trained macrophages in the air pouch model of PA57 infection was investigated. In all experiments the effect of trained and naïve macrophages was compared.
RESULTS: Trained macrophages acquired a specific phenotype with mixed pro-inflammatory and pro-resolution characteristics, however they retained anti-bacterial properties. Most importantly, transfer of trained macrophages into infected air pouches markedly ameliorated the course of infection. PA57 bacterial growth and formation of biofilm were significantly suppressed. The level of serum amyloid A (SAA), a systemic inflammation biomarker, was reduced.
CONCLUSIONS: Training of murine macrophages with S. cerevisiae β-glucan improved macrophage defense properties along with inhibition of secretion of some detrimental inflammatory agents. We suggest that training of macrophages with such β-glucans might be a new therapeutic strategy in P. aeruginosa biofilm infections, including CF, to promote eradication of pathogens and resolution of inflammation.

Keywords:   Saccharomyces cerevisiae β-glucan; Biofilm P. Aeruginosa ; Inflammation; Trained macrophages

DOI:  https://doi.org/10.1007/s00011-024-01898-1
Int Immunopharmacol. 2024 Jun 13. pii: S1567-5769(24)00902-0. [Epub ahead of print]137 112382

Primary infection enhances neutrophil-mediated host defense by educating HSPCs.

Peng Wu, Qingyu Zhang, Xianqun Xu, Songjiang He, Zheming Liu, Yirong Li, Rongxia Guo.

  Hematopoietic stem and progenitor cells (HSPCs) can give rise to all kinds of immune cells including neutrophils. Neutrophils are the first line of defense in the innate immune system with a short lifespan, due to which it is well-accepted that neutrophils have no immune memory. However, recent reports showed that the changes in HSPCs induced by primary stimulation could last a long time, which contributes to enhancing response to subsequent infection by generating more monocytes or macrophages equipped with stronger anti-bacterial function. Here, we used the reinfection mice model to reveal that primary infection could improve neutrophil-mediated host defense by training neutrophil progenitors in mammals, providing a new idea to enhance neutrophil number and improve neutrophil functions, which is pretty pivotal for patients with compromised or disordered immunity.

Keywords:  HSPCs; Host defense; Neutrophils; Reinfection

DOI:  https://doi.org/10.1016/j.intimp.2024.112382
Cell Host Microbe. 2024 Jun 12. pii: S1931-3128(24)00183-5. [Epub ahead of print]32(6): 863-874

Nutrient acquisition strategies by gut microbes.

Matthew K Muramatsu, Sebastian E Winter.

  The composition and function of the gut microbiota are intimately tied to nutrient acquisition strategies and metabolism, with significant implications for host health. Both dietary and host-intrinsic factors influence community structure and the basic modes of bacterial energy metabolism. The intestinal tract is rich in carbon and nitrogen sources; however, limited access to oxygen restricts energy-generating reactions to fermentation. By contrast, increased availability of electron acceptors during episodes of intestinal inflammation results in phylum-level changes in gut microbiota composition, suggesting that bacterial energy metabolism is a key driver of gut microbiota function. In this review article, we will illustrate diverse examples of microbial nutrient acquisition strategies in the context of habitat filters and anatomical location and the central role of energy metabolism in shaping metabolic strategies to support bacterial growth in the mammalian gut.

Keywords:  bacterial metabolism; fermentation; gut microbiota; respiration

DOI:  https://doi.org/10.1016/j.chom.2024.05.011
Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00184-0. [Epub ahead of print]

Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.

Jing Zhang, Yu Wang, Meiyang Fan, Yanglong Guan, Wentao Zhang, Fumeng Huang, Zhengqiang Zhang, Xiaomeng Li, Bingyu Yuan, Wenbin Liu, Manman Geng, Xiaowei Li, Jing Xu, Congshan Jiang, Wenjuan Zhao, Feng Ye, Wenhua Zhu, Liesu Meng, Shemin Lu, Rikard Holmdahl.

  Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.

Keywords:  Kupffer cells; NCF1; ferroptosis; hepatocytes; iron deposition; lipid peroxidation; macrophages; metabolic dysfunction-associated steatohepatitis; oxidized phospholipids; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cmet.2024.05.008
Front Immunol. 2024 ;15 1408772

The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.

Julia Teppan, Juliana Schwanzer, Sonja Rittchen, Thomas Bärnthaler, Jörg Lindemann, Barsha Nayak, Bernhard Reiter, Petra Luschnig, Aitak Farzi, Akos Heinemann, Eva Sturm.

  Introduction: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm.Methods and results: We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo.
Discussion: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.

Keywords:  REV ERB agonist SR9009; circadian proteins; inflammation; inverse ROR agonist SR1001; macrophages; molecular circadian clock

DOI:  https://doi.org/10.3389/fimmu.2024.1408772
J Vis Exp. 2024 May 24.

Immunocompetent Intestine-on-Chip Model for Analyzing Gut Mucosal Immune Responses.

Adrian Feile, Valentin D Wegner, Martin Raasch, Alexander S Mosig.

An advanced intestine-on-chip model recreating epithelial 3D organotypic villus-like and crypt-like structures has been developed. The immunocompetent model includes Human Umbilical Vein Endothelial Cells (HUVEC), Caco-2 intestinal epithelial cells, tissue-resident macrophages, and dendritic cells, which self-organize within the tissue, mirroring characteristics of the human intestinal mucosa. A unique aspect of this platform is its capacity to integrate circulating human primary immune cells, enhancing physiological relevance. The model is designed to investigate the intestinal immune system's response to bacterial and fungal colonization and infection. Due to its enlarged cavity size, the model offers diverse functional readouts such as permeation assays, cytokine release, and immune cell infiltration, and is compatible with immunofluorescence measurement of 3D structures formed by the epithelial cell layer. It hereby provides comprehensive insights into cell differentiation and function. The intestine-on-chip platform has demonstrated its potential in elucidating complex interactions between surrogates of a living microbiota and human host tissue within a microphysiological perfused biochip platform.

DOI: https://doi.org/10.3791/66603
Cell Host Microbe. 2024 Jun 12. pii: S1931-3128(24)00178-1. [Epub ahead of print]32(6): 794-803

Mechanisms of bacterial immunity, protection, and survival during interbacterial warfare.

Nolan W Kennedy, Laurie E Comstock.

  Most bacteria live in communities, often with closely related strains and species with whom they must compete for space and resources. Consequently, bacteria have acquired or evolved mechanisms to antagonize competitors through the production of antibacterial toxins. Similar to bacterial systems that combat phage infection and mechanisms to thwart antibiotics, bacteria have also acquired and evolved features to protect themselves from antibacterial toxins. Just as there is a large body of research identifying and characterizing antibacterial proteins and toxin delivery systems, studies of bacterial mechanisms to resist and survive assault from competitors' weapons have also expanded tremendously. Emerging data are beginning to reveal protective processes and mechanisms that are as diverse as the toxins themselves. Protection against antibacterial toxins can be acquired by horizontal gene transfer, receptor or target alteration, induction of protective functions, physical barriers, and other diverse processes. Here, we review recent studies in this rapidly expanding field.

Keywords:  T6SS; antagonism; antibacterial toxin; immunity protein; interbacterial defense

DOI:  https://doi.org/10.1016/j.chom.2024.05.006
Life Sci. 2024 Jun 08. pii: S0024-3205(24)00393-X. [Epub ahead of print] 122803

Regulatory mechanisms of amino acids in ferroptosis.

Heying Yao, Wei Jiang, Xiang Liao, Dongqing Wang, Haitao Zhu.

  Ferroptosis, an iron-dependent non-apoptotic regulated cell death process, is associated with the pathogenesis of various diseases. Amino acids, which are indispensable substrates of vital activities, significantly regulate ferroptosis. Amino acid metabolism is involved in maintaining iron and lipid homeostasis and redox balance. The regulatory effects of amino acids on ferroptosis are complex. An amino acid may exert contrasting effects on ferroptosis depending on the context. This review systematically and comprehensively summarized the distinct roles of amino acids in regulating ferroptosis and highlighted the emerging opportunities to develop clinical therapeutic strategies targeting amino acid-mediated ferroptosis.

Keywords:  Amino acids; Ferroptosis; Metabolic reprogramming; Redox balance

DOI:  https://doi.org/10.1016/j.lfs.2024.122803
Cell Host Microbe. 2024 Jun 12. pii: S1931-3128(24)00132-X. [Epub ahead of print]32(6): 913-924.e7

Bacterial esterases reverse lipopolysaccharide ubiquitylation to block host immunity.

Magdalena Szczesna, Yizhou Huang, Rachel E Lacoursiere, Francesca Bonini, Vito Pol, Fulya Koc, Beatrice Ward, Paul P Geurink, Jonathan N Pruneda, Teresa L M Thurston.

  Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved two mechanisms to block the activity of Ring finger protein 213 (RNF213)-mediated non-canonical ubiquitylation of bacterial lipopolysaccharide (LPS), thereby preventing the initiation of antibacterial autophagy. First, Burkholderia's polysaccharide capsule blocks RNF213 association with bacteria and second, the Burkholderia deubiquitylase (DUB), TssM, directly reverses the activity of RNF213 through a previously unrecognized esterase activity. Structural analysis provides insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from its isopeptidase function. Furthermore, a putative TssM homolog also displays esterase activity and removes ubiquitin from LPS, establishing this as a virulence mechanism. Of note, we also find that additional immune-evasion mechanisms exist, revealing that overcoming this arm of the host's immune response is critical to the pathogen.

Keywords:  Autophagy; Burkholderia; RNF213; TssM; Ubiquitin esterase; bacterial effector; cell-autonomous immunity; non-canonical ubiquitylation

DOI:  https://doi.org/10.1016/j.chom.2024.04.012
Microb Cell Fact. 2024 Jun 12. 23(1): 172

Exploring the interaction and impact of probiotic and commensal bacteria on vitamins, minerals and short chain fatty acids metabolism.

Luis G Bermúdez-Humarán, Benoit Chassaing, Philippe Langella.

  There is increasing evidence that probiotic and commensal bacteria play a role in substrate metabolism, energy harvesting and intestinal homeostasis, and may exert immunomodulatory activities on human health. In addition, recent research suggests that these microorganisms interact with vitamins and minerals, promoting intestinal and metabolic well-being while producing vital microbial metabolites such as short-chain fatty acids (SCFAs). In this regard, there is a flourishing field exploring the intricate dynamics between vitamins, minerals, SCFAs, and commensal/probiotic interactions. In this review, we summarize some of the major hypotheses beyond the mechanisms by which commensals/probiotics impact gut health and their additional effects on the absorption and metabolism of vitamins, minerals, and SCFAs. Our analysis includes comprehensive review of existing evidence from preclinical and clinical studies, with particular focus on the potential interaction between commensals/probiotics and micronutrients. Finally, we highlight knowledge gaps and outline directions for future research in this evolving field.

Keywords:  Energy metabolism; Gut health; Immunity; Minerals; Probiotics; Synergy; Vitamins

DOI:  https://doi.org/10.1186/s12934-024-02449-3
Nat Microbiol. 2024 Jun 11.

Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms.

Lisa Osbelt, Éva D H Almási, Marie Wende, Sabine Kienesberger, Alexander Voltz, Till R Lesker, Uthayakumar Muthukumarasamy, Nele Knischewski, Elke Nordmann, Agata A Bielecka, María Giralt-Zúñiga, Eugen Kaganovitch, Caroline Kühne, Claas Baier, Michael Pietsch, Mathias Müsken, Marina C Greweling-Pils, Rolf Breinbauer, Antje Flieger, Dirk Schlüter, Rolf Müller, Marc Erhardt, Ellen L Zechner, Till Strowig.

The Klebsiella oxytoca species complex is part of the human microbiome, especially during infancy and childhood. K. oxytoca species complex strains can produce enterotoxins, namely, tilimycin and tilivalline, while also contributing to colonization resistance (CR). The relationship between these seemingly contradictory roles is not well understood. Here, by coupling ex vivo assays with CRISPR-mutagenesis and various mouse models, we show that K. oxytoca provides CR against Salmonella Typhimurium. In vitro, the antimicrobial activity against various Salmonella strains depended on tilimycin production and was induced by various simple carbohydrates. In vivo, CR against Salmonella depended on toxin production in germ-free mice, while it was largely toxin-independent in mice with residual microbiota. This was linked to the relative levels of toxin-inducing carbohydrates in vivo. Finally, dulcitol utilization was essential for toxin-independent CR in gnotobiotic mice. Together, this demonstrates that nutrient availability is key to both toxin-dependent and substrate-driven competition between K. oxytoca and Salmonella.

DOI: https://doi.org/10.1038/s41564-024-01710-0
Antioxid Redox Signal. 2024 Jun 14.

SIRT3-mediated OPA1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization.

Maomao Sun, Yuying Li, Gege Xu, Junrui Zhu, Ruimin Lu, Sheng An, Zhenhua Zeng, Zhiya Deng, Ran Cheng, Qin Zhang, Yi Yao, Junjie Wu, Yuan Zhang, Hongbin Hu, Zhonqing Chen, Qiaobing Huang, Jie Wu.

AIMS: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on SIRT3-induced optic atrophy protein 1 (OPA1) deacetylation.RESULTS: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3TYP-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI.
INNOVATION: Our study revealed for the first time the regulation of mitochondrial dynamics and AMs polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease.
CONCLUSIONS: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI, and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury.

DOI: https://doi.org/10.1089/ars.2023.0322
Food Chem Toxicol. 2024 Jun 11. pii: S0278-6915(24)00328-4. [Epub ahead of print]190 114762

The role of HMGB1 on SiC NPs-induced inflammation response in lung epithelial-macrophage co-culture system.

Xiao Chen, Linyuan Zhang, Changyan Yu, Airu Duan, Bo Jiao, Yuanyuan Chen, Yufei Dai, Bin Li.

  In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.

Keywords:  AM-AT II co-culture; High mobility group box 1 (HMGB1); Inflammatory; Silicon carbide nanoparticles (SiC NPs); TLR4–RAGE crosstalk

DOI:  https://doi.org/10.1016/j.fct.2024.114762
Front Cell Infect Microbiol. 2024 ;14 1423386

Editorial: Reviews in microbiome in health & disease.

Suhana Chattopadhyay, Leena Malayil.



Keywords:  diseases; dysbiosis; gut microbiome; homeostasis; reviews

DOI:  https://doi.org/10.3389/fcimb.2024.1423386
Front Immunol. 2024 ;15 1402024

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway.

Zhanpeng Chen, Xingxing Kong, Quan Ma, Jinyun Chen, Yuqin Zeng, Huazhen Liu, Xiaomin Wang, Shuihua Lu.

  Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and replication. Cholesterol is the main carbon source during the infection process of Mtb. Cholesterol metabolism in macrophages is tightly associated with cell functions such as phagocytosis of pathogens, antigen presentation, inflammatory responses, and tissue repair. Research has shown that Mtb infection increases the uptake of low-density lipoprotein (LDL) and cholesterol by macrophages, and enhances de novo cholesterol synthesis in macrophages. Excessive cholesterol is converted into cholesterol esters, while the degradation of cholesterol esters in macrophages is inhibited by Mtb. Furthermore, Mtb infection suppresses the expression of ATP-binding cassette (ABC) transporters in macrophages, impeding cholesterol efflux. These alterations result in the massive accumulation of cholesterol in macrophages, promoting the formation of lipid droplets and foam cells, which ultimately facilitates the persistent survival of Mtb and the progression of tuberculosis (TB), including granuloma formation, tissue cavitation, and systemic dissemination. Mtb infection may also promote the conversion of cholesterol into oxidized cholesterol within macrophages, with the oxidized cholesterol exhibiting anti-Mtb activity. Recent drug development has discovered that reducing cholesterol levels in macrophages can inhibit the invasion of Mtb into macrophages and increase the permeability of anti-tuberculosis drugs. The development of drugs targeting cholesterol metabolic pathways in macrophages, as well as the modification of existing drugs, holds promise for the development of more efficient anti-tuberculosis medications.

Keywords:  MTB; TB; cholesterol metabolism; foam cell; lipid droplet; macrophages; oxidized cholesterol

DOI:  https://doi.org/10.3389/fimmu.2024.1402024
J Cyst Fibros. 2024 Jun 08. pii: S1569-1993(24)00063-8. [Epub ahead of print]

Metabolomics analysis of bronchoalveolar lavage fluid predicts unique features of the lower airway in pediatric cystic fibrosis.

John B O'Connor, Madison Mottlowitz, Brandie D Wagner, J Kirk Harris, Theresa A Laguna.

  BACKGROUND: Progressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function.METHODS: BALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed.
RESULTS: One hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function.
CONCLUSIONS: The lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.

Keywords:  Bronchoalveolar lavage; Cystic fibrosis; Infection; Inflammation; Metabolome; Pediatrics

DOI:  https://doi.org/10.1016/j.jcf.2024.04.017
Cell Signal. 2024 Jun 09. pii: S0898-6568(24)00225-0. [Epub ahead of print]121 111257

Nemo mRNA vaccination improves airway barrier function in mice with airway allergy.

Xianhai Zeng, Lihuan Wang, Xiwen Zhang, Haoyue Zheng, Shuo Song, Tao Xu, Huanping Zhang, Pingchang Yang.

  Epithelial barrier dysfunction plays an important role in the pathogenesis of Th2 bias. The mechanism requires further clarification. NEMO is associated with regulating apoptotic activities in the cell. The purpose of this study is to investigate the role of insufficient Nemo signals in developing Th2 bias in the respiratory tract. Nemof/fEpcam-Cre mice (A mouse strain carrying NEMO-deficient epithelial cells. NemoKO mice, in short) was generated. An airway Th2 bias mouse model was established with the ovalbumin/alum protocol. The NemoKO mice exhibited spontaneous airway Th2 bias. Respiratory tract epithelial barrier integrity was compromised in NemoKO mice. Apoptosis was found in approximately 10% of the epithelial cells of the respiratory tract in NemoKO mice. The reconstruction of the Nemo expression restored homeostasis within the epithelial barrier of the airways. Restoration of Nemo gene expression in epithelial cells by Nemo mRNA vaccination alleviated Th2 bias in mice with airway allergy. To sum up, NEMO plays an important role in maintaining the integrity of the epithelial barrier in the respiratory tract. Administration of NEMO mRNA vaccines can restore epithelial barrier functions and alleviate Th2 bias in the airways.

Keywords:  Apoptosis; Barrier functions; Epithelial cells; RNA vaccination; Th2 bias

DOI:  https://doi.org/10.1016/j.cellsig.2024.111257
Front Nutr. 2024 ;11 1399687

Fine-tuning of mononuclear phagocytes for improved inflammatory responses: role of soybean-derived immunomodulatory compounds.

Hiroyuki Tezuka, Shinjiro Imai.

  The concept of inflammation encompasses beneficial and detrimental aspects, which are referred to as infectious and sterile inflammations, respectively. Infectious inflammation plays a crucial role in host defense, whereas sterile inflammation encompasses allergic, autoimmune, and lifestyle-related diseases, leading to detrimental effects. Dendritic cells and macrophages, both of which are representative mononuclear phagocytes (MNPs), are essential for initiating immune responses, suggesting that the regulation of MNPs limits excessive inflammation. In this context, dietary components with immunomodulatory properties have been identified. Among them, soybean-derived compounds, including isoflavones, saponins, flavonoids, and bioactive peptides, act directly on MNPs to fine-tune immune responses. Notably, some soybean-derived compounds have demonstrated the ability to alleviate the symptom of allergy and autoimmunity in mouse models. In this review, we introduce and summarize the roles of soybean-derived compounds on MNP-mediated inflammatory responses. Understanding the mechanism by which soybean-derived molecules regulate MNPs could provide valuable insights for designing safe immunomodulators.

Keywords:  allergy; anti-inflammation; dendritic cells; macrophages; mononuclear phagocytes; phytochemicals; soybeans

DOI:  https://doi.org/10.3389/fnut.2024.1399687
Probiotics Antimicrob Proteins. 2024 Jun 12.

A Lactobacillus Combination Ameliorates Lung Inflammation in an Elastase/LPS-induced Mouse Model of Chronic Obstructive Pulmonary Disease.

Huan-Ting Shen, Yi-Ting Fang, Wan-Hua Tsai, Chia-Hsuan Chou, Ming-Shyan Huang, Yao-Tsung Yeh, Jiun-Ting Wu, Cheng-Hsieh Huang, Bing-Yen Wang, Wen-Wei Chang.

  Chronic obstructive pulmonary disease (COPD) is the world's leading lung disease and lacks effective and specific clinical strategies. Probiotics are increasingly used to support the improvement of the course of inflammatory diseases. In this study, we evaluated the potential of a lactic acid bacteria (LAB) combination containing Limosilactobacillus reuteri GMNL-89 and Lacticaseibacillus paracasei GMNL-133 to decrease lung inflammation and emphysema in a COPD mouse model. This model was induced by intranasal stimulation with elastase and LPS for 4 weeks, followed by 2 weeks of oral LAB administration. The results showed that the LAB combination decreased lung emphysema and reduced inflammatory cytokines (IL-1β, IL-6, TNF-α) in the lung tissue of COPD mice. Microbiome analysis revealed that Bifidobacterium and Akkermansia muciniphila, reduced in the gut of COPD mice, could be restored after LAB treatment. Microbial α-diversity in the lungs decreased in COPD mice but was reversed after LAB administration, which also increased the relative abundance of Candidatus arthromitus in the gut and decreased Burkholderia in the lungs. Furthermore, LAB-treated COPD mice exhibited increased levels of short-chain fatty acids, specifically acetic acid and propionic acid, in the cecum. Additionally, pulmonary emphysema and inflammation negatively correlated with C. arthromitus and Adlercreutzia levels. In conclusion, the combination of L. reuteri GMNL-89 and L. paracasei GMNL-133 demonstrates beneficial effects on pulmonary emphysema and inflammation in experimental COPD mice, correlating with changes in gut and lung microbiota, and providing a potential strategy for future adjuvant therapy.

Keywords:   Lactobacillus ; COPD; Gut microbiota; Gut-lung axis; Short chain fatty acids

DOI:  https://doi.org/10.1007/s12602-024-10300-9
Wound Repair Regen. 2024 Jun 09.

Understanding Staphylococcus aureus in hyperglycaemia: A review of virulence factor and metabolic adaptations.

Madeline J O'Connor, Angelica V Bartler, Kelly C Ho, Kenneth Zhang, Rolando J Casas Fuentes, Bradley A Melnick, Kristin N Huffman, Seok Jong Hong, Robert D Galiano.

  Staphylococcus aureus is one of the most commonly detected bacteria in diabetic skin and soft tissue infections. The incidence and severity of skin and soft tissue infections are higher in patients with diabetes, indicating a potentiating mechanism of hyperglycaemia and infection. The goal of this review is to explore the metabolic and virulence factor adaptations of S. aureus under hyperglycaemic conditions. Primary data from identified studies were included and summarised in this paper. Understanding the nexus of hyperglycaemia, metabolism, and virulence factors provides insights into the complexity of diabetic skin and soft tissue infections attributed to S. aureus.

Keywords:  diabetes; metabolic adaptations; soft tissue infection; virulence factors

DOI:  https://doi.org/10.1111/wrr.13192
BMC Microbiol. 2024 Jun 14. 24(1): 212

Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.

Jingwen Zhou, Chunyan He, Han Yang, Wen Shu, Qingzhong Liu.

  BACKGROUND: Long-term treatment with trimethoprim-sulfamethoxazole (SXT) can lead to the formation of small-colony variants (SCVs) of Staphylococcus aureus. However, the mechanism behind SCVs formation remains poorly understood. In this study, we explored the phenotype and omics-based characterization of S. aureus SCVs induced by SXT and shed light on the potential causes of SCV formation.METHODS: Stable SCVs were obtained by continuously treating S. aureus isolates using 12/238 µg/ml of SXT, characterized by growth kinetics, antibiotic susceptibility testing, and auxotrophism test. Subsequently, a pair of representative strains (SCV and its parental strain) were selected for genomic, transcriptomic and metabolomic analysis.
RESULTS: Three stable S. aureus SCVs were successfully screened and proven to be homologous to their corresponding parental strains. Phenotypic tests showed that all SCVs were non-classical mechanisms associated with impaired utilization of menadione, heme and thymine, and exhibited slower growth and higher antibiotic minimum inhibitory concentrations (MICs), compared to their corresponding parental strains. Genomic data revealed 15 missense mutations in 13 genes in the representative SCV, which were involved in adhesion, intramolecular phosphate transfer on ribose, transport pathways, and phage-encoded proteins. The combination analysis of transcriptome and metabolome identified 35 overlapping pathways possible associated with the phenotype switching of S. aureus. These pathways mainly included changes in metabolism, such as purine metabolism, pyruvate metabolism, amino acid metabolism, and ABC transporters, which could play a crucial role in promoting SCVs development by affecting nucleic acid synthesis and energy metabolism in bacteria.
CONCLUSION: This study provides profound insights into the causes of S. aureus SCV formation induced by SXT. The findings may offer valuable clues for developing new strategies to combat S. aureus SCV infections.

Keywords:   Staphylococcus aureus ; Genomics; Metabolomics; Small colony variant; Sulfamethoxazole-trimethoprim; Transcriptomics

DOI:  https://doi.org/10.1186/s12866-024-03364-8
Cell Death Dis. 2024 Jun 11. 15(6): 407

ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.

Caterina Licini, Gianluca Morroni, Guendalina Lucarini, Veronica Angela Maria Vitto, Fiorenza Orlando, Sonia Missiroli, Gloria D'Achille, Mariasole Perrone, Tatiana Spadoni, Laura Graciotti, Giorgia Bigossi, Mauro Provinciali, Annamaria Offidani, Monica Mattioli-Belmonte, Oscar Cirioni, Paolo Pinton, Oriana Simonetti, Saverio Marchi.

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.

DOI: https://doi.org/10.1038/s41419-024-06765-9