bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–07–21
forty-two papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis.
  2. Regulation of macrophage activation by lactylation in lung disease.
  3. Persistent enrichment of multidrug-resistant Klebsiella in oral and nasal communities during long-term starvation.
  4. Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells.
  5. Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.
  6. Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor.
  7. Navigating commensal dysbiosis: Gastrointestinal host-pathogen interplay orchestrating opportunistic infections.
  8. Sex differences in airway disease: estrogen and airway surface liquid dynamics.
  9. Postbiotic lactobacilli induce cutaneous antimicrobial response and restore the barrier to inhibit the intracellular invasion of Staphylococcus aureus in vitro and ex vivo.
  10. Preserving the efficacy of antibiotics to tackle antibiotic resistance.
  11. Host control of the microbiome: Mechanisms, evolution, and disease.
  12. Fatty acid oxidation in immune function.
  13. Distinct prophage gene profiles of Staphylococcus aureus strains from atopic dermatitis patients and healthy individuals.
  14. Pyroptosis, gasdermins and allergic diseases.
  15. E-Cigarette Use, Cigarette Smoking, and Sex are Associated with Nasal Microbiome Dysbiosis.
  16. Lung-resident CD3-NK1.1+CD69+CD103+ Cells Play an Important Role in Bacillus Calmette-Guérin Vaccine-Induced Protective Immunity against Mycobacterium tuberculosis Infection.
  17. Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization.
  18. Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.
  19. Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old.
  20. Reduced sialylation of airway mucin impairs mucus transport by altering the biophysical properties of mucin.
  21. A MRSA mystery: how PBP4 and cyclic-di-AMP join forces against β-lactam antibiotics.
  22. Rational design of ROS generation nanosystems to regulate innate immunity of macrophages, dendrtical and natural killing cells for immunotherapy.
  23. Host and pathogen genetic diversity shape vaccine-mediated protection to Mycobacterium tuberculosis.
  24. Gut microbiota and epigenetic choreography: Implications for human health: A review.
  25. Pyroptosis and its role in autoimmune skin disease.
  26. LincR-PPP2R5C regulates IL-1β ubiquitination in macrophages and promotes airway inflammation and emphysema in a murine model of COPD.
  27. Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma.
  28. The two alternative NADH:quinone oxidoreductases from Staphylococcus aureus: two players with different molecular and cellular roles.
  29. Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
  30. Sphingosine kills intracellular Pseudomonas aeruginosa and Staphylococcus aureus.
  31. Facile metabolic reprogramming distinguishes mycobacterial adaptation to hypoxia and starvation: ketosis drives starvation-induced persistence in M. bovis BCG.
  32. Effect of Lactobacillus gasseri BIO6369 and Lacticaseibacillus rhamnosus BIO5326 on Gastric Carcinogenesis Induced by Helicobacter pylori Infection.
  33. Association Between Gut and Nasal Microbiota and Allergic Rhinitis: A Systematic Review.
  34. Building a human lung from pluripotent stem cells to model respiratory viral infections.
  35. Rethinking Combination Therapy for S. aureus bacteremia: A Fading Paradigm.
  36. How bile acids and the microbiota interact to shape host immunity.
  37. Integrated Single-Cell Analysis Reveals Spatially and Temporally Dynamic Heterogeneity in Fibroblast States During Wound Healing.
  38. Prolonged hospitalization signature and early antibiotic effects on the nasopharyngeal resistome in preterm infants.
  39. Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity.
  40. Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease.
  41. Editorial overview: Linking cellular regulation and metabolic functions: from signals to mechanisms.
  42. Editorial: The role of probiotics, postbiotics, and microbial metabolites in preventing and treating chronic diseases, volume II.
  1. Cell Mol Life Sci. 2024 Jul 13. 81(1): 300
    Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis.
    Yihuang Lin, Mankai Yang, Chubin Cheng, Jichang Wu, Bin Yu, Xianrong Zhang.
       BACKGROUND: Age-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood.
    RESULTS: Our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure.
    CONCLUSIONS: These findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.
    Keywords:   Staphylococcus aureus ; CXCL10; CXCL9; Innate immune; Monocytes; Osteomyelitis
    DOI:  https://doi.org/10.1007/s00018-024-05311-2
  2. Front Immunol. 2024 ;15 1427739
    Regulation of macrophage activation by lactylation in lung disease.
    Yungeng Wei, Hua Guo, Shixing Chen, Xiao Xiao Tang.
      Lactylation is a process where lactate, a cellular metabolism byproduct, is added to proteins, altering their functions. In the realm of macrophage activation, lactylation impacts inflammatory response and immune regulation. Understanding the effects of lactylation on macrophage activation is vital in lung diseases, as abnormal activation and function are pivotal in conditions like pneumonia, pulmonary fibrosis, COPD, and lung cancer. This review explores the concept of lactylation, its regulation of macrophage activation, and recent research progress in lung diseases. It offers new insights into lung disease pathogenesis and potential therapeutic targets.
    Keywords:  immune regulation; lactylation; lung disease; macrophage; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2024.1427739
  3. Microbiome. 2024 Jul 20. 12(1): 132
    Persistent enrichment of multidrug-resistant Klebsiella in oral and nasal communities during long-term starvation.
    Jett Liu, Nell Spencer, Daniel R Utter, Alex S Grossman, Lei Lei, Nídia Castro Dos Santos, Wenyuan Shi, Jonathon L Baker, Hatice Hasturk, Xuesong He, Batbileg Bor.
       BACKGROUND: The human oral and nasal cavities can act as reservoirs for opportunistic pathogens capable of causing acute infection. These microbes asymptomatically colonize the human oral and nasal cavities which facilitates transmission within human populations via the environment, and they routinely possess clinically significant antibiotic resistance genes. Among these opportunistic pathogens, the Klebsiella genus stands out as a notable example, with its members frequently linked to nosocomial infections and multidrug resistance. As with many colonizing opportunistic pathogens, the essential transmission factors influencing the spread of Klebsiella species among both healthy and diseased individuals remain unclear.
    RESULTS: Here, we explored a possible explanation by investigating the ability of oral and nasal Klebsiella species to outcompete their native microbial community members under in vitro starvation conditions, which could be analogous to external hospital environments or the microenvironment of mechanical ventilators. When K. pneumoniae and K. aerogenes were present within a healthy human oral or nasal sample, the bacterial community composition shifted dramatically under starvation conditions and typically became enriched in Klebsiella species. Furthermore, introducing K. pneumoniae exogenously into a native microbial community lacking K. pneumoniae, even at low inoculum, led to repeated enrichment under starvation. Precise monitoring of K. pneumoniae within these communities undergoing starvation indicated rapid initial growth and prolonged viability compared to other members of the microbiome. K. pneumoniae strains isolated from healthy individuals' oral and nasal cavities also exhibited resistance to multiple classes of antibiotics and were genetically similar to clinical and gut isolates. In addition, we found that in the absence of Klebsiella species, other understudied opportunistic pathogens, such as Peptostreptococcus, increased in relative abundance under starvation conditions.
    CONCLUSIONS: Our findings establish an environmental and microbiome community circumstance that allows for the enrichment of Klebsiella species and other opportunistic pathogens. Klebsiella's enrichment may hinge on its ability to quickly outgrow other members of the microbiome. The ability to outcompete other commensal bacteria and to persist under harsh environmental conditions could be an important factor that contributes to enhanced transmission in both commensal and pathogenic contexts. Video Abstract.
    Keywords:   Klebsiella ; Commensal bacteria; Microbiome ecology; Multidrug resistance; Nasal microbiome; Nosocomial infection; Opportunistic pathogen; Oral microbiome
    DOI:  https://doi.org/10.1186/s40168-024-01854-5
  4. J Hepatol. 2024 Jul 11. pii: S0168-8278(24)02363-8. [Epub ahead of print]
    Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells.
    Mohamed Amer Musrati, Benoit Stijlemans, Abdulkader Azouz, Daliya Kancheva, Sarah Mesbahi, Eva Hadadi, Els Lebegge, Leen Ali, Karen De Vlaminck, Isabelle Scheyltjens, Niels Vandamme, Maida Zivalj, Naela Assaf, Yvon Elkrim, Ilham Ahmidi, Camille Huart, Mohamed Lamkanfi, Martin Guilliams, Patrick De Baetselier, Stanislas Goriely, Kiavash Movahedi, Jo A Van Ginderachter.
       BACKGROUND AND AIMS: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver instructs long-term alterations to the liver macrophage compartment.
    METHODS: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single cell CITE-sequencing, single nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection.
    RESULTS: We show that T. b. brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection.
    CONCLUSION: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term.
    IMPACT AND IMPLICATIONS: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches.
    Keywords:  Trypanosoma; epigenetic remodeling; liver inflammation; macrophage niche; ontogeny; tissue-resident macrophage; trained immunity
    DOI:  https://doi.org/10.1016/j.jhep.2024.07.007
  5. Front Immunol. 2024 ;15 1405376
    Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response.
    Rhea Nickerson, Christina S Thornton, Brent Johnston, Amy H Y Lee, Zhenyu Cheng.
      Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.
    Keywords:  Pseudomonas aeruginosa; adaptive immune response; chronic lung disease; inflammation; innate immune response; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2024.1405376
  6. Immun Inflamm Dis. 2024 Jul;12(7): e1316
    Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor.
    Kexin Tian, Dehong Jing, Junzhe Lan, Mingming Lv, Tingting Wang.
       BACKGROUND: The gastrointestinal tract contains a wide range of microorganisms that have evolved alongside the immune system of the host. The intestinal mucosa maintains balance within the intestines by utilizing the mucosal immune system, which is controlled by the complex gut mucosal immune network.
    OBJECTIVE: This review aims to comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with commensal bacteria.
    RESULTS: The gut mucosal immune network includes gut-associated lymphoid tissue, mucosal immune cells, cytokines, and chemokines. The connection between microbiota and the immune system occurs through the engagement of bacterial components with pattern recognition receptors found in the intestinal epithelium and antigen-presenting cells. This interaction leads to the activation of both innate and adaptive immune responses. The interaction between the microbial community and the host is vital for maintaining the balance and health of the host's mucosal system.
    CONCLUSION: The gut mucosal immune network maintains a delicate equilibrium between active immunity, which defends against infections and damaging non-self antigens, and immunological tolerance, which allows for the presence of commensal microbiota and dietary antigens. This balance is crucial for the maintenance of intestinal health and homeostasis. Disturbance of gut homeostasis leads to enduring or severe gastrointestinal ailments, such as colorectal cancer and inflammatory bowel disease. Utilizing these factors can aid in the development of cutting-edge mucosal vaccines that have the ability to elicit strong protective immune responses at the primary sites of pathogen invasion.
    Keywords:  CRC; IBD; commensal microbiome; intestinal mucosal immunity; mucosal vaccine; oral tolerance
    DOI:  https://doi.org/10.1002/iid3.1316
  7. Microbiol Res. 2024 Jul 03. pii: S0944-5013(24)00233-7. [Epub ahead of print]286 127832
    Navigating commensal dysbiosis: Gastrointestinal host-pathogen interplay orchestrating opportunistic infections.
    Nisha Tewari, Priyankar Dey.
      The gut commensals, which are usually symbiotic or non-harmful bacteria that live in the gastrointestinal tract, have a positive impact on the health of the host. This review, however, specifically discuss distinct conditions where commensals aid in the development of pathogenic opportunistic infections. We discuss that the categorization of gut bacteria as either pathogens or non-pathogens depends on certain circumstances, which are significantly affected by the tissue microenvironment and the dynamic host-microbe interaction. Under favorable circumstances, commensals have the ability to transform into opportunistic pathobionts by undergoing overgrowth. These conditions include changes in the host's physiology, simultaneous infection with other pathogens, effective utilization of nutrients, interactions between different species of bacteria, the formation of protective biofilms, genetic mutations that enhance pathogenicity, acquisition of genes associated with virulence, and the ability to avoid the host's immune response. These processes allow commensals to both initiate infections themselves and aid other pathogens in populating the host. This review highlights the need of having a detailed and sophisticated knowledge of the two-sided nature of gut commensals. Although commensals mostly promote health, they may also become harmful in certain changes in the environment or the body's functioning. This highlights the need of acknowledging the intricate equilibrium in interactions between hosts and microbes, which is crucial for preserving intestinal homeostasis and averting diseases. Finally, we also emphasize the further need of research to better understand and anticipate the behavior of gut commensals in different situations, since they play a crucial and varied role in human health and disease.
    Keywords:  Bacterial infection; Colonization fitness; Gut microbiota; Immune response; Inflammation; Pathoadaptive mutation
    DOI:  https://doi.org/10.1016/j.micres.2024.127832
  8. Biol Sex Differ. 2024 Jul 18. 15(1): 56
    Sex differences in airway disease: estrogen and airway surface liquid dynamics.
    Brian J Harvey, Noel G McElvaney.
      Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review.
    Keywords:  Airway surface liquid; Asthma; COVID-19; Cystic fibrosis; Estrogen; Ion channels
    DOI:  https://doi.org/10.1186/s13293-024-00633-z
  9. FASEB J. 2024 Jul 31. 38(14): e23801
    Postbiotic lactobacilli induce cutaneous antimicrobial response and restore the barrier to inhibit the intracellular invasion of Staphylococcus aureus in vitro and ex vivo.
    Miroslav Dinić, Jamie L Burgess, Jovanka Lukić, Paola Catanuto, Dušan Radojević, Jelena Marjanović, Rebecca Verpile, Seth R Thaller, Tammy Gonzalez, Nataša Golić, Ivana Strahinić, Marjana Tomic-Canic, Irena Pastar.
      Intracellular pathogens including Staphylococcus aureus contribute to the non-healing phenotype of chronic wounds. Lactobacilli, well known as beneficial bacteria, are also reported to modulate the immune system, yet their role in cutaneous immunity remains largely unknown. We explored the therapeutic potential of bacteria-free postbiotics, bioactive lysates of lactobacilli, to reduce intracellular S. aureus colonization and promote healing. Fourteen postbiotics derived from various lactobacilli species were screened, and Latilactobacillus curvatus BGMK2-41 was selected for further analysis based on the most efficient ability to reduce intracellular infection by S. aureus diabetic foot ulcer clinical isolate and S. aureus USA300. Treatment of both infected keratinocytes in vitro and infected human skin ex vivo with BGMK2-41 postbiotic cleared S. aureus. Keratinocytes treated in vitro with BGMK2-41 upregulated expression of antimicrobial response genes, of which DEFB4, ANG, and RNASE7 were also found upregulated in treated ex vivo human skin together with CAMP exclusively upregulated ex vivo. Furthermore, BGMK2-41 postbiotic treatment has a multifaceted impact on the wound healing process. Treatment of keratinocytes stimulated cell migration and the expression of tight junction proteins, while in ex vivo human skin BGMK2-41 increased expression of anti-inflammatory cytokine IL-10, promoted re-epithelialization, and restored the epidermal barrier via upregulation of tight junction proteins. Together, this provides a potential therapeutic approach for persistent intracellular S. aureus infections.
    Keywords:   Staphylococcus aureus ; intracellular infection; lactobacilli; postbiotic; skin barrier; wound healing
    DOI:  https://doi.org/10.1096/fj.202400054RR
  10. Microb Biotechnol. 2024 Jul;17(7): e14528
    Preserving the efficacy of antibiotics to tackle antibiotic resistance.
    Pablo Laborda, Teresa Gil-Gil, José Luis Martínez, Sara Hernando-Amado.
      Different international agencies recognize that antibiotic resistance is one of the most severe human health problems that humankind is facing. Traditionally, the introduction of new antibiotics solved this problem but various scientific and economic reasons have led to a shortage of novel antibiotics at the pipeline. This situation makes mandatory the implementation of approaches to preserve the efficacy of current antibiotics. The concept is not novel, but the only action taken for such preservation had been the 'prudent' use of antibiotics, trying to reduce the selection pressure by reducing the amount of antibiotics. However, even if antibiotics are used only when needed, this will be insufficient because resistance is the inescapable outcome of antibiotics' use. A deeper understanding of the alterations in the bacterial physiology upon acquisition of resistance and during infection will help to design improved strategies to treat bacterial infections. In this article, we discuss the interconnection between antibiotic resistance (and antibiotic activity) and bacterial metabolism, particularly in vivo, when bacteria are causing infection. We discuss as well how understanding evolutionary trade-offs, as collateral sensitivity, associated with the acquisition of resistance may help to define evolution-based therapeutic strategies to fight antibiotic resistance and to preserve currently used antibiotics.
    DOI:  https://doi.org/10.1111/1751-7915.14528
  11. Science. 2024 Jul 19. 385(6706): eadi3338
    Host control of the microbiome: Mechanisms, evolution, and disease.
    Jacob Wilde, Emma Slack, Kevin R Foster.
      Many species, including humans, host communities of symbiotic microbes. There is a vast literature on the ways these microbiomes affect hosts, but here we argue for an increased focus on how hosts affect their microbiomes. Hosts exert control over their symbionts through diverse mechanisms, including immunity, barrier function, physiological homeostasis, and transit. These mechanisms enable hosts to shape the ecology and evolution of microbiomes and generate natural selection for microbial traits that benefit the host. Our microbiomes result from a perpetual tension between host control and symbiont evolution, and we can leverage the host's evolved abilities to regulate the microbiota to prevent and treat disease. The study of host control will be central to our ability to both understand and manipulate microbiotas for better health.
    DOI:  https://doi.org/10.1126/science.adi3338
  12. Front Immunol. 2024 ;15 1420336
    Fatty acid oxidation in immune function.
    Felicia Kemp, Erica L Braverman, Craig A Byersdorfer.
      Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism's ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.
    Keywords:  adoptive cellular therapies; fatty acid oxidation (FAO); immune cell differentiation; immunometabolism; metabolic adaptation; metabolic dysregulation
    DOI:  https://doi.org/10.3389/fimmu.2024.1420336
  13. Microbiol Spectr. 2024 Jul 16. e0091524
    Distinct prophage gene profiles of Staphylococcus aureus strains from atopic dermatitis patients and healthy individuals.
    Zhongjie Wang, Xue Peng, Claudia Hülpüsch, Mohammadali Khan Mirzaei, Matthias Reiger, Claudia Traidl-Hoffmann, Li Deng, Michael Schloter.
      Staphylococcus aureus strains exhibit varying associations with atopic dermatitis (AD), but the genetic determinants underpinning the pathogenicity are yet to be fully characterized. To reveal the genetic differences between S. aureus strains from AD patients and healthy individuals (HE), we developed and employed a random forest classifier to identify potential marker genes responsible for their phenotypic variations. The classifier was able to effectively distinguish strains from AD and HE. We also uncovered strong links between certain marker genes and phage functionalities, with phage holin emerging as the most pivotal differentiating factor. Further examination of S. aureus gene content highlighted the genetic diversity and functional implications of prophages in driving differentiation between strains from AD and HE. The HE group exhibited greater gene content diversity, largely influenced by their prophages. While strains from both AD and HE universally housed prophages, those in the HE group were distinctively higher at the strain level. Moreover, although prophages in the HE group exhibited variously higher enrichment of differential functions, the AD group displayed a notable enrichment of virulence factors within their prophages, underscoring the important contribution of prophages to the pathogenesis of AD-associated strains. Overall, prophages significantly shape the genetic and functional profiles of S. aureus strains, shedding light on their pathogenic potential and elucidating the mechanisms behind the phenotypic variations in AD and HE environments.
    IMPORTANCE: Through a nuanced exploration of Staphylococcus aureus strains obtained from atopic dermatitis (AD) patients and healthy controls (HE), our research unveils pivotal genetic determinants influencing their pathogenic associations. Utilizing a random forest classifier, we illuminate distinct marker genes, with phage holin emerging as a critical differential factor, revealing the profound impact of prophages on genetic and pathogenic profiles. HE strains exhibited a diverse gene content, notably shaped by unique, heightened prophages. Conversely, AD strains emphasized a pronounced enrichment of virulence factors within prophages, signifying their key role in AD pathogenesis. This work crucially highlights prophages as central architects of the genetic and functional attributes of S. aureus strains, providing vital insights into pathogenic mechanisms and phenotypic variations, thereby paving the way for targeted AD therapeutic approaches and management strategies by demystifying specific genetic and pathogenic mechanisms.
    Keywords:  Staphylococcus aureus; atopic dermatitis; pathogenesis; prophage; random forest
    DOI:  https://doi.org/10.1128/spectrum.00915-24
  14. Allergy. 2024 Jul 14.
    Pyroptosis, gasdermins and allergic diseases.
    Ronald Allan Panganiban, Kari C Nadeau, Quan Lu.
      Pyroptosis is an inflammatory form of programmed cell death that is distinct from necrosis and apoptosis. Pyroptosis is primarily mediated by the gasdermin family of proteins (GSDMA-E and PVJK), which, when activated by proteolytic cleavage, form pores in the plasma membrane, leading to cell death. While much of the past research on pyroptosis has focused on its role in cancer, metabolic disorders, and infectious diseases, recent experimental and observational studies have begun to implicate pyroptosis in allergic diseases. These studies suggest that gasdermin-mediated pyroptosis contributes to the development of allergic conditions and could offer novel targets for therapy. Here, we review our current understanding of pyroptosis with an emphasis on the role of gasdermins as executioners of pyroptosis and potential mediators to allergic disease. We highlight new discoveries that establish a mechanistic link between the biochemical actions of gasdermins and the onset of allergic diseases. Additionally, we discuss how pyroptosis and gasdermins might contribute to the dysfunction of epithelial barrier, a key factor believed to initiate the progression of various allergic diseases.
    Keywords:  asthma; barrier; basic mechanisms; inflammation
    DOI:  https://doi.org/10.1111/all.16236
  15. Nicotine Tob Res. 2024 Jul 17. pii: ntae176. [Epub ahead of print]
    E-Cigarette Use, Cigarette Smoking, and Sex are Associated with Nasal Microbiome Dysbiosis.
    Elise Hickman, Cristian Roca, Bryan T Zorn, Meghan E Rebuli, Carole Robinette, Matthew C Wolfgang, Ilona Jaspers.
       INTRODUCTION: Previous research suggests that e-cigarettes can alter immune function, including in the nasal mucosa, in unique ways. The respiratory microbiome plays a key role in respiratory host defense, but the effects of e-cigarettes on the respiratory or nasal microbiome, are not well understood.
    METHODS: Using 16S rRNA gene sequencing on nasal samples from adult e-cigarette users, smokers, and nonsmokers, we determined that e-cigarette use and cigarette smoking are associated with differential respiratory microbiome dysbiosis and substantial sex-dependent differences in the nasal microbiome, particularly in e-cigarette users.
    RESULTS: Staphylococcus aureus, a common respiratory pathogen, was more abundant in both e-cigarette users and smokers in comparison with nonsmokers, while Lactobacillus iners, often consider a protective species, was more abundant in smokers but less abundant in e-cigarette users in comparison with nonsmokers. In addition, we identified significant dysbiosis of the nasal microbiome between e-cigarette users and smokers with high versus low serum cotinine levels, an indicator of tobacco product use and toxicant exposure. We also analyzed nasal lavage fluid for immune mediators associated with host-microbiota interactions.
    CONCLUSIONS: Our analysis identified disruption of immune mediators in the nose of e-cigarette users and smokers, which is indicative of disrupted respiratory mucosal immune responses. Taken together, our data identified unique, sex-dependent host immune dysfunction associated with e-cigarette use in the nasal mucosa. More broadly, our data highlight the need for continued inclusion and careful consideration of sex as an important variable in the context of toxicant exposures.
    IMPLICATIONS: This is the first study investigating the effects of e-cigarette use and sex on the nasal microbiome, which is considered an important gatekeeper for protecting the lower respiratory tract from pathogens. We found significant sex, exposure group, and serum cotinine level associated differences in the composition of the nasal microbiome, demonstrating the importance of considering sex in future nasal microbiome studies and warranting further investigation of the mechanisms by which e-cigarette use dysregulates nasal immune homeostasis.
    DOI:  https://doi.org/10.1093/ntr/ntae176
  16. J Immunol. 2024 Jul 15. pii: ji2200728. [Epub ahead of print]
    Lung-resident CD3-NK1.1+CD69+CD103+ Cells Play an Important Role in Bacillus Calmette-Guérin Vaccine-Induced Protective Immunity against Mycobacterium tuberculosis Infection.
    Olamipejo Durojaye, Abhinav Vankayalapati, Padmaja Paidipally, Tanmoy Mukherjee, Ramakrishna Vankayalapati, Rajesh Kumar Radhakrishnan.
      Tissue-resident immune cells play important roles in local tissue homeostasis and infection control. There is no information on the functional role of lung-resident CD3-NK1.1+CD69+CD103+ cells in intranasal Bacillus Calmette-Guérin (BCG)-vaccinated and/or Mycobacterium tuberculosis (Mtb)-infected mice. Therefore, we phenotypically and functionally characterized these cells in mice vaccinated intranasally with BCG. We found that intranasal BCG vaccination increased CD3-NK1.1+ cells with a tissue-resident phenotype (CD69+CD103+) in the lungs during the first 7 d after BCG vaccination. Three months post-BCG vaccination, Mtb infection induced the expansion of CD3-NK1.1+CD69+CD103+ (lung-resident) cells in the lung. Adoptive transfer of lung-resident CD3-NK1.1+CD69+CD103+ cells from the lungs of BCG-vaccinated mice to Mtb-infected naive mice resulted in a lower bacterial burden and reduced inflammation in the lungs. Our findings demonstrated that intranasal BCG vaccination induces the expansion of CD3-NK1.1+CD69+CD103+ (lung-resident) cells to provide protection against Mtb infection.
    DOI:  https://doi.org/10.4049/jimmunol.2200728
  17. bioRxiv. 2024 Jul 11. pii: 2024.07.11.603094. [Epub ahead of print]
    Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization.
    Skye R S Fishbein, Anna L DeVeaux, Sakshi Khanna, Aura L Ferreiro, James Liao, Wesley Agee, Jie Ning, Bejan Mahmud, Miranda J Wallace, Tiffany Hink, Kimberly A Reske, Janaki Guruge, Sidh Leekha, Erik R Dubberke, Gautam Dantas.
      Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in clinical presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of outcomes. Microbiota-humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clade 1 lineages and identified commensal Blautia associated with markers of non-pathogenic colonization. Using gnotobiotic mice engrafted with defined human microbiota, we observed strain-specific CDI severity across clade 1 strains. Yet, mice engrafted with a higher diversity community were protected from severe disease across all strains without suppression of C. difficile colonization. These results indicate that when colonization resistance has been breached without overt infection, commensals can attenuate a diversity of virulent strains without inhibiting pathogen colonization, providing insight into determinants of stable C. difficile carriage.
    DOI:  https://doi.org/10.1101/2024.07.11.603094
  18. Immunity. 2024 Jul 06. pii: S1074-7613(24)00316-9. [Epub ahead of print]
    Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.
    Olaf Perdijk, Alana Butler, Matthew Macowan, Roxanne Chatzis, Edyta Bulanda, Rhiannon D Grant, Nicola L Harris, Tomasz P Wypych, Benjamin J Marsland.
      Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.
    Keywords:  airway epithelial cells; allergy; antibiotics; early life; gut-lung axis; indole-3-propionic acid; metabolites; microbiota; redox balance; window of opportunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.010
  19. Eur Respir Rev. 2024 Apr;pii: 230266. [Epub ahead of print]33(172):
    Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old.
    Hermelijn H Smits, Simon P Jochems.
      Respiratory viral infections frequently lead to severe respiratory disease, particularly in vulnerable populations such as young children, individuals with chronic lung conditions and older adults, resulting in hospitalisation and, in some cases, fatalities. The innate immune system plays a crucial role in monitoring for, and initiating responses to, viruses, maintaining a state of preparedness through the constant expression of antimicrobial defence molecules. Throughout the course of infection, innate immunity remains actively involved, contributing to viral clearance and damage control, with pivotal contributions from airway epithelial cells and resident and newly recruited immune cells. In instances where viral infections persist or are not effectively eliminated, innate immune components prominently contribute to the resulting pathophysiological consequences. Even though both young children and older adults are susceptible to severe respiratory disease caused by various respiratory viruses, the underlying mechanisms may differ significantly. Children face the challenge of developing and maturing their immunity, while older adults contend with issues such as immune senescence and inflammaging. This review aims to compare the innate immune responses in respiratory viral infections across both age groups, identifying common central hubs that could serve as promising targets for innovative therapeutic and preventive strategies, despite the apparent differences in underlying mechanisms.
    DOI:  https://doi.org/10.1183/16000617.0266-2023
  20. Sci Rep. 2024 Jul 17. 14(1): 16568
    Reduced sialylation of airway mucin impairs mucus transport by altering the biophysical properties of mucin.
    Elex S Harris, Hannah J McIntire, Marina Mazur, Hinnerk Schulz-Hildebrandt, Hui Min Leung, Guillermo J Tearney, Stefanie Krick, Steven M Rowe, Jarrod W Barnes.
      Mucus stasis is a pathologic hallmark of muco-obstructive diseases, including cystic fibrosis (CF). Mucins, the principal component of mucus, are extensively modified with hydroxyl (O)-linked glycans, which are largely terminated by sialic acid. Sialic acid is a negatively charged monosaccharide and contributes to the biochemical/biophysical properties of mucins. Reports suggest that mucin sialylation may be altered in CF; however, the consequences of reduced sialylation on mucus clearance have not been fully determined. Here, we investigated the consequences of reduced sialylation on the charge state and conformation of the most prominent airway mucin, MUC5B, and defined the functional consequences of reduced sialylation on mucociliary transport (MCT). Reduced sialylation contributed to a lower charged MUC5B form and decreased polymer expansion. The inhibition of total mucin sialylation de novo impaired MCT in primary human bronchial epithelial cells and rat airways, and specific α-2,3 sialylation blockade was sufficient to recapitulate these findings. Finally, we show that ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3Gal1) expression is downregulated in CF and partially restored by correcting CFTR via Elexacaftor/Tezacaftor/Ivacaftor treatment. Overall, this study demonstrates the importance of mucin sialylation in mucus clearance and identifies decreased sialylation by ST3Gal1 as a possible therapeutic target in CF and potentially other muco-obstructive diseases.
    DOI:  https://doi.org/10.1038/s41598-024-66510-2
  21. mBio. 2024 Jul 19. e0121024
    A MRSA mystery: how PBP4 and cyclic-di-AMP join forces against β-lactam antibiotics.
    Taylor M Gardner, Melinda R Grosser.
      The high-level resistance to next-generation β-lactams frequently found in Staphylococcus aureus isolates lacking mec, which encodes the transpeptidase PBP2a traditionally associated with methicillin-resistant Staphylococcus aureus (MRSA), has remained incompletely understood for decades. A new study by Lai et al. found that the co-occurrence of mutations in pbp4 and gdpP, which respectively cause increased PBP4-mediated cell wall crosslinking and elevated cyclic-di-AMP levels, produces synergistic β-lactam resistance rivaling that of PBP2a-producing MRSA (L.-Y. Lai, N. Satishkumar, S. Cardozo, V. Hemmadi, et al., mBio 15:e02889-23. 2024, https://doi.org/10.1128/mbio.02889-23). The combined mutations are sufficient to explain the high-level β-lactam resistance of some mec-lacking strains, but the mechanism of synergy remains elusive and an avenue for further research. Importantly, the authors establish that co-occurrence of these mutations leads to antibiotic therapy failure in a Caenorhabditis elegans infection model. These results underscore the need to consider this unique and novel β-lactam resistance mechanism during the clinical diagnosis of MRSA, rather than relying on mec as a diagnostic.
    Keywords:  MRSA; PBP4; cyclic-di-AMP; gdpP; methicillin-resistant lacking mec (MRLM); β-lactam resistance
    DOI:  https://doi.org/10.1128/mbio.01210-24
  22. Int Immunopharmacol. 2024 Jul 17. pii: S1567-5769(24)01216-5. [Epub ahead of print]139 112695
    Rational design of ROS generation nanosystems to regulate innate immunity of macrophages, dendrtical and natural killing cells for immunotherapy.
    Yan Gao, Di Huang, Shuodan Huang, Huiying Li, Bing Xia.
      Innate immunity serves as the first line of host defense in the body against pathogenic infections or malignant diseases. Reactive oxygen species (ROS), as vital signaling mediators, can efficiently elicit innate immune responses to oxidative-related stress or damage. In the era of nanomedicine, various immunostimulatory nanosystems have been extensively designed and synthesized to elicit immune responses for the immunotherapy of cancer or infectious diseases. In this review, we emphasize that ROS derived from nanosystems regulates innate immune cells to potentiate immunotherapeutic efficacy, such as primarily dendritic cells, macrophages, or natural killer cells. Meanwhile, we also summarize the pathway of ROS generation triggered by exogenous nanosystems in innate immune cells of DCs, macrophages, and NK cells.
    Keywords:  Cancer; Infectious diseases; Innate immune cells; Nanosystems; ROS
    DOI:  https://doi.org/10.1016/j.intimp.2024.112695
  23. Front Immunol. 2024 ;15 1427846
    Host and pathogen genetic diversity shape vaccine-mediated protection to Mycobacterium tuberculosis.
    Sara B Cohen, Courtney R Plumlee, Lindsay Engels, Dat Mai, Tara A Murray, Ana N Jahn, Bridget Alexander, Jared L Delahaye, Lauren M Cross, Karolina Maciag, Sam Schrader, Kaitlin Durga, Elizabeth S Gold, Alan Aderem, Michael Y Gerner, Benjamin H Gern, Alan H Diercks, Kevin B Urdahl.
      To investigate how host and pathogen diversity govern immunity against Mycobacterium tuberculosis (Mtb), we performed a large-scale screen of vaccine-mediated protection against aerosol Mtb infection using three inbred mouse strains [C57BL/6 (B6), C3HeB/FeJ (C3H), Balb/c x 129/SvJ (C129F1)] and three Mtb strains (H37Rv, CDC1551, SA161) representing two lineages and distinct virulence properties. We compared three protective modalities, all of which involve inoculation with live mycobacteria: Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, delivered either subcutaneously or intravenously, and concomitant Mtb infection (CoMtb), a model of pre-existing immunity in which a low-level Mtb infection is established in the cervical lymph node following intradermal inoculation. We examined lung bacterial burdens at early (Day 28) and late (Day 98) time points after aerosol Mtb challenge and histopathology at Day 98. We observed substantial heterogeneity in the reduction of bacterial load afforded by these modalities at Day 28 across the combinations and noted a strong positive correlation between bacterial burden in unvaccinated mice and the degree of protection afforded by vaccination. Although we observed variation in the degree of reduction in bacterial burdens across the nine mouse/bacterium strain combinations, virtually all protective modalities performed similarly for a given strain-strain combination. We also noted dramatic variation in histopathology changes driven by both host and bacterial genetic backgrounds. Vaccination improved pathology scores for all infections except CDC1551. However, the most dramatic impact of vaccination on lesion development occurred for the C3H-SA161 combination, where vaccination entirely abrogated the development of the large necrotic lesions that arise in unvaccinated mice. In conclusion, we find that substantial TB heterogeneity can be recapitulated by introducing variability in both host and bacterial genetics, resulting in changes in vaccine-mediated protection as measured both by bacterial burden as well as histopathology. These differences can be harnessed in future studies to identify immune correlates of vaccine efficacy.
    Keywords:  genetics; heterogeneity; protection; tuberculosis; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2024.1427846
  24. Medicine (Baltimore). 2024 Jul 19. 103(29): e39051
    Gut microbiota and epigenetic choreography: Implications for human health: A review.
    Bailee Kim, Angel Song, Andrew Son, Yonghwan Shin.
      The interwoven relationship between gut microbiota and the epigenetic landscape constitutes a pivotal axis in understanding human health and disease. Governed by a myriad of dietary, genetic, and environmental influences, the gut microbiota orchestrates a sophisticated metabolic interplay, shaping nutrient utilization, immune responses, and defenses against pathogens. Recent strides in genomics and metabolomics have shed light on the intricate connections between these microbial influencers and the host's physiological dynamics, presenting a dynamic panorama across diverse disease spectra. DNA methylation and histone modifications, as key players in epigenetics, intricately align with the dynamic orchestration of the gut microbiota. This seamless collaboration, notably evident in conditions like inflammatory bowel disease and obesity, has captured the attention of researchers, prompting an exploration of its nuanced choreography. Nevertheless, challenges abound. Analyzing data is intricate due to the multifaceted nature of the gut microbiota and the limitations of current analytical methods. This underscores the need for a multidisciplinary approach, where diverse disciplines converge to pave innovative research pathways. The integration of insights from microbiome and epigenome studies assumes paramount importance in unraveling the complexities of this intricate partnership. Deciphering the synchronized interactions within this collaboration offers a deeper understanding of these delicate interplays, potentially heralding revolutionary strides in treatment modalities and strategies for enhancing public health.
    DOI:  https://doi.org/10.1097/MD.0000000000039051
  25. Exp Dermatol. 2024 Jul;33(7): e15135
    Pyroptosis and its role in autoimmune skin disease.
    Yuanjun Yao, Zehong Wang, Junqin Li, Aihong Peng, Yue Cao, Nannan Liang, Kaiming Zhang.
      Autoimmune skin disease is a kind of heterogeneous disease with complicated pathogenesis. Many factors such as genetic, infectious, environmental and even psychological factors may interact together to trigger a synergistic effect for the development of abnormal innate and adaptive immune responses. Although the exact mechanisms remain unclear, recent evidence suggests that pyroptosis plays a pivotal role in the development of autoimmune skin disease. The feature of pyroptosis is the first formation of pores in cellular membranes, then cell rupture and the release of intracellular substances and pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) and IL-18. This hyperactive inflammatory programmed cell death damages the homeostasis of the immune system and advances autoimmunity. This review briefly summarises the molecular regulatory mechanisms of pyrin domain-containing protein 3 (NLRP3) inflammasome and gasdermin family, as well as the molecular mechanisms of pyroptosis, highlights the latest progress of pyroptosis in autoimmune skin disease, including systemic lupus erythematosus, psoriasis, atopic dermatitis and systemic scleroderma and attempts to identify its potential advantages as a therapeutic target or prognostic biomarker for these diseases.
    Keywords:  NLRP3 inflammasome; autoimmune skin disease; gasdermin family; pyroptosis
    DOI:  https://doi.org/10.1111/exd.15135
  26. Int Immunopharmacol. 2024 Jul 16. pii: S1567-5769(24)01201-3. [Epub ahead of print]139 112680
    LincR-PPP2R5C regulates IL-1β ubiquitination in macrophages and promotes airway inflammation and emphysema in a murine model of COPD.
    Min Wang, Manni Zhu, Xinyu Jia, Jingjing Wu, Qi Yuan, Tingting Xu, Zhengxia Wang, Mao Huang, Ningfei Ji, Mingshun Zhang.
      Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity and mortality. Macrophages release IL-1β and orchestrate airway inflammation in COPD. Previously, we explored the role of a new lncRNA, LincR-PPP2R5C, in regulating Th2 cells in asthma. Here, we established a murine model of COPD and explored the roles and mechanisms by which LincR-PPP2R5C regulates IL-1β in macrophages. LincR-PPP2R5C was highly expressed in pulmonary macrophages from COPD-like mice. LincR-PPP2R5C deficiency ameliorated emphysema and pulmonary inflammation, as characterized by reduced IL-1β in macrophages. Unexpectedly, in both lung tissues and macrophages, LincR-PPP2R5C deficiency decreased the expression of the IL-1β protein but not the IL-1β mRNA. Furthermore, we found that LincR-PPP2R5C deficiency increased the level of ubiquitinated IL-1β in macrophages, which was mediated by PP2A activity. Targeting PP2A with FTY720 decreased IL-1β and improved COPD. In conclusion, LincR-PPP2R5C regulates IL-1β ubiquitination by affecting PP2A activity in macrophages, contributing to the airway inflammation and emphysema in a murine model of COPD. PP2A and IL-1β ubiquitination in macrophages might be new therapeutic avenues for COPD therapy.
    Keywords:  COPD; IL-1β; Macrophage; PP2A; Ubiquitination; lncRNA
    DOI:  https://doi.org/10.1016/j.intimp.2024.112680
  27. Chemosphere. 2024 Jul 16. pii: S0045-6535(24)01779-X. [Epub ahead of print] 142885
    Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma.
    Hongmiao Yu, Caiyan Zhang, Hongguang Pan, Xia Gao, Xiang Wang, Wenfeng Xiao, Shang Yan, Yajing Gao, Jinrong Fu, Yufeng Zhou.
      Particulate matter of aerodynamic diameter ≤2.5 μm (PM2.5) exposure induces oxidative stress in lung tissues. Ferroptosis is a form of regulated cell death based on oxidative damage and lipid peroxidation. Whether PM2.5 exposure-induced oxidative stress can promote ferroptosis to aggravate asthma is not known. To investigate if PM2.5 exposure induces oxidative stress to promote ferroptosis and influence asthma development, a cockroach extract-induced asthma model in mice was used for in vivo studies. Airway epithelial cell (AEC) ferroptosis was detected by assays (CCK8, malonaldehyde, and 4-hydroxynonenal). Molecular mechanisms were investigated by real-time reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry, liquid chromatography-tandem mass spectrometry, and chromatin immunoprecipitation. We found that exposure to PM2.5 and Indeno[1,2,3-cd] pyrene (IP; one of the prominent absorbed polycyclic aromatic hydrocarbons in PM2.5) enhanced the sensitivity of AECs to ferroptosis to aggravate asthma, whereas ferroptosis inhibitors and cytosolic phospholipase A2 (cPLA2) inhibitors reversed this augmented inflammatory response in mice suffering from asthma. IP treatment enhanced cPLA2 expression/activation through aryl hydrocarbon receptor (AhR) genomic and non-genomic pathways, resulting in arachidonic-acid release to promote the sensitivity of AECs to ferroptosis. IP exposure enhanced the release of leukotriene-B4 from lung macrophages, resulting in enhanced expression of acyl-coA synthetase long chain family member4(ACSL4) and the sensitivity of AECs to ferroptosis. This finding suggests that exposure to PM2.5 and IP promote ferroptosis sensitivity in AECs to aggravate asthma, which may provide new targets for the prevention and treatment of asthma.
    Keywords:  Aryl hydrocarbon receptor; Asthma; Ferroptosis; PM(2.5); Polycyclic aromatic hydrocarbons
    DOI:  https://doi.org/10.1016/j.chemosphere.2024.142885
  28. Microbiol Spectr. 2024 Jul 16. e0415223
    The two alternative NADH:quinone oxidoreductases from Staphylococcus aureus: two players with different molecular and cellular roles.
    Filipa V Sena, Filipe M Sousa, Ana R Pereira, Teresa Catarino, Eurico J Cabrita, Mariana G Pinho, Francisco R Pinto, Manuela M Pereira.
      Staphylococcus aureus is an opportunistic pathogen that has emerged as a major public health threat due to the increased incidence of its drug resistance. S. aureus presents a remarkable capacity to adapt to different niches due to the plasticity of its energy metabolism. In this work, we investigated the energy metabolism of S. aureus, focusing on the alternative NADH:quinone oxidoreductases, NDH-2s. S. aureus presents two genes encoding NDH-2s (NDH-2A and NDH-2B) and lacks genes coding for Complex I, the canonical respiratory NADH:quinone oxidoreductase. This observation makes the action of NDH-2s crucial for the regeneration of NAD+ and, consequently, for the progression of metabolism. Our study involved the comprehensive biochemical characterization of NDH-2B and the exploration of the cellular roles of NDH-2A and NDH-2B, utilizing knockout mutants (Δndh-2a and Δndh-2b). We show that NDH-2B uses NADPH instead of NADH, does not establish a charge-transfer complex in the presence of NADPH, and its reduction by this substrate is the catalytic rate-limiting step. In the case of NDH-2B, the reduction of the flavin is inherently slow, and we suggest the establishment of a charge transfer complex between NADP+ and FADH2, as previously observed for NDH-2A, to slow down quinone reduction and, consequently, prevent the overproduction of reactive oxygen species, which is potentially unnecessary. Furthermore, we observed that the lack of NDH-2A or NDH-2B impacts cell growth, volume, and division differently. The absence of these enzymes results in distinct metabolic phenotypes, emphasizing the unique cellular roles of each NDH-2 in energy metabolism.IMPORTANCEStaphylococcus aureus is an opportunistic pathogen, posing a global challenge in clinical medicine due to the increased incidence of its drug resistance. For this reason, it is essential to explore and understand the mechanisms behind its resistance, as well as the fundamental biological features such as energy metabolism and the respective players that allow S. aureus to live and survive. Despite its prominence as a pathogen, the energy metabolism of S. aureus remains underexplored, with its respiratory enzymes often escaping thorough investigation. S. aureus bioenergetic plasticity is illustrated by its ability to use different respiratory enzymes, two of which are investigated in the present study. Understanding the metabolic adaptation strategies of S. aureus to bioenergetic challenges may pave the way for the design of therapeutic approaches that interfere with the ability of the pathogen to successfully adapt when it invades different niches within its host.
    Keywords:  NAD(P)H; alternative NADH oxidase; charge-transfer complex; membrane proteins; monotopic proteins; quinones; respiratory chain
    DOI:  https://doi.org/10.1128/spectrum.04152-23
  29. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516
    Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
    Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.
      Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.
    Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network
    DOI:  https://doi.org/10.1016/j.celrep.2024.114516
  30. Pathog Dis. 2024 Jul 19. pii: ftae016. [Epub ahead of print]
    Sphingosine kills intracellular Pseudomonas aeruginosa and Staphylococcus aureus.
    Helene May, Yongjie Liu, Stephanie Kadow, Michael J Edwards, Simone Keitsch, Barbara Wilker, Markus Kamler, Heike Grassmé, Yuqing Wu, Erich Gulbins.
      Sphingosine has been previously shown to kill many strains of pathogenic bacteria including Pseudomonas aeruginosa, Staphyloccus aureus, Acinetobacter and atypical mycobacteria. However, these studies were performed on isolated or extracellular bacteria and it is unknown whether sphingosine also targets intracellular bacteria. Here, we demonstrate that exogenously-added sphingosine directly binds to extracellular P. aeruginosa and S. aureus, but also targets and binds to intracellular bacteria. Intracellular sphingosine and bacteria were identified by sequential immunostainings. We further show that exogenously-added sphingosine also kills intracellular P. aeruginosa and S. aureus using modified gentamycin assays. Intracellular killing of P. aeruginosa and S. aureus by sphingosine is not mediated by improved phagosomal-lysosomal fusion. In summary, our data indicate that sphingosine binds to and most likely also directly kills extra- and intracellular P. aeruginosa and S. aureus.
    Keywords:   Pseudomonas aeruginosa ; Staphyloccus aureus ; Sphingosine; ceramide; cystic fibrosis; sphingolipids
    DOI:  https://doi.org/10.1093/femspd/ftae016
  31. Commun Biol. 2024 Jul 16. 7(1): 866
    Facile metabolic reprogramming distinguishes mycobacterial adaptation to hypoxia and starvation: ketosis drives starvation-induced persistence in M. bovis BCG.
    Nick K Davis, Yok Hian Chionh, Megan E McBee, Fabian Hia, Duanduan Ma, Liang Cui, Mariam Lucila Sharaf, Weiling Maggie Cai, Watthanachai Jumpathong, Stuart S Levine, Sylvie Alonso, Peter C Dedon.
      Mycobacteria adapt to infection stresses by entering a reversible non-replicating persistence (NRP) with slow or no cell growth and broad antimicrobial tolerance. Hypoxia and nutrient deprivation are two well-studied stresses commonly used to model the NRP, yet little is known about the molecular differences in mycobacterial adaptation to these distinct stresses that lead to a comparable NRP phenotype. Here we performed a multisystem interrogation of the Mycobacterium bovis BCG (BCG) starvation response, which revealed a coordinated metabolic shift away from the glycolysis of nutrient-replete growth to depletion of lipid stores, lipolysis, and fatty acid ß-oxidation in NRP. This contrasts with BCG's NRP hypoxia response involving a shift to cholesterol metabolism and triglyceride storage. Our analysis reveals cryptic metabolic vulnerabilities of the starvation-induced NRP state, such as their newfound hypersensitivity to H2O2. These observations pave the way for developing precision therapeutics against these otherwise drug refractory pathogens.
    DOI:  https://doi.org/10.1038/s42003-024-06562-2
  32. Helicobacter. 2024 Jul-Aug;29(4):29(4): e13108
    Effect of Lactobacillus gasseri BIO6369 and Lacticaseibacillus rhamnosus BIO5326 on Gastric Carcinogenesis Induced by Helicobacter pylori Infection.
    Marine Jauvain, Gorann Lepied, Lucie Bénéjat, Nathalie Roudier, Christelle Dussert, Philippe Lehours, Christine Varon, Emilie Bessède.
       BACKGROUND: Helicobacter pylori infection-associated gastric adenocarcinoma is influenced by various factors, including the digestive microbiota. Lactic acid bacteria role in digestive carcinogenesis has been discussed, and some Lactobacillaceae family species have been shown to act against H. pylori-induced inflammation and colonization. However, their effects on H. pylori-related carcinogenesis have not yet been studied. Lactobacillaceae family effects on the epithelial-to-mesenchymal transition (EMT), emergence of cells with cancer stem cell (CSC) properties and the pro-inflammatory response of gastric epithelial cells to H. pylori infection were investigated.
    MATERIALS AND METHODS: A co-culture model of AGS gastric epithelial cells infected with a carcinogenic strain of H. pylori associated with 18 different probiotic strains candidates were used. Different EMT indicators and CSC properties were studied, including quantification of the mesenchymal phenotype, tumorsphere formation, EMT marker expression, and tight junction evaluation with immunofluorescence microscopy. The effect of the strains on the pro-inflammatory response to H. pylori was also evaluated by quantifying interleukin-8 (IL-8) production using ELISA.
    RESULTS: Among the strains tested, Lactobacillus gasseri BIO6369 and Lacticaseibacillus rhamnosus BIO5326 induced a 30.6% and 38.4% reduction in the mesenchymal phenotype, respectively, caused a significant decrease in Snail and Zeb1 EMT marker expression and prevented the loss of tight junctions induced by H. pylori infection. A separate co-culture with a Boyden chamber maintained the effects induced by the two strains. H. pylori-induced IL-8 production was also significantly reduced in the presence of L. gasseri BIO6369 and L. rhamnosus BIO5326.
    CONCLUSION: Lactobacillus gasseri BIO6369 and L. rhamnosus BIO5326 strains decreased epithelial-to-mesenchymal transition and inflammation induced by H. pylori infection, suggesting that these species may have a protective effect against H. pylori-induced gastric carcinogenesis.
    Keywords:   Helicobacter pylori ; Lactobacillus species; epithelial‐to‐mesenchymal transition; gastric cancer; probiotic
    DOI:  https://doi.org/10.1111/hel.13108
  33. J Asthma Allergy. 2024 ;17 633-651
    Association Between Gut and Nasal Microbiota and Allergic Rhinitis: A Systematic Review.
    Yucheng Hu, Rong Zhang, Junjie Li, Huan Wang, Meiya Wang, Qiuyi Ren, Yueqi Fang, Li Tian.
      Allergic rhinitis is a chronic non-infectious inflammation of the nasal mucosa mediated by specific IgE. Recently, the human microbiome has drawn broad interest as a potential new target for treating this condition. This paper succinctly summarizes the main findings of 17 eligible studies published by February 2024, involving 1044 allergic rhinitis patients and 954 healthy controls from 5 countries. These studies examine differences in the human microbiome across important mucosal interfaces, including the nasal and intestinal areas, between patients and controls. Overall, findings suggest variations in the gut microbiota between allergic rhinitis patients and healthy individuals, although the specific bacterial taxa that significantly changed were not always consistent across studies. Due to the limited scope of existing research and patient coverage, the relationship between the nasal microbiome and allergic rhinitis remains inconclusive. The article discusses the potential immune-regulating role of the gut microbiome in allergic rhinitis. Further well-designed clinical trials with large-scale recruitment of allergic rhinitis patients are encouraged.
    Keywords:  allergic rhinitis; immunomodulation; microbiota dysbiosis; nasal microbiome; short-chain fatty acids
    DOI:  https://doi.org/10.2147/JAA.S472632
  34. Respir Res. 2024 Jul 15. 25(1): 277
    Building a human lung from pluripotent stem cells to model respiratory viral infections.
    Declan L Turner, Sahel Amoozadeh, Hannah Baric, Ed Stanley, Rhiannon B Werder.
      To protect against the constant threat of inhaled pathogens, the lung is equipped with cellular defenders. In coordination with resident and recruited immune cells, this defence is initiated by the airway and alveolar epithelium following their infection with respiratory viruses. Further support for viral clearance and infection resolution is provided by adjacent endothelial and stromal cells. However, even with these defence mechanisms, respiratory viral infections are a significant global health concern, causing substantial morbidity, socioeconomic losses, and mortality, underlining the need to develop effective vaccines and antiviral medications. In turn, the identification of new treatment options for respiratory infections is critically dependent on the availability of tractable in vitro experimental models that faithfully recapitulate key aspects of lung physiology. For such models to be informative, it is important these models incorporate human-derived, physiologically relevant versions of all cell types that normally form part of the lungs anti-viral response. This review proposes a guideline using human induced pluripotent stem cells (iPSCs) to create all the disease-relevant cell types. iPSCs can be differentiated into lung epithelium, innate immune cells, endothelial cells, and fibroblasts at a large scale, recapitulating in vivo functions and providing genetic tractability. We advocate for building comprehensive iPSC-derived in vitro models of both proximal and distal lung regions to better understand and model respiratory infections, including interactions with chronic lung diseases.
    Keywords:  Disease modelling; Epithelium; Induced pluripotent stem cells; Lung models; Respiratory infections; Stem cell models
    DOI:  https://doi.org/10.1186/s12931-024-02912-0
  35. New Microbiol. 2024 Jul;47(2): 183-185
    Rethinking Combination Therapy for S. aureus bacteremia: A Fading Paradigm.
    Sergio Venturini, Ingrid Reffo, Manuela Avolio, Giancarlo Basaglia, Giovanni Del Fabro, Astrid Callegari, Igor Bramuzzo, Maurizio Tonizzo, Riccardo Lucis, Elisa Pontoni, Laura De Santi, Massimo Crapis.
      Staphylococcus aureus bacteremia presents clinical complexities, with prolonged duration associated with unfavorable outcomes. This research delves into unconventional treatments, such as combinations involving daptomycin, oxacillin, ceftaroline, and fosfomycin, with the aim of swiftly sterilizing bloodstream infection to reduce complications. Our examination of 30 MSSA bacteremia patients with infective endocarditis uncovers differing results between single-agent therapies (oxacillin or daptomycin) and combined treatment plans. Microbiologic clearance at the 72 hour mark demonstrates greater efficacy within the combination cohort (bacteremia persistence 29%) versus monotherapy (bacteremia persistence 78%). This limited case series suggests the potential superiority of combination therapy, prompting further investigations.
    Keywords:  Bacteremia; Staphylococcus aureus; combination therapy; endocarditis; monotherapy
  36. Nat Rev Immunol. 2024 Jul 15.
    How bile acids and the microbiota interact to shape host immunity.
    Michael H Lee, Sean-Paul Nuccio, Ipsita Mohanty, Lee R Hagey, Pieter C Dorrestein, Hiutung Chu, Manuela Raffatellu.
      Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
    DOI:  https://doi.org/10.1038/s41577-024-01057-x
  37. J Invest Dermatol. 2024 Jul 15. pii: S0022-202X(24)01884-0. [Epub ahead of print]
    Integrated Single-Cell Analysis Reveals Spatially and Temporally Dynamic Heterogeneity in Fibroblast States During Wound Healing.
    Axel A Almet, Yingzi Liu, Qing Nie, Maksim V Plikus.
      Wound healing is a dynamic process over temporal and spatial scales. Key to repair outcomes are fibroblasts, yet how they modulate healing across time and in different wound regions remains incompletely understood. By integrating single-cell RNA-sequencing datasets of mouse skin and wounds, we infer that fibroblasts are the most transcriptionally dynamic skin-resident cells, evolving during postnatal skin maturation, and rapidly after injury towards distinct late scar states. We show that transcriptional dynamics in fibroblasts are largely driven by genes encoding extracellular matrix and signaling factors. Lineage trajectory inference and spatial gene mapping reveal that Prg4-expressing fibroblasts transiently emerge along early wound edges. Within days, they become replaced by long-lasting and likely non-interconverting fibroblast populations, including Col25a1-expressing and Pamr1-expressing fibroblasts that occupy subepidermal and deep scar regions, respectively, where they engage in reciprocal signaling with immune cells. Signaling inference shows that fibroblast-immune crosstalk repeatedly uses some signaling pathways across wound healing time, while use of other signaling pathways is time- and space-limited. Collectively, we uncovered high transcriptional plasticity by wound fibroblasts, with early states transiently forming distinct micro-niches along wound edges and in the fascia, followed by stable states, that stratify scar tissue into molecularly dissimilar upper and lower layers.
    Keywords:  data integration; fibroblasts; scar; single-cell RNA-sequencing; wound healing
    DOI:  https://doi.org/10.1016/j.jid.2024.06.1281
  38. Nat Commun. 2024 Jul 17. 15(1): 6024
    Prolonged hospitalization signature and early antibiotic effects on the nasopharyngeal resistome in preterm infants.
    Achal Dhariwal, Polona Rajar, Gabriela Salvadori, Heidi Aarø Åmdal, Dag Berild, Ola Didrik Saugstad, Drude Fugelseth, Gorm Greisen, Ulf Dahle, Kirsti Haaland, Fernanda Cristina Petersen.
      Respiratory pathogens, commonly colonizing nasopharynx, are among the leading causes of death due to antimicrobial resistance. Yet, antibiotic resistance determinants within nasopharyngeal microbial communities remain poorly understood. In this prospective cohort study, we investigate the nasopharynx resistome development in preterm infants, assess early antibiotic impact on its trajectory, and explore its association with clinical covariates using shotgun metagenomics. Our findings reveal widespread nasopharyngeal carriage of antibiotic resistance genes (ARGs) with resistomes undergoing transient changes, including increased ARG diversity, abundance, and composition alterations due to early antibiotic exposure. ARGs associated with the critical nosocomial pathogen Serratia marcescens persist up to 8-10 months of age, representing a long-lasting hospitalization signature. The nasopharyngeal resistome strongly correlates with microbiome composition, with inter-individual differences and postnatal age explaining most of the variation. Our report on the collateral effects of antibiotics and prolonged hospitalization underscores the urgency of further studies focused on this relatively unexplored reservoir of pathogens and ARGs.
    DOI:  https://doi.org/10.1038/s41467-024-50433-7
  39. Nat Commun. 2024 Jul 13. 15(1): 5898
    Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity.
    Henry Quach, Spencer Farrell, Ming Jia Michael Wu, Kayshani Kanagarajah, Joseph Wai-Hin Leung, Xiaoqiao Xu, Prajkta Kallurkar, Andrei L Turinsky, Christine E Bear, Felix Ratjen, Brian Kalish, Sidhartha Goyal, Theo J Moraes, Amy P Wong.
      Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10-19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.
    DOI:  https://doi.org/10.1038/s41467-024-50281-5
  40. Cell Host Microbe. 2024 Jul 10. pii: S1931-3128(24)00231-2. [Epub ahead of print]
    Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease.
    Elisabeth Urbauer, Doriane Aguanno, Nora Mindermann, Hélène Omer, Amira Metwaly, Tina Krammel, Tim Faro, Marianne Remke, Sandra Reitmeier, Stefanie Bärthel, Johannes Kersting, Zihua Huang, Feng Xian, Manuela Schmidt, Dieter Saur, Samuel Huber, Bärbel Stecher, Markus List, David Gómez-Varela, Katja Steiger, Matthieu Allez, Eva Rath, Dirk Haller.
      Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10-/-), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.
    Keywords:  Bacteroides; IBD; cell stress; heat shock protein 60; inflammation; intestinal epithelial cells; metabolic injury; microbiome; mitochondrial dysfunction; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chom.2024.06.013
  41. Curr Opin Microbiol. 2024 Jul 17. pii: S1369-5274(24)00089-4. [Epub ahead of print]80 102513
    Editorial overview: Linking cellular regulation and metabolic functions: from signals to mechanisms.
    Jürgen Lassak, Natalia Tschowri.
      
    DOI:  https://doi.org/10.1016/j.mib.2024.102513
  42. Front Cell Infect Microbiol. 2024 ;14 1442855
    Editorial: The role of probiotics, postbiotics, and microbial metabolites in preventing and treating chronic diseases, volume II.
    Chuanlin Luo, Shengjie Li, Tingtao Chen.
      
    Keywords:  chronic disease; fecal microbiota transplantation; gut microbiota; gut-X axis; probiotics
    DOI:  https://doi.org/10.3389/fcimb.2024.1442855
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