bims-bac4me 2024-06-02 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024–06–02
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Acid-treated Staphylococcus aureus induces acute silkworm hemolymph melanization.
Human skin bacterial microbiota homeostasis: A delicate balance between health and disease.
'Smart' antibiotic can kill deadly bacteria while sparing the microbiome.
Daily briefing: 'Smart' antibiotic spares the microbiome.
Lung infection with classical Klebsiella pneumoniae strains establishes robust macrophage-dependent protection against heterologous reinfection.
The cholera toxin B subunit induces trained immunity in dendritic cells and promotes CD8 T cell antitumor immunity.
Staphylococcus aureus Conquers Host by Hijacking Mitochondria via PFKFB3 in Epithelial Cells.
Staphylococcus aureus Serine protease-like protein A (SplA) induces IL-8 by keratinocytes and synergizes with IL-17A.
Multifaceted mitochondria in innate immunity.
The guardians of pulmonary harmony: alveolar macrophages orchestrating the symphony of lung inflammation and tissue homeostasis.
Newly Isolated Limosilactobacillus reuteri B1/1 Modulates the Expression of Cytokines and Antimicrobial Proteins in a Porcine ex Vivo Model.
The Yin and Yang of pathogens and probiotics: interplay between Salmonella enterica sv. Typhimurium and Bifidobacterium infantis during co-infection.
Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.
Understanding How Pre- and Probiotics Affect the Gut Microbiome and Metabolic Health.
Salmonella Typhimurium expansion in the inflamed murine gut is dependent on aspartate derived from ROS-mediated microbiota lysis.
Tyndallized bacteria prime bronchial epithelial cells to mount an effective innate immune response against infections.
Methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus produce antimicrobial substances against members of the skin microbiota in children with atopic dermatitis.
Unveiling the immune dynamics of Neisseria persistent oral colonization.
The role of dendritic cells in respiratory viral infection.
Airway IL-1β is related to disease severity and mucociliary function in bronchiectasis.
Bacterial and fungal communities in chronic rhinosinusitis with nasal polyps.
Gut commensals require Peyer's patches to induce protective systemic IgA responses.
Control of Inflammatory Response by Tissue Microenvironment.
Role of bacterial multidrug efflux pumps during infection.
Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration.
TRIM33 plays a critical role in regulating dendritic cell differentiation and homeostasis by modulating Irf8 and Bcl2l11 transcription.
Three-Dimensional Cell Culture Models to Investigate the Epithelial Barrier in Eosinophilic Esophagitis.
Mutualistic interactions of lactate-producing lactobacilli and lactate-utilizing Veillonella dispar: Lactate and glutamate cross-feeding for the enhanced growth and short-chain fatty acid production.
GSDMD protects intestinal epithelial cells against bacterial infections through its N-terminal activity impacting intestinal immune homeostasis.
Lactate exacerbates lung damage induced by nano-microplastics through the gut microbiota-HIF1a/PTBP1 pathway.
Microbial metabolites as modulators of host physiology.
Streptococcus agalactiae glycolipids promote virulence by thwarting immune cell clearance.
Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.
Taking Microbiome Science to the Next Level: Recommendations to Advance the Emerging Field of Microbiome-based Therapeutics and Diagnostics.
In vitro screening of the impact of dietary prebiotic components, probiotic strains, and their symbiotic combinations on colonic microbiota in children with cystic fibrosis.
Mapping the immune cell landscape of severe atopic dermatitis by single-cell RNA-seq.
The interrelation between microbial immunoglobulin coating, vaginal microbiota, ethnicity, and preterm birth.

PLoS One. 2024 ;19(5): e0298502

Acid-treated Staphylococcus aureus induces acute silkworm hemolymph melanization.

Yasuhiko Matsumoto, Eri Sato, Takashi Sugita.

The skin microbiome maintains healthy human skin, and disruption of the microbiome balance leads to inflammatory skin diseases such as folliculitis and atopic dermatitis. Staphylococcus aureus and Cutibacterium acnes are pathogenic bacteria that simultaneously inhabit the skin and cause inflammatory diseases of the skin through the activation of innate immune responses. Silkworms are useful invertebrate animal models for evaluating innate immune responses. In silkworms, phenoloxidase generates melanin as an indicator of innate immune activation upon the recognition of bacterial or fungal components. We hypothesized that S. aureus and C. acnes interact to increase the innate immunity-activating properties of S. aureus. In the present study, we showed that acidification is involved in the activation of silkworm hemolymph melanization by S. aureus. Autoclaved-killed S. aureus (S. aureus [AC]) alone does not greatly activate silkworm hemolymph melanization. On the other hand, applying S. aureus [AC] treated with C. acnes culture supernatant increased the silkworm hemolymph melanization. Adding C. acnes culture supernatant to the medium decreased the pH. S. aureus [AC] treated with propionic acid, acetic acid, or lactic acid induced higher silkworm hemolymph melanization activity than untreated S. aureus [AC]. S. aureus [AC] treated with hydrochloric acid also induced silkworm hemolymph melanization. The silkworm hemolymph melanization activity of S. aureus [AC] treated with hydrochloric acid was inhibited by protease treatment of S. aureus [AC]. These results suggest that acid treatment of S. aureus induces innate immune activation in silkworms and that S. aureus proteins are involved in the induction of innate immunity in silkworms.

DOI: https://doi.org/10.1371/journal.pone.0298502
mLife. 2023 Jun;2(2): 107-120

Human skin bacterial microbiota homeostasis: A delicate balance between health and disease.

Yibin Zhu, Xi Yu, Gong Cheng.

  As the largest organ of the body, the skin acts as a barrier to prevent diseases and harbors a variety of beneficial bacteria. Furthermore, the skin bacterial microbiota plays a vital role in health and disease. Disruption of the barrier or an imbalance between symbionts and pathogens can lead to skin disorders or even systemic diseases. In this review, we first provide an overview of research on skin bacterial microbiota and human health, including the composition of skin bacteria in a healthy state, as well as skin bacterial microbiota educating the immune system and preventing the invasion of pathogens. We then discuss the diseases that result from skin microbial dysbiosis, including atopic dermatitis, common acne, chronic wounds, psoriasis, viral transmission, cutaneous lupus, cutaneous lymphoma, and hidradenitis suppurativa. Finally, we highlight the progress that utilizes skin microorganisms for disease therapeutics, such as bacteriotherapy and skin microbiome transplantation. A deeper knowledge of the interaction between human health and disease and the homeostasis of the skin bacterial microbiota will lead to new insights and strategies for exploiting skin bacteria as a novel therapeutic target.

Keywords:  homeostasis; human diseases; skin bacterial microbiota; therapeutics

DOI:  https://doi.org/10.1002/mlf2.12064
Nature. 2024 May 29.

'Smart' antibiotic can kill deadly bacteria while sparing the microbiome.

Fred Schwaller.



Keywords:  Antibiotics; Drug discovery; Medical research; Microbiology

DOI:  https://doi.org/10.1038/d41586-024-01566-8
Nature. 2024 May 30.

Daily briefing: 'Smart' antibiotic spares the microbiome.

Katrina Krämer.

DOI: https://doi.org/10.1038/d41586-024-01639-8
Microbes Infect. 2024 May 28. pii: S1286-4579(24)00105-9. [Epub ahead of print] 105369

Lung infection with classical Klebsiella pneumoniae strains establishes robust macrophage-dependent protection against heterologous reinfection.

Joseph J Mackel, Casey L Goltz, Emily Guo, David A Rosen.

  At present there is no approved vaccine for prevention of infection by the opportunistic bacterium Klebsiella pneumoniae (Kp); success in treating these infections is increasingly challenged by the spread of antibiotic resistance. Preclinical investigation of adaptive immunity elicited by lung infection with live classical Kp may reveal host mechanisms of protection against this pathogen. Here, we utilize multiple virulent classical Kp strains to demonstrate that following lung infection, surviving wild-type mice develop protective immunity against both homologous and heterologous (heterotypic) reinfection. For Kp strains with low capacity to disseminate from the lung, this immunity is B-cell-independent. We further demonstrate that this immune protection is also effective against subsequent challenge with hypervirulent Kp if the strains share the same capsule type. Systemic inoculation fails to elicit the same protective effect as lung inoculation, revealing a lung-specific immune effector function is responsible for this protection. We therefore utilized clodronate-loaded liposomes to substantially deplete both alveolar macrophages and lung interstitial macrophages, finding that simultaneous depletion of both subsets entirely ablates protection. These findings indicate that following initial lung infection with Kp, lung macrophages mediate protection against ensuing Kp challenge.

Keywords:  Klebsiella pneumoniae; clodronate depletion; heterologous infection; lung immunity; lung macrophage; pneumonia

DOI:  https://doi.org/10.1016/j.micinf.2024.105369
Front Immunol. 2024 ;15 1362289

The cholera toxin B subunit induces trained immunity in dendritic cells and promotes CD8 T cell antitumor immunity.

Araceli Tepale-Segura, Julián A Gajón, Samira Muñoz-Cruz, Octavio Castro-Escamilla, Laura C Bonifaz.

   Introduction: Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved.
Methods: We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo.
Results: CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo.
Conclusion: Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.

Keywords:  CD8 T cells; CTB adjuvant; dendritic cells; melanoma; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2024.1362289
J Infect Dis. 2024 May 28. pii: jiae263. [Epub ahead of print]

Staphylococcus aureus Conquers Host by Hijacking Mitochondria via PFKFB3 in Epithelial Cells.

Xing Gao, Shiyuan Feng, Binfeng Wu, Laizhen Liu, Yuanyuan Xu, Jinqiu Zhang, Jinfeng Miao.

  Staphylococcus aureus (S. aureus) persists within mammary epithelial cells for an extended duration, exploiting the host metabolic resources to facilitate replication. This study revealed a mechanism by which intracellular S. aureus reprograms host metabolism, with PFKFB3 playing a crucial role in this process. Mechanistically, S. aureus induced mitochondrial damage, leading to increased levels of mitochondrial reactive oxygen species (mROS) and dysfunction in electron transport chain (ETC). Moreover, S. aureus shifted the balance of mitochondrial dynamics from fusion to fission, subsequently activating PINK1-PRKN-dependent mitophagy, causing loss of the sirtuin 3 (SIRT3) to stabilize hypoxic inducible factor 1α (HIF1α), and shifting the host metabolism toward enhanced glycolysis. The inhibition of PFKFB3 reversed the mitochondrial damage and degradation of SIRT3 induced by S. aureus. Overall, our findings elucidate the mechanism by which S. aureus reprograms host metabolism and offer insights into the treatment of S. aureus infection.

Keywords:   Staphylococcus aureus ; HIF1α; PFKFB3; SIRT3; glycolysis; mitophagy

DOI:  https://doi.org/10.1093/infdis/jiae263
Cytokine. 2024 May 28. pii: S1043-4666(24)00137-6. [Epub ahead of print]180 156634

Staphylococcus aureus Serine protease-like protein A (SplA) induces IL-8 by keratinocytes and synergizes with IL-17A.

D P De Donato, R Effner, M Nordengrün, A Lechner, M N Darisipudi, T Volz, B Hagl, B M Bröker, E D Renner.

   BACKGROUND: Serine protease-like (Spl) proteins produced by Staphylococcus (S.) aureus have been associated with allergic inflammation. However, effects of Spls on the epidermal immune response have not been investigated.
OBJECTIVES: To assess the epidermal immune response to SplA, SplD and SplE dependent on differentiation of keratinocytes and a Th2 or Th17 cytokine milieu.
METHODS: Human keratinocytes of healthy controls and a STAT3-hyper-IgE syndrome (STAT3-HIES) patient were cultured in different calcium concentrations in the presence of Spls and Th2 or Th17 cytokines. Keratinocyte-specific IL-8 production and concomitant migration of neutrophils were assessed.
RESULTS: SplE and more significantly SplA, induced IL-8 in keratinocytes. Suprabasal-like keratinocytes showed a higher Spl-mediated IL-8 production and neutrophil migration compared to basal-like keratinocytes. Th17 cytokines amplified Spl-mediated IL-8 production, which correlated with neutrophil recruitment. Neutrophil recruitment by keratinocytes of the STAT3-HIES patient was similar to healthy control cells.
CONCLUSION: S. aureus-specific Spl proteases synergized with IL-17A on human keratinocytes with respect to IL-8 release and neutrophil migration, highlighting the importance of keratinocytes and Th17 immunity in barrier function.

Keywords:  Keratinocytes; Neutrophil migration; S. aureus; STAT3-hyper IgE syndrome (HIES); Serine protease-like proteins (Spls); Th2/Th17 immunity

DOI:  https://doi.org/10.1016/j.cyto.2024.156634
NPJ Metab Health Dis. 2024 ;2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

  The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Keywords:  Energy metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44324-024-00008-3
Eur Respir Rev. 2024 Apr 30. pii: 230263. [Epub ahead of print]33(172):

The guardians of pulmonary harmony: alveolar macrophages orchestrating the symphony of lung inflammation and tissue homeostasis.

Learta Pervizaj-Oruqaj, Maximiliano Ruben Ferrero, Ulrich Matt, Susanne Herold.

Recent breakthroughs in single-cell sequencing, advancements in cellular and tissue imaging techniques, innovations in cell lineage tracing, and insights into the epigenome collectively illuminate the enigmatic landscape of alveolar macrophages in the lung under homeostasis and disease conditions. Our current knowledge reveals the cellular and functional diversity of alveolar macrophages within the respiratory system, emphasising their remarkable adaptability. By synthesising insights from classical cell and developmental biology studies, we provide a comprehensive perspective on alveolar macrophage functional plasticity. This includes an examination of their ontology-related features, their role in maintaining tissue homeostasis under steady-state conditions and the distinct contribution of bone marrow-derived macrophages (BMDMs) in promoting tissue regeneration and restoring respiratory system homeostasis in response to injuries. Elucidating the signalling pathways within inflammatory conditions, the impact of various triggers on tissue-resident alveolar macrophages (TR-AMs), as well as the recruitment and polarisation of macrophages originating from the bone marrow, presents an opportunity to propose innovative therapeutic approaches aimed at modulating the equilibrium between phenotypes to induce programmes associated with a pro-regenerative or homeostasis phenotype of BMDMs or TR-AMs. This, in turn, can lead to the amelioration of disease outcomes and the attenuation of detrimental inflammation. This review comprehensively addresses the pivotal role of macrophages in the orchestration of inflammation and resolution phases after lung injury, as well as ageing-related shifts and the influence of clonal haematopoiesis of indeterminate potential mutations on alveolar macrophages, exploring altered signalling pathways and transcriptional profiles, with implications for respiratory homeostasis.

DOI: https://doi.org/10.1183/16000617.0263-2023
Front Biosci (Landmark Ed). 2024 May 10. 29(5): 180

Newly Isolated Limosilactobacillus reuteri B1/1 Modulates the Expression of Cytokines and Antimicrobial Proteins in a Porcine ex Vivo Model.

Zuzana Kiššová, Jana Štofilová, Dagmar Mudroňová, Viera Karaffová.

   BACKGROUND: The epithelia of the intestine perform various functions, playing a crucial role in providing a physical barrier and an innate immune defense against infections. By generating a "three-dimensional" (3D) model of cell co-cultures using the IPEC-J2 cell line and porcine blood monocyte-derived macrophages (MDMs), we are getting closer to mimicking the porcine intestine ex vivo.Methods: The effect of Limosilactobacillus reuteri B1/1 and Limosilactobacillus fermentum CCM 7158 (indicator strain) on the relative gene expression of interleukins (IL-1β, IL-6, IL-8, IL-18 and IL-10), genes encoding receptors for TLR4 and TLR2, tight junction proteins such as claudin-1 (CLDN1), occludin (OCLN) and important antimicrobial proteins such as lumican (LUM) and olfactomedin-4 (OLMF-4) was monitored in this model.
RESULTS: The results obtained from this pilot study point to the immunomodulatory potential of newly isolated L. reuteri B1/1, as it was able to suppress the enhanced pro-inflammatory response to lipopolysaccharide (LPS) challenge in both cell types. L. reuteri B1/1 was even able to up-regulate the mRNA levels of genes encoding antimicrobial proteins LUM and OLFM-4 and to increase tight junction (TJ)-related genes CLDN1 and OCLN, which were significantly down-regulated in LPS-induced IPEC-J2 cells. Conversely, L. fermentum CCM 7158, chosen as an indicator lactic acid bacteria (LAB) strain, increased the mRNA levels of the investigated pro-inflammatory cytokines (IL-18, IL-6, and IL-1β) in MDMs when LPS was simultaneously applied to basally deposited macrophages. Although L. fermentum CCM 7158 induced the production of pro-inflammatory cytokines, synchronous up-regulation of the anti-inflammatory cytokine IL-10 was detected in both LAB strains used in both cell cultures.
CONCLUSIONS: The obtained results suggest that the recently isolated LAB strain L. reuteri B1/1 has the potential to alleviate epithelial disruption caused by LPS and to influence the production of antimicrobial molecules by enterocytes.

Keywords:  IPEC-J2; MDM; co-culture; cytokines; lactobacilli; tight-junctions

DOI:  https://doi.org/10.31083/j.fbl2905180
Front Microbiol. 2024 ;15 1387498

The Yin and Yang of pathogens and probiotics: interplay between Salmonella enterica sv. Typhimurium and Bifidobacterium infantis during co-infection.

Claire Shaw, Bart C Weimer, Reed Gann, Prerak T Desai, Jigna D Shah.

  Probiotic bacteria have been proposed as an alternative to antibiotics for the control of antimicrobial resistant enteric pathogens. The mechanistic details of this approach remain unclear, in part because pathogen reduction appears to be both strain and ecology dependent. Here we tested the ability of five probiotic strains, including some from common probiotic genera Lactobacillus and Bifidobacterium, to reduce binding of Salmonella enterica sv. Typhimurium to epithelial cells in vitro. Bifidobacterium longum subsp. infantis emerged as a promising strain; however, S. Typhimurium infection outcome in epithelial cells was dependent on inoculation order, with B. infantis unable to rescue host cells from preceding or concurrent infection. We further investigated the complex mechanisms underlying this interaction between B. infantis, S. Typhimurium, and epithelial cells using a multi-omics approach that included gene expression and altered metabolism via metabolomics. Incubation with B. infantis repressed apoptotic pathways and induced anti-inflammatory cascades in epithelial cells. In contrast, co-incubation with B. infantis increased in S. Typhimurium the expression of virulence factors, induced anaerobic metabolism, and repressed components of arginine metabolism as well as altering the metabolic profile. Concurrent application of the probiotic and pathogen notably generated metabolic profiles more similar to that of the probiotic alone than to the pathogen, indicating a central role for metabolism in modulating probiotic-pathogen-host interactions. Together these data imply crosstalk via small molecules between the epithelial cells, pathogen and probiotic that consistently demonstrated unique molecular mechanisms specific probiotic/pathogen the individual associations.

Keywords:  Salmonella; arginine; bifidobacteria; host-microbe association; nitric oxide; probiotic

DOI:  https://doi.org/10.3389/fmicb.2024.1387498
Cytotherapy. 2024 May 19. pii: S1465-3249(24)00717-5. [Epub ahead of print]

Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.

Hazel Dunbar, Ian J Hawthorne, Courteney Tunstead, Eóin N McNamee, Daniel J Weiss, Michelle E Armstrong, Seamas C Donnelly, Karen English.

   BACKGROUND: Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism.
AIM: This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo.
METHODS: Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production.
CONCLUSIONS: This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.

Keywords:  bone marrow-derived macrophages; house dust mite; innate training; macrophage migration inhibitory factor; mesenchymal stromal cells; polarization

DOI:  https://doi.org/10.1016/j.jcyt.2024.05.010
Am J Physiol Endocrinol Metab. 2024 May 29.

Understanding How Pre- and Probiotics Affect the Gut Microbiome and Metabolic Health.

Patricia Martins Bock, Andreza Francisco Martins, Beatriz D'Agord Schaan.

  The gut microbiome, a complex assembly of microorganisms, significantly impacts human health by influencing nutrient absorption, the immune system, and disease response. These microorganisms form a dynamic ecosystem that is critical to maintaining overall well-being. Prebiotics and probiotics are pivotal in regulating gut microbiotacomposition. Prebiotics nourish beneficial bacteria, and promote their growth, while probiotics help maintain balance within the microbiome. This intricate balance extends to several aspects of health, including maintaining the integrity of the gut barrier, regulating immune responses, and producing metabolites crucial for metabolic health. Dysbiosis, or an imbalance in the gut microbiota, has been linked to metabolic disorders such as type 2 diabetes, obesity, and cardiovascular disease. Impaired gut barrier function, endotoxemia, and low-grade inflammation are associated with toll-like receptors influencing pro-inflammatory pathways. Short-chain fatty acids derived from microbial fermentation modulate anti-inflammatory and immune system pathways. Prebiotics positively influence gut microbiota, while probiotics, especially Lactobacillus and Bifidobacterium strains, may improve metabolic outcomes, such as glycemic control in diabetes. It is important to consider strain-specific effects and study variability when interpreting these findings, highlighting the need for further research to optimize their therapeutic potential. The aim of this report is therefore to review the role of the gut microbiota in metabolic health and disease and the effects of prebiotics and probiotics on the gut microbiome and their therapeutic role, integrating a broad understanding of physiological mechanisms with a clinical perspective.

Keywords:  Diabetes Mellitus; Microbiota; Obesity

DOI:  https://doi.org/10.1152/ajpendo.00054.2024
Cell Host Microbe. 2024 May 17. pii: S1931-3128(24)00142-2. [Epub ahead of print]

Salmonella Typhimurium expansion in the inflamed murine gut is dependent on aspartate derived from ROS-mediated microbiota lysis.

Woongjae Yoo, Nicolas G Shealy, Jacob K Zieba, Teresa P Torres, Madi Baltagulov, Julia D Thomas, Catherine D Shelton, Anna G McGovern, Nora J Foegeding, Erin E Olsan, Mariana X Byndloss.

  Inflammation boosts the availability of electron acceptors in the intestinal lumen, creating a favorable niche for pathogenic Enterobacteriaceae. However, the mechanisms linking intestinal inflammation-mediated changes in luminal metabolites and pathogen expansion remain unclear. Here, we show that mucosal inflammation induced by Salmonella enterica serovar Typhimurium (S. Tm) infection increases intestinal levels of the amino acid aspartate. S. Tm used aspartate-ammonia lyase (aspA)-dependent fumarate respiration for growth in the murine gut only during inflammation. AspA-dependent growth advantage was abolished in the gut of germ-free mice and restored in gnotobiotic mice colonized with members of the classes Bacteroidia and Clostridia. Reactive oxygen species (ROS) produced during the host response caused lysis of commensal microbes, resulting in the release of microbiota-derived aspartate that was used by S. Tm, in concert with nitrate-dependent anaerobic respiration, to outcompete commensal Enterobacteriaceae. Our findings demonstrate the role of microbiota-derived amino acids in driving respiration-dependent S. Tm expansion during colitis.

Keywords:  Enterobacteriaceae; Salmonella Typhimurium; amino acids; colonization resistance; intestinal inflammation; microbe-microbe interactions; microbial metabolism; microbiome

DOI:  https://doi.org/10.1016/j.chom.2024.05.001
Hum Cell. 2024 May 30.

Tyndallized bacteria prime bronchial epithelial cells to mount an effective innate immune response against infections.

Serena Di Vincenzo, Caterina Di Sano, Claudia D'Anna, Maria Ferraro, Velia Malizia, Andreina Bruno, Marta Cristaldi, Chiara Cipollina, Valentina Lazzara, Paola Pinto, Stefania La Grutta, Elisabetta Pace.

  Airway epithelium represents a physical barrier against toxic substances and pathogens but also presents pattern recognition receptors on the epithelial cells that detect pathogens leading to molecule release and sending signals that activate both the innate and adaptive immune responses. Thus, impaired airway epithelial function and poor integrity may increase the recurrence of infections. Probiotic use in respiratory diseases as adjuvant of traditional therapy is increasingly widespread. There is growing interest in the use of non-viable heat-killed bacteria, such as tyndallized bacteria (TB), due to safety concerns and to their immunomodulatory properties. This study explores in vitro the effects of a TB blend on the immune activation of airway epithelium. 16HBE bronchial epithelial cells were exposed to different concentrations of TB. Cell viability, TB internalization, TLR2 expression, IL-6, IL-8 and TGF-βl expression/release, E-cadherin expression and wound healing were assessed. We found that TB were tolerated, internalized, increased TLR2, E-cadherin expression, IL-6 release and wound healing but decreased both IL-8 and TGF-βl release. In conclusion, TB activate TLR2 pathway without inducing a relevant pro-inflammatory response and improve barrier function, leading to the concept that TB preserve epithelial homeostasis and could be used as strategy to prevent and to manage respiratory infection, exacerbations included.

Keywords:  Bronchial epithelial cells; Epithelial homeostasis; Innate immune responses; Tyndallized bacteria

DOI:  https://doi.org/10.1007/s13577-024-01080-z
FEMS Microbiol Ecol. 2024 May 14. pii: fiae070. [Epub ahead of print]100(6):

Methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus produce antimicrobial substances against members of the skin microbiota in children with atopic dermatitis.

Lorrayne Cardoso Guimarães, Gizele Duarte Garcia, Fernanda Sampaio Cavalcante, Graciela Maria Dias, Felipe Miceli de Farias, Simone Saintive, Eliane de Dios Abad, Dennis de Carvalho Ferreira, Kátia Regina Netto Dos Santos.

  Coagulase-negative Staphylococcus (CoNS) species inhibiting Staphylococcus aureus has been described in the skin of atopic dermatitis (AD) patients. This study evaluated whether Staphylococcus spp. from the skin and nares of AD and non-AD children produced antimicrobial substances (AMS). AMS production was screened by an overlay method and tested against NaOH, proteases and 30 indicator strains. Clonality was assessed by pulsed-field gel electrophoresis. Proteinaceous AMS-producers were investigated for autoimmunity by the overlay method and presence of bacteriocin genes by polymerase chain reaction. Two AMS-producers had their genome screened for AMS genes. A methicillin-resistant S. aureus (MRSA) produced proteinaceous AMS that inhibited 51.7% of the staphylococcal indicator strains, and it was active against 60% of the colonies selected from the AD child where it was isolated. On the other hand, 57 (8.8%) CoNS from the nares and skin of AD and non-AD children, most of them S. epidermidis (45.6%), reduced the growth of S. aureus and other CoNS species. Bacteriocin-related genes were detected in the genomes of AMS-producers. AMS production by CoNS inhibited S. aureus and other skin microbiota species from children with AD. Furthermore, an MRSA colonizing a child with AD produced AMS, reinforcing its contribution to dysbiosis and disease severity.

Keywords:   Staphylococcus aureus ; antimicrobial substance; atopic dermatitis; bacteriocin; coagulase-negative Staphylococcus; skin microbiota

DOI:  https://doi.org/10.1093/femsec/fiae070
Infect Immun. 2024 May 30. e0004824

Unveiling the immune dynamics of Neisseria persistent oral colonization.

Mario Alles, Manuja Gunasena, Tauqir Zia, Adonis D'Mello, Saroj Bhattarai, Will Mulhern, Luke Terry, Trenton Scherger, Saranga Wijeratne, Sachleen Singh, Asela J Wijeratne, Dhanuja Kasturiratna, Hervé Tettelin, Nathan J Weyand, Namal P M Liyanage.

  Commensal bacteria are crucial in maintaining host physiological homeostasis, immune system development, and protection against pathogens. Despite their significance, the factors influencing persistent bacterial colonization and their impact on the host still need to be fully understood. Animal models have served as valuable tools to investigate these interactions, but most have limitations. The bacterial genus Neisseria, which includes both commensal and pathogenic species, has been studied from a pathogenicity to humans perspective but lacks models that study immune responses in the context of long-term persistence. Neisseria musculi, a recently described natural commensal of mice, offers a unique opportunity to study long-term host-commensal interactions. In this study, for the first time, we have used this model to study the transcriptional, phenotypic, and functional dynamics of immune cell signatures in the mucosal and systemic tissue of mice in response to N. musculi colonization. We found key genes and pathways vital for immune homeostasis in palate tissue, validated by flow cytometry of immune cells from the lung, blood, and spleen. This study offers a novel avenue for advancing our understanding of host-bacteria dynamics and may provide a platform for developing efficacious interventions against mucosal persistence by pathogenic Neisseria.

Keywords:  NK cells; Neisseria; host-microbes interactions; immune dynamics; immune homeostasis; monocytes; mucosal immunity; vaccine

DOI:  https://doi.org/10.1128/iai.00048-24
Eur Respir Rev. 2024 Apr 30. pii: 230250. [Epub ahead of print]33(172):

The role of dendritic cells in respiratory viral infection.

Elisabeth De Leeuw, Hamida Hammad.

Respiratory viral infections represent one of the major causes of death worldwide. The recent coronavirus disease 2019 pandemic alone claimed the lives of over 6 million people around the globe. It is therefore crucial to understand how the immune system responds to these threats and how respiratory infection can be controlled and constrained. Dendritic cells (DCs) are one of the key players in antiviral immunity because of their ability to detect pathogens. They can orchestrate an immune response that will, in most cases, lead to viral clearance. Different subsets of DCs are present in the lung and each subset can contribute to antiviral responses through various mechanisms. In this review, we discuss the role of the different lung DC subsets in response to common respiratory viruses, with a focus on respiratory syncytial virus, influenza A virus and severe acute respiratory syndrome coronavirus 2. We also review how lung DC-mediated responses to respiratory viruses can lead to the worsening of an existing chronic pulmonary disease such as asthma. Throughout the review, we discuss results obtained from animal studies as well as results generated from infected patients.

DOI: https://doi.org/10.1183/16000617.0250-2023
Eur Respir J. 2024 May 29. pii: 2301966. [Epub ahead of print]

Airway IL-1β is related to disease severity and mucociliary function in bronchiectasis.

Lidia Perea, Mathieu Bottier, Erin Cant, Hollian Richardson, Alison J Dicker, Morven Shuttleworth, Yan Hui Giam, Hani Abo-Leyah, Simon Finch, Jeffrey T-J Huang, Michal Shteinberg, Pieter C Goeminne, Eva Polverino, Josje Altenburg, Francesco Blasi, Tobias Welte, Stefano Aliberti, Oriol Sibila, James D Chalmers, Amelia Shoemark.

RATIONALE: The inflammasome is a key regulatory complex of the inflammatory response leading to IL-1β release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated.
OBJECTIVES: To characterize the role of airway IL-1β in bronchiectasis including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity.
METHODS: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (High versus Low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study IL-1β effect on cilia function.
MEASUREMENTS AND MAIN RESULTS: Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and increased Th1, Th2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in-vitro.
CONCLUSIONS: A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.

DOI: https://doi.org/10.1183/13993003.01966-2023
PLoS One. 2024 ;19(5): e0304634

Bacterial and fungal communities in chronic rhinosinusitis with nasal polyps.

Eray Uzunoğlu, Ayşe Kalkancı, Esra Kılıç, Yusuf Kızıl, Utku Aydil, Kadir Serdar Diker, Süleyman Sabri Uslu.

OBJECTIVE: Multiple inflammatory mechanisms dynamically interact in the development of chronic rhinosinusitis with nasal polyps (CRSwNP). Disruption of the relationship between host and environmental factors on the mucosal surface leads to the development of inflammation. Microorganisms constitute the most important part of environmental factors.
METHODS: 28 volunteers (18 CRSwNP patients and 10 healthy individuals) were included in the study. Eight patients were recurrent nasal polyposis cases, and the remaining were primary cases. Swab samples were taken from the middle meatus under endoscopic examination from all participants. After DNA extraction, a library was created with the Swift Amplicon 16S + ITS kit and sequenced with Illumina Miseq. Sequence analysis was performed using QIIME, UNITE v8.2 database for ITS and Silva v138 for 16S rRNA.
RESULTS: The predominant bacteria in all groups were Firmicutes, Proteobacteria, Actinobacteria as phyla and Staphylococcus, Corynebacterium, Sphingomonas as genera. Comparison of bacterial communities of CRSwNP patients and control group highlighted Corynebacterium, as the differentiating taxa for control group and Streptococcus, Moraxella, Rothia, Micrococcus, Gemella, and Prevotella for CRSwNP patients. The predominant fungal genus in all groups was Malassezia. Staphylococcus; showed a statistically significant negative correlation with Dolosigranulum. Corynebacterium had a positive correlation with Anaerococcus, and a negative correlation with Neisseria, Prevotella, Fusobacterium and Peptostreptococcus.
CONCLUSION: Nasal microbiome of CRSwNP patients shows greater inter-individual variation than the control group. Corynebacterium is less abundant in patients with CRSwNP compared to the control group. Malassezia is the predominant fungus in the nasal cavity and paranasal sinuses and correlates positively with the abundance of Corynebacterium.

DOI: https://doi.org/10.1371/journal.pone.0304634
Res Sq. 2024 May 13. pii: rs.3.rs-4220532. [Epub ahead of print]

Gut commensals require Peyer's patches to induce protective systemic IgA responses.

Joel Wilmore, Joshua Harris, Victoria Zoccoli-Rodriguez, Mara Delaney, Tania Cruz, Brian Guadette.

Gut educated IgA secreting plasma cells that disseminate beyond the mucosa and into systemic tissues have been described as providing beneficial effects from disease in several contexts. Several bacteria have been implicated in the induction of systemic IgA, however the mechanisms that result in differential levels of induction by each bacterial species are still unknown. Here we show, the commensal bacteria, Bacteroides fragilis (Bf), is an efficient inducer of systemic IgA responses. The ability of Bf to induce the production of bone marrow IgA plasma cells and high levels of serum IgA relied on high levels of gut colonization in a dose-dependent manner. Colonization induced Bf-specific IgA responses were severely diminished in the absence of Peyer's patches, but not the murine cecal patch. Colonization of mice with Bf, a natural human commensal, resulted in few changes within the microbiome and the host transcriptional profile in the gut, suggesting a commensal relationship with the host. Bf colonization did benefit the mice by inducing systemic IgA that led to increased protection in a bowel perforation model resulting in lower peritoneal abscess formation. These findings demonstrate a critical role for bacterial colonization and Peyer's patches in the induction of robust systemic IgA responses that confer protection from bacterial dissemination outside of the gut.

DOI: https://doi.org/10.21203/rs.3.rs-4220532/v1
bioRxiv. 2024 May 14. pii: 2024.05.10.592432. [Epub ahead of print]

Control of Inflammatory Response by Tissue Microenvironment.

Zhongyang Wu, Scott D Pope, Nasiha S Ahmed, Diana L Leung, Stephanie Hajjar, Qiuyu Yue, Diya M Anand, Elizabeth B Kopp, Daniel Okin, Weiyi Ma, Jonathan C Kagan, Diana C Hargreaves, Ruslan Medzhitov, Xu Zhou.

Inflammation is an essential defense response but operates at the cost of normal functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as a novel intracellular pH sensor. Acidic pH disrupts the transcription condensates containing BRD4 and MED1, via histidine-enriched intrinsically disordered regions. Crucially, decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo , acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environmental sensing to directly control inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
Highlights: Acidic pH regulates a switch-like gene-specific inflammatory response in macrophagesAcidic pH impacts chromatin remodeling and transcription circuits to control inflammatory programsBRD4 transcriptional condensates are regulated by intracellular pH via pH-sensitive motifs located within the intrinsically disordered regionTissue inflammation decreases intracellular pH and disrupts BRD4 condensates as a negative feedback.

DOI: https://doi.org/10.1101/2024.05.10.592432
World J Microbiol Biotechnol. 2024 Jun 01. 40(7): 226

Role of bacterial multidrug efflux pumps during infection.

Pablo Laborda, Søren Molin, Helle Krogh Johansen, José Luis Martínez, Sara Hernando-Amado.

  Multidrug efflux pumps are protein complexes located in the cell envelope that enable bacteria to expel, not only antibiotics, but also a wide array of molecules relevant for infection. Hence, they are important players in microbial pathogenesis. On the one hand, efflux pumps can extrude exogenous compounds, including host-produced antimicrobial molecules. Through this extrusion, pathogens can resist antimicrobial agents and evade host defenses. On the other hand, efflux pumps also have a role in the extrusion of endogenous compounds, such as bacterial intercommunication signaling molecules, virulence factors or metabolites. Therefore, efflux pumps are involved in the modulation of bacterial behavior and virulence, as well as in the maintenance of the bacterial homeostasis under different stresses found within the host. This review delves into the multifaceted roles that efflux pumps have, shedding light on their impact on bacterial virulence and their contribution to bacterial infection. These observations suggest that strategies targeting bacterial efflux pumps could both reinvigorate the efficacy of existing antibiotics and modulate the bacterial pathogenicity to the host. Thus, a comprehensive understanding of bacterial efflux pumps can be pivotal for the development of new effective strategies for the management of infectious diseases.

Keywords:  Antibiotic resistance; Bacterial virulence; Host-microbe interactions; Infection; Multidrug efflux pumps

DOI:  https://doi.org/10.1007/s11274-024-04042-7
bioRxiv. 2024 May 14. pii: 2024.05.10.593451. [Epub ahead of print]

Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration.

Andréa B Ball, Anthony E Jones, Kaitlyn B Nguyễn, Amy Rios, Nico Marx, Wei Yuan Hsieh, Krista Yang, Brandon R Desousa, Kristen K O Kim, Michaela Veliova, Zena Marie Del Mundo, Orian S Shirihai, Cristiane Benincá, Linsey Stiles, Steven J Bensinger, Ajit S Divakaruni.

Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally, in vivo activation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.

DOI: https://doi.org/10.1101/2024.05.10.593451
Cell Mol Immunol. 2024 May 31.

TRIM33 plays a critical role in regulating dendritic cell differentiation and homeostasis by modulating Irf8 and Bcl2l11 transcription.

Xiangyi Shen, Xiaoguang Li, Tao Wu, Tingting Guo, Jiaoyan Lv, Zhimin He, Maocai Luo, Xinyi Zhu, Yujie Tian, Wenlong Lai, Chen Dong, Xiaoyu Hu, Li Wu.

  The development of distinct dendritic cell (DC) subsets, namely, plasmacytoid DCs (pDCs) and conventional DC subsets (cDC1s and cDC2s), is controlled by specific transcription factors. IRF8 is essential for the fate specification of cDC1s. However, how the expression of Irf8 is regulated is not fully understood. In this study, we identified TRIM33 as a critical regulator of DC differentiation and maintenance. TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages. TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors. TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II (S2 Pol II) levels at Irf8 gene sites. Moreover, TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11, thereby maintaining DC homeostasis. Taken together, our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression. The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.

Keywords:  BIM; Dendritic cell; IRF8; TRIM33; Transcription regulation

DOI:  https://doi.org/10.1038/s41423-024-01179-1
J Vis Exp. 2024 May 10.

Three-Dimensional Cell Culture Models to Investigate the Epithelial Barrier in Eosinophilic Esophagitis.

Tanay Kaymak, Jan Hendrik Niess.

The squamous epithelium of the esophagus is directly exposed to the environment, continuously facing foreign antigens, including food antigens and microbes. Maintaining the integrity of the epithelial barrier is critical for preventing infections and avoiding inflammation caused by harmless food-derived antigens. This article provides simplified protocols for generating human esophageal organoids and air-liquid interface cultures from patient biopsies to study the epithelial compartment of the esophagus in the context of tissue homeostasis and disease. These protocols have been significant scientific milestones in the last decade, describing three-dimensional organ-like structures from patient-derived primary cells, organoids, and air-liquid interface cultures. They offer the possibility to investigate the function of specific cytokines, growth factors, and signaling pathways in the esophageal epithelium within a three-dimensional framework while maintaining the phenotypic and genetic properties of the donor. Organoids provide information on tissue microarchitecture by assessing the transcriptome and proteome after cytokine stimulation. In contrast, air-liquid interface cultures allow the assessment of the epithelial barrier integrity through transepithelial resistance (TEER) or macromolecule flux measurements. Combining these organoids and air-liquid interface cultures is a powerful tool to advance research in impaired esophageal epithelial barrier conditions.

DOI: https://doi.org/10.3791/66503
Microb Biotechnol. 2024 May;17(5): e14484

Mutualistic interactions of lactate-producing lactobacilli and lactate-utilizing Veillonella dispar: Lactate and glutamate cross-feeding for the enhanced growth and short-chain fatty acid production.

Shi-Min Zhang, Jia-He Hung, Tran Ngoc Yen, Shir-Ly Huang.

The human gut hosts numerous ecological niches for microbe-microbe and host-microbe interactions. Gut lactate homeostasis in humans is crucial and relies on various bacteria. Veillonella spp., gut lactate-utilizing bacteria, and lactate-producing bacteria were frequently co-isolated. A recent clinical trial has revealed that lactate-producing bacteria in humans cross-feed lactate to Veillonella spp.; however, their interspecies interaction mechanisms remain unclear. Veillonella dispar, an obligate anaerobe commonly found in the human gut and oral cavity, ferments lactate into acetate and propionate. In our study, we investigated the interaction between V. dispar ATCC 17748T and three representative phylogenetically distant strains of lactic acid bacteria, Lactobacillus acidophilus ATCC 4356T, Lacticaseibacillus paracasei subsp. paracasei ATCC 27216T, and Lactiplantibacillus plantarum ATCC 10241. Bacterial growth, viability, metabolism and gene level adaptations during bacterial interaction were examined. V. dispar exhibited the highest degree of mutualism with L. acidophilus. During co-culture of V. dispar with L. acidophilus, both bacteria exhibited enhanced growth and increased viability. V. dispar demonstrated an upregulation of amino acid biosynthesis pathways and the aspartate catabolic pathway. L. acidophilus also showed a considerable number of upregulated genes related to growth and lactate fermentation. Our results support that V. dispar is able to enhance the fermentative capability of L. acidophilus by presumably consuming the produced lactate, and that L. acidophilus cross-feed not only lactate, but also glutamate, to V. dispar during co-culture. The cross-fed glutamate enters the central carbon metabolism in V. dispar. These findings highlight an intricate metabolic relationship characterized by cross-feeding of lactate and glutamate in parallel with considerable gene regulation within both L. acidophilus (lactate-producing) and V. dispar (lactate-utilizing). The mechanisms of mutualistic interactions between a traditional probiotic bacterium and a potential next-generation probiotic bacterium were elucidated in the production of short-chain fatty acids.

DOI: https://doi.org/10.1111/1751-7915.14484
J Biomed Res. 2024 May 25. 1-12

GSDMD protects intestinal epithelial cells against bacterial infections through its N-terminal activity impacting intestinal immune homeostasis.

Honghui Li, Jie Pu, Dongxue Yang, Lu Liu, Yingchao Hu, Shuo Yang, Bingwei Wang.

The intestinal mucosal barrier serves as a vital guardian for gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Recent studies have found the intricate roles of Gasdermin D (GSDMD), a key executioner of pyroptosis downstream of the inflammasome, within the intestine, including controlling colitis in intestinal macrophage and the regulatory function in goblet cell mucus secretion. Thus, the exact role and nature of GSDMD's regulatory function in maintaining intestinal immune homeostasis and defending against pathogens remain elucidation. Here, we uncover that GSDMD plays a key role in defending against intestinal Citrobacter rodentium infection, with high expression in intestinal epithelial and lamina propria myeloid cells. Our results show that GSDMD specifically acts in intestinal epithelial cells to fight the infection, independently of its effects on antimicrobial peptides or mucin secretion. Instead, the resistance is mediated through GSDMD's N-terminal fragments, highlighting its importance in intestinal immunity. However, the specific underlying mechanism of GSDMD N-terminal activity in protection against intestinal bacterial infections still needs further study to clarify in the future.

DOI: https://doi.org/10.7555/JBR.38.20240041
Exp Mol Med. 2024 May 29.

Lactate exacerbates lung damage induced by nano-microplastics through the gut microbiota-HIF1a/PTBP1 pathway.

Xin Chen.

DOI: https://doi.org/10.1038/s12276-024-01229-8
Adv Microb Physiol. 2024 ;pii: S0065-2911(23)00029-2. [Epub ahead of print]84 83-133

Microbial metabolites as modulators of host physiology.

Susan A Joyce, David J Clarke.

  The gut microbiota is increasingly recognised as a key player in influencing human health and changes in the gut microbiota have been strongly linked with many non-communicable conditions in humans such as type 2 diabetes, obesity and cardiovascular disease. However, characterising the molecular mechanisms that underpin these associations remains an important challenge for researchers. The gut microbiota is a complex microbial community that acts as a metabolic interface to transform ingested food (and other xenobiotics) into metabolites that are detected in the host faeces, urine and blood. Many of these metabolites are only produced by microbes and there is accumulating evidence to suggest that these microbe-specific metabolites do act as effectors to influence human physiology. For example, the gut microbiota can digest dietary complex polysaccharides (such as fibre) into short-chain fatty acids (SCFA) such as acetate, propionate and butyrate that have a pervasive role in host physiology from nutrition to immune function. In this review we will outline our current understanding of the role of some key microbial metabolites, such as SCFA, indole and bile acids, in human health. Whilst many studies linking microbial metabolites with human health are correlative we will try to highlight examples where genetic evidence is available to support a specific role for a microbial metabolite in host health and well-being.

Keywords:  Azo-drugs; Bile salts; Choline; Indole; Microbiota; Short-chain fatty acids; TMA(O); Xenobiotics

DOI:  https://doi.org/10.1016/bs.ampbs.2023.12.001
Sci Adv. 2024 May 31. 10(22): eadn7848

Streptococcus agalactiae glycolipids promote virulence by thwarting immune cell clearance.

Luke R Joyce, Sol Kim, Brady L Spencer, Priya M Christensen, Kelli L Palmer, Ziqiang Guan, Julie A Siegenthaler, Kelly S Doran.

Streptococcus agalactiae [group B Streptococcus (GBS)] is a leading cause of neonatal meningitis, with late-onset disease (LOD) occurring after gastrointestinal tract colonization in infants. Bacterial membrane lipids are essential for host-pathogen interactions, and the functions of glycolipids are yet to be fully elucidated. GBS synthesizes three major glycolipids: glucosyl-diacylglycerol (Glc-DAG), diglucosyl-DAG (Glc2-DAG), and lysyl-Glc-DAG (Lys-Glc-DAG). Here, we identify the enzyme, IagB, as responsible for biosynthesis of Glc-DAG, the precursor for the two other glycolipids in GBS. To examine the collective role of glycolipids to GBS virulence, we adapted a murine model of neonatal meningitis to simulate LOD. The GBS∆iagB mutant traversed the gut-epithelial barrier comparable to wild type but was severely attenuated in bloodstream survival, resulting in decreased bacterial loads in the brain. The GBS∆iagB mutant was more susceptible to neutrophil killing and membrane targeting by host antimicrobial peptides. This work reveals an unexplored function of GBS glycolipids with their ability to protect the bacterial cell from host antimicrobial killing.

DOI: https://doi.org/10.1126/sciadv.adn7848
Nat Commun. 2024 May 27. 15(1): 4484

Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.

Samira Schiefer, Benjamin G Hale.

Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.

DOI: https://doi.org/10.1038/s41467-024-48800-5
Gastroenterology. 2024 May 28. pii: S0016-5085(24)05000-5. [Epub ahead of print]

Taking Microbiome Science to the Next Level: Recommendations to Advance the Emerging Field of Microbiome-based Therapeutics and Diagnostics.

Biotherapeutics Subcommittee of the AGA Center for Gut Microbiome Research and Education



Keywords:  Microbiome; therapeutics; translation

DOI:  https://doi.org/10.1053/j.gastro.2024.05.023
Food Funct. 2024 May 28.

In vitro screening of the impact of dietary prebiotic components, probiotic strains, and their symbiotic combinations on colonic microbiota in children with cystic fibrosis.

Jazmín Viteri-Echeverría, Ana Andrés, Joaquim Calvo-Lerma, Ana Heredia, Jorge García-Hernández, Andrea Asensio-Grau.

Children with Cystic Fibrosis (CF) are more likely to have intestinal dysbiosis due to recurrent antibiotic therapy and the conventional hypercaloric diet administered to them. This study aimed at evaluating the effect of isolated prebiotic components and probiotic strains, and their combinations as potential synbiotics, on the intestinal microbiota of CF children. A static in vitro colonic fermentation model was used by colonizing vials with faecal inoculum, a culture medium, and the substrates to be tested. Post treatment, aliquots were taken to determine ammonium, lactate, and short-chain fatty acids production and to profile the microbiota composition by 16s rRNA sequencing. At genus level, Escherichia-Shigella decreased (15.8%) with the treatment pectin + L. rhamnosus, followed by the beta-glucan + L. salivarius (15.5%). Inversely, the most increase in Bacteroides (44%) was obtained by the treatment with Pectin + L. reuteri. Lactate and acetic acid production was significantly increased with prebiotics and their combinations with L. rhamnosus and L. salivarius. In conclusion, the use of beta-glucan and pectin in combination with probiotic strains from the Lactobacillaceae family suggest potential to modulate dysbiosis and metabolic activity on CF colonic microbiota, encouraging further studies in animal studies or clinical settings to confirm the findings in vivo.

DOI: https://doi.org/10.1039/d4fo00325j
Allergy. 2024 Jun;79(6): 1584-1597

Mapping the immune cell landscape of severe atopic dermatitis by single-cell RNA-seq.

Seon-Pil Jin, Kyungchun Lee, Yoon Ji Bang, Yun-Hui Jeon, Sunyoung Jung, So-Jung Choi, Ji Su Lee, Junhan Kim, Emma Guttman-Yassky, Chung-Gyu Park, Hyun Je Kim, Seunghee Hong, Dong Hun Lee.

   BACKGROUND: Efforts to profile atopic dermatitis (AD) tissues have intensified, yet comprehensive analysis of systemic immune landscapes in severe AD remains crucial.
METHODS: Employing single-cell RNA sequencing, we analyzed over 300,000 peripheral blood mononuclear cells from 12 severe AD patients (Eczema area and severity index (EASI) > 21) and six healthy controls.
RESULTS: Results revealed significant immune cell shifts in AD patients, including increased Th2 cell abundance, reduced NK cell clusters with compromised cytotoxicity, and correlated Type 2 innate lymphoid cell proportions with disease severity. Moreover, unique monocyte clusters reflecting activated innate immunity emerged in very severe AD (EASI > 30). While overall dendritic cells (DCs) counts decreased, a distinct Th2-priming subset termed "Th2_DC" correlated strongly with disease severity, validated across skin tissue data, and flow cytometry with additional independent severe AD samples. Beyond the recognized role of Th2 adaptive immunity, our findings highlight significant innate immune cell alterations in severe AD, implicating their roles in disease pathogenesis and therapeutic potentials.
CONCLUSION: Apart from the widely recognized role of Th2 adaptive immunity in AD pathogenesis, alterations in innate immune cells and impaired cytotoxic cells have also been observed in severe AD. The impact of these alterations on disease pathogenesis and the effectiveness of potential therapeutic targets requires further investigation.

Keywords:  atopic dermatitis; chronic inflammatory disease; innate immunity; severe atopic dermatitis; single‐cell RNA‐Seq

DOI:  https://doi.org/10.1111/all.16121
Microbiome. 2024 May 28. 12(1): 99

The interrelation between microbial immunoglobulin coating, vaginal microbiota, ethnicity, and preterm birth.

H J Schuster, A C Breedveld, S P F Matamoros, R van Eekelen, R C Painter, M Kok, P J Hajenius, P H M Savelkoul, M van Egmond, R van Houdt.

   BACKGROUND: Vaginal microbiota composition is associated with spontaneous preterm birth (sPTB), depending on ethnicity. Host-microbiota interactions are thought to play an important underlying role in this association between ethnicity, vaginal microbiota and sPTB.
METHODS: In a prospective cohort of nulliparous pregnant women, we assessed vaginal microbiota composition, vaginal immunoglobulins (Igs), and local inflammatory markers. We performed a nested case-control study with 19 sPTB cases, matched based on ethnicity and midwifery practice to 19 term controls.
RESULTS: Of the 294 included participants, 23 pregnancies ended in sPTB. We demonstrated that Lactobacillus iners-dominated microbiota, diverse microbiota, and ethnicity were all independently associated with sPTB. Microbial Ig coating was associated with both microbiota composition and ethnicity, but a direct association with sPTB was lacking. Microbial IgA and IgG coating were lowest in diverse microbiota, especially in women of any ethnic minority. When correcting for microbiota composition, increased microbial Ig coating correlated with increased inflammation.
CONCLUSION: In these nulliparous pregnant women, vaginal microbiota composition is strongly associated with sPTB. Our results support that vaginal mucosal Igs might play a pivotal role in microbiota composition, microbiota-related inflammation, and vaginal community disparity within and between ethnicities. This study provides insight in host-microbe interaction, suggesting that vaginal mucosal Igs play an immunomodulatory role similar to that in the intestinal tract. Video Abstract.

Keywords:  Ethnicity; Host-microbiota interaction; Immunoglobulins; Nulliparous women; Spontaneous preterm birth; Vaginal microbiota

DOI:  https://doi.org/10.1186/s40168-024-01787-z