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Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade in multiple myeloma

ABSTRACT: Prevotella melaninogenica could be a promising strategy to treat smoldering multiple myeloma and to make immunotherapy

PROVIDER: PRJEB94047 | ENA |

REPOSITORIES: ENA

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Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade in multiple myeloma

Project description:Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may act as drivers of smoldering multiple myeloma (SMM) to MM evolution. We demonstrate here that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice affected by Early-MM, mimicking human SMM, significantly delayed evolution to full-blown MM. Mechanistically, P. melaninogenica increased the production of short-chain fatty acids (SCFAs), preventing skew of dendritic cells towards a pro-Th17 phenotype and accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing immune checkpoint blockade (ICB)-induced effector CD8+ T cells. P. melaninogenica also attenuated IL-17-mediated skin lesions that mimicked ICB-induced immune-related adverse events. Thus, modulation of the gut microbiota or SCFAs administration with or without ICB might represent treatment options for patients affected by plasma cell dyscrasias and other hematologic or solid tumors where IL-17 acts as driving force.

2025-10-03 | GSE306088 | GEO

CFTR mutation abrogates Prevotella regulation of epithelial cell defense against Staphylococcus aureus

Project description:Background: The oral anaerobe Prevotella melaninogenica is enriched in the lungs of people with cystic fibrosis (pwCF), yet its functional impact on respiratory tract homeostasis remains incompletely understood. Prior studies identified immune modulatory effects following lung exposure to Prevotella, but the relevance of these findings for CF infections is unknown. Methods: The impact of P. melaninogenica on infection with the CF pathogen Staphylococcus aureus was evaluated using a mouse lung infection model and human respiratory tract cystic fibrosis transmembrane conductance regulator (CFTR) mutant and isogenic wild-type (WT)-corrected CFBE41o- epithelial cells. RNA-sequencing was performed to compare Prevotella-induced signaling programs in WT-corrected versus CFTR mutant cells. Results: P. melaninogenica significantly reduced S. aureus lung infection, which was associated with elevated S. aureus killing by lung neutrophils and impaired S. aureus adherence to epithelial cells. Live or heat-killed Prevotella were sufficient to mediate these effects, which were dependent on the toll-like receptor TLR2. Prevotella impairment of S. aureus adherence also required CFTR function, as this effect was lost in CFTR mutant cells but restored by CFTR modulator therapy. RNA-sequencing identified several antibacterial defense pathways selectively upregulated by Prevotella in WT corrected epithelial cells, correlating with higher IL-8 and IL-6 cytokine production. Conclusions: P. melaninogenica enhanced neutrophil and epithelial defense against S. aureus, but these benefits were lost with CFTR dysfunction. CFTR modulator therapy rescued Prevotella responsiveness in respiratory epithelial cells, highlighting the potential for synergistic effects of host-microbiome interactions and CFTR targeted therapies.

2025-12-09 | GSE305398 | GEO

Prevotella melaninogenica

Project description:Prevotella melaninogenica overview

| PRJNA37359 | ENA

Project description:Aerotolerance of Prevotella Melaninogenica

| PRJNA1400211 | ENA

Single-cell RNA sequencing reveals how myeloid cell reprogramming by commensal Prevotella enhances defense against Streptococcus pneumoniae lung infection

Project description:Streptococcus pneumoniae expresses a suite of virulence factors that modulate the innate immune response, delaying effective clearance. However, immune interactions with other bacteria influence this dynamic. Depletion of respiratory tract anaerobes including Prevotella is associated with increased mortality from pneumonia, an effect that can be replicated by pre-exposure to Prevotella melaninogenica in mice. Here, we demonstrate using single-cell RNA sequencing that P. melaninogenica shifts myeloid cell transcriptional profiles during pneumococcal infection from interferon-dominant to pro-phagocytic, correlating with increased S. pneumoniae phagocytosis and clearance from the lung. In neutrophils, improved antibacterial defense was dependent on TNF signaling through TNFR2. Prevotella-enhanced defense also required the recruitment of monocyte-derived macrophages, with selective enrichment of a Cxcl3+ population which differed from the C1qa+ population dominant during S. pneumoniae infection in unprimed mice. This work reveals an optimized innate immune defense program which may contribute to natural infection resistance mediated by respiratory tract commensal-host interactions.

2026-06-26 | GSE313404 | GEO

Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade in multiple myeloma

Project description:Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade in multiple myeloma

| PRJNA1309103 | ENA

Prevotella melaninogenica strain:GAI 07411

Project description:Whple genome sequence of Prevotella melaninogenica GAI 07411

| PRJDB5703 | ENA

Transcriptome sequencing of primary human oral keratinocytes co-cultured with Prevotella melaninogenica

Project description:Oral lichen planus (OLP) is a common oral mucosal disease, of which the etiology and pathogenesis are still unclear. Microorganisms may play an essential role in the pathogenesis of OLP. Previous studies of our group found that the composition ratio of Prevotella melaninogenica (Pm) on the buccal mucosa surface of OLP patients increased significantly. In addition, Pm could invade the epithelium of OLP. As the first physical defense of the oral mucosa, oral keratinocytes may interact directly with Pm in OLP. Therefore, this study aimed to explore the impact of Pm on primary human oral keratinocytes' transcriptome.

2022-12-14 | GSE220609 | GEO