bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.06.18.599634

Reduction of fungal dysbiosis is involved in the attenuation of Dextran Sodium Sulfate-Induced Mouse Colitis Mediated by GILZ protein and yeast extract compound

Gentili, M.·Nunzi, E.·Sabbatini, S.·Lusenti, E.·Cari, L.·Mencacci, A.·Ballet, N.·Migliorati, G.·Riccardi, C.·Ronchetti, S.·Monari, C.
View original source ↗Export metadata ↓

Abstract

Inflammatory bowel diseases (IBD), such as Crohns disease and ulcerative colitis, have a complex and multifactorial pathogenesis that remains not fully elucidated. Recent research suggests that intestinal fungal dysbiosis may contribute to the development and persistence of IBD. In this study, we explored, for the first time, the effects of the glucocorticoid-induced leucine zipper (GILZ) protein, known to have protective effects on the gut mucosa in preclinical IBD models, in combination with a yeast extract, which supports the growth of beneficial microorganisms, in a mouse model of ulcerative colitis. The combined treatment produced significant protection against severe disease outcomes in the mice, including the restoration of intestinal barrier integrity and the reduction of pro-inflammatory cytokines. Specifically, GILZ primarily acted on the gut permeability, while the yeast extract mainly reduced pro-inflammatory cytokines. Notably, both treatments were effective in restoring the intestinal burden of clinically important Candida and former Candida species. Analysis of the intestinal fungal communities revealed that both treatments were able to reduce colitis-associated fungal dysbiosis, promoting a fungal composition similar to that of healthy mice. This effect was mainly the result of a decreased abundance of the Meyerozima genus, which was dominant in the colitic mice. Thus, combined treatment regimens with the GILZ protein and yeast extract could represent a new strategy for the treatment of inflammatory bowel diseases, by targeting multiple mechanisms at the basis of IBD, including the fungal dysbiosis. IMPORTANCEInflammatory bowel diseases (IBD), including Crohns disease and ulcerative colitis, are characterized by chronic inflammation and have a complex, multifactorial pathogenesis that is not yet fully understood. Currently, no established therapeutic strategy can consistently manage IBD effectively. Recent research indicates that intestinal fungal dysbiosis could potentially contribute to the development and persistence of chronic IBD, highlighting the importance of investigating alternative therapeutic strategies able to attenuate fungal dysbiosis in the context of intestinal inflammation. In this study, we demonstrate that a combination of a recombinant protein (GILZp) and a compound with prebiotic properties could represent a new therapeutic strategy for the treatment of IBD, as it not only decreases inflammation and restores the integrity of the epithelial barrier, but reduces fungal dysbiosis associated with DSS-induced colitis.

Explore related subjects

microbiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Gentili, M., Nunzi, E., Sabbatini, S., Lusenti, E., Cari, L., Mencacci, A., Ballet, N., Migliorati, G., Riccardi, C., Ronchetti, S., Monari, C.. 2024-06-19. Reduction of fungal dysbiosis is involved in the attenuation of Dextran Sodium Sulfate-Induced Mouse Colitis Mediated by GILZ protein and yeast extract compound. https://doi.org/10.1101/2024.06.18.599634

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A population-scale landscape of the subgingival microbiome reveals divergent routes to periodontal dysbiosis

Periodontitis is an archetypical mucosal inflammatory disease in which microbiome dysbiosis at the tooth-epithelial interface interacts with host genetic and behavioral risk factors to drive immune-mediated tissue destruction. Although subgingival microbiome compositional shifts are thought to parallel disease severity, microbiome variation at the population-level and its relationship to periodontal clinical phenotypes and disease-modifying factors remain poorly defined. Here, we use unsupervised manifold learning to map the compositional landscape of the subgingival microbiome in 1,355 adults spanning periodontal health to severe periodontitis. We identified eight latent microbiome states organized along a branching continuum from eubiosis to dysbiosis. An intermediate microbial configuration marked ecological destabilization and bifurcation into two distinct periodontitis-associated dysbiotic trajectories, distinguished by links to gingival inflammation and smoking. Although the microbiome trajectories broadly tracked periodontal destruction, a minority of individuals showed discordant microbiome-clinical phenotypes, with some individuals with periodontitis retaining otherwise eubiotic microbiomes enriched for low-abundance pathobionts, while some cases of health or mild disease had highly dysbiotic communities, suggesting distinct host susceptibility. Together, these findings define a population-scale ecological landscape of the subgingival microbiome, reveal divergent trajectories to periodontal dysbiosis, and highlight heterogeneity in the relationship between microbial community structure and clinical disease expression.

microbiology↗
bioRxiv2026

The iron-binding siderophore enterobactin is required for the response of multi-drug resistant Klebsiella pneumoniae to zinc limitation

To persist during infection Klebsiella pneumoniae must overcome nutrient iron and zinc limitation imposed by the host immune system through a process called nutritional immunity. Secreted small molecule siderophores are a major virulence determinant of Klebsiella pneumoniae pathogenesis and are presumed to overcome nutritional immunity by binding iron for bacterial acquisition. In this work, we set out to identify how a multi-drug resistant K. pneumoniae grows in zinc limited environments. Using unbiased transcriptomics, proteomics, and an arrayed transposon screen, we identified that synthesis and uptake of the siderophore enterobactin is required to allow for growth in low zinc conditions. Iron-specific chelators did not replicate this phenotype and addition of supplemental iron through heme in growth media could not complement severe growth defects of enterobactin mutant K. pneumoniae experiencing zinc limitation. Finally, zinc starvation induced enterobactin production independent of the canonical zinc uptake regulator (Zur) transcription factor suggesting an unidentified regulatory mechanism by which Gram-negative pathogens may respond to zinc stress. Together, these studies expand the role of enterobactin beyond iron regulation and highlight a previously unreported link between iron and zinc homeostasis in Klebsiella pneumoniae.

microbiology↗
bioRxiv2026

A microbiota-derived protease links phage susceptibility to host epithelial responses

Bacteriophages are major ecological drivers of gut microbial ecology, yet whether bacterial mechanisms that determine phage susceptibility have consequences for the mammalian host remains poorly understood. Here, we identify dipeptidyl peptidase 11 (Dpp11a), the predominant active serine protease of the prevalent gut commensal Phocaeicola vulgatus, as an unexpected bacterial defence factor. Dpp11a protects against environmental proteases and confers resistance to bacteriophage infection. Metatranscriptomic analyses further reveal increased expression of both dpp11a and P. vulgatus-associated phage transcripts in ulcerative colitis stool samples, indicating that both components of this interaction are transcriptionally active in disease-associated human microbiomes. Using the microfluidic gut-on-a-chip co-culture model HuMiX, we show that the absence of Dpp11 is accompanied by altered epithelial tight-junction remodelling during phage-bacterial infection. Together, our findings reveal that the consequences of bacterial phage defence can extend beyond phage-bacterium interactions to the mammalian epithelium.

microbiology↗