Rousselle, T. V. | Search bioRxiv

bioRxiv2025

Cellular and Molecular Resolution of Focal Segmental Glomerulosclerosis Recurrence in Human Allografts

Primary Focal Segmental Glomerulosclerosis (FSGS) is an important cause of end-stage renal disease (ESRD). Primary FSGS recurrence rates in transplanted kidneys are high, with 25-50% in first transplants and up to 80% in second transplants, often leading to graft loss. To investigate the molecular and cellular events underlying recurrent primary FSGS (reFSGS), we performed single-nucleus RNA sequencing (snRNA-seq) on kidney transplant biopsies from patients with reFSGS and controls with normal allograft function. Our analysis revealed that podocyte loss in reFSGS is driven by metabolic and structural dysregulation rather than apoptosis. Overexpression of vascular endothelial growth factor (VEGF)-A by podocytes was observed, potentially disrupting glomerular endothelial cell growth and permeability. Parietal epithelial cells (PECs) exhibited dedifferentiation towards a podocyte-like state, potentially compensating for podocyte loss, but this was associated with increased collagen deposition and glomerular sclerosis. Ligand-receptor interactions between glomerular cells and B cells further promoted extracellular matrix deposition and fibrosis. Additionally, tubular cells demonstrated evidence of tubular sclerosis and impaired regenerative potential, accompanied by increased interactions with T cells. These findings provide novel insights into the pathogenesis of reFSGS and identify potential therapeutic targets. This study establishes a foundation for future research to further investigate cell-type-specific interventions in recurrent FSGS.

molecular biology↗

bioRxiv2020

The gut mycobiome of healthy mice is shaped by the environment and shapes metabolic outcomes in response to diet

ObjectiveAs an active interface between the host and their diet, the gut bacteriome influences host metabolic adaptation. However, the contribution of gut fungi to host metabolic outcomes is not yet understood. Therefore, we aimed to determine if host metabolic response to an ultraprocessed diet reflects gut fungal community composition. DesignWe compared jejunal fungi and bacteria from 72 healthy mice with the same genetic background but different starting mycobiomes before and after 8 weeks on an ultra-processed or standardized diet using 16S and internal transcribed spacer region 2 ribosomal RNA sequencing. We measured host body composition using magnetic resonance imaging, examined changes in metabolically active host tissues and quantified serum metabolic biomarkers. ResultsGut fungal communities are highly variable between mice, differing by vendor, age and sex. After exposure to an ultra-processed diet for 8 weeks, persistent differences in fungal community composition strongly associate with differential deposition of body mass in male mice compared to mice on standardized diet. Fat deposition in the liver, genomic adaptation of metabolically active tissues and serum metabolic biomarkers are correlated with alterations in fungal diversity and community composition. Variation in fungi from the genera Thermomyces and Saccharomyces most strongly associate with increased weight gain. ConclusionsIn the gut of healthy mice, host-microbe metabolic interactions strongly reflect variability in fungal communities. Our results confirm the importance of luminal fungal communities to host metabolic adaptation to dietary exposure. Gut fungal communities may represent a therapeutic target for the prevention and treatment of metabolic disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/158287v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1d80579org.highwire.dtl.DTLVardef@14f5729org.highwire.dtl.DTLVardef@1e379bcorg.highwire.dtl.DTLVardef@14d2ab6_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefO_LIWhat is already known about this subject? Gut bacterial communities have evolved to influence the metabolic outcomes of the host in mammals. Evidence from across the lifespan suggests that differences in composition of these communities is associated with energy consumption. However, gut microbial communities, while often equated to bacteria, are diverse, multi-kingdom ecologies and limited information is available for the role of other kingdoms of life, such as fungi. C_LIO_LIWhat are the new findings? Gut fungal communities, collectively termed the mycobiome, are less diverse and abundant than bacterial communities in the gastrointestinal tract. This study identifies the considerable influence of the environment and dietary exposure on the composition of jejunal fungal communities in healthy mice with the same genetic background. After exposure to processed diet, differences in fungal community composition in male mice were strongly correlated with persistent differences body composition and markers of metabolic tone. C_LIO_LIHow might it impact on clinical practice in the foreseeable future? These results verify that the baseline metabolic tone of health mice strongly reflects the ecological complexity of the gastrointestinal mycobiome. Variation in the composition of gut fungal communities is likely an underappreciated source of experimental and clinical variability in metabolic studies. Gastrointestinal fungi are likely a target for prevention and treatment of metabolic disease. C_LI

microbiology↗