Manipulation of Gut Microbiota Ameliorates Microalbuminuria in Mouse Model via Metabolic and Inflammatory Blood-Gut-Kidney Cross-Talk: An Integrative Single-Cell and Spatial Transcriptome Analysis

Background: Gut dysbiosis is present in chronic kidney disease (CKD) patients. Gut microbiota manipulation represents a novel and promising therapeutic approach to tackle the gut-kidney interaction. However, the candidate live bioproducts and the pathophysiology linked to their renoprotective effects remain obscure in CKD. Methods: Feces of 228 (16S rRNA sequencing, discovery cohort) and 93 (shotgun metagenomic sequencing, validation cohort) CKD patients were collected to evaluate candidate compounds of live biotherapeutic products for CKD treatments. Bacteroides spp were retrieved as the most discriminatory taxa associated with CKD. Clinical isolates of Bacteroid spp were retrieved from 10 healthy volunteers. High-fat diet (HFD, mimicking mild CKD) and adenine (mimicking moderate CKD) models were used to elucidate the causal relationship of such bacterial candidates. Microbiome, metabolome as well as single-cell and spatial transcriptome analyses were conducted to explain the pathophysiology of gut-kidney interaction after Bacteroides spp feeding. Results: Colonization of Bacteroid spp in both HFD and adenine-induced mouse models of CKD by oral gavage ameliorated the morphological (podocyte foot process effacement) and functional changes (microalbuminuria levels) in the kidney. Metabolically, improvements in levels of glucose, cholesterol, TNF-a, IL-1a, IL-1b were seen. Single-cell and spatial transcriptomic sequencing analyses revealed the involvement of altered immune responses in the mouse kidney. Specifically, the elevation in the expression levels of genes associated with renal inflammation by systematic metabolic abnormalities was reversed by gut colonization of Bacteroid spp. Moreover, gene expression profiles of colon tissues from Bacteroid spp-treated CKD mice showed that genes related to endotoxic shock responses were differentially expressed, highlighting potential organ crosstalk with coordinated metabolic and inflammatory responses after Bacteroid spp treatment. Conclusion: These experimental findings implicate Bacteroid spp as a promising live biotherapeutic product for CKD, providing potential avenues for microbiome-based modality of renal insufficiency.