Outer membrane vesicles derived from gut microbiota mediate tubulointerstitial inflammation: a potential new mechanism for diabetic kidney disease

Abstract

Rationale: Chronic tubulointerstitial inflammation is a common pathological process in diabetic kidney disease (DKD). However, its underlying mechanism is largely unknown. This study aims at investigating the role of gut microbiota-derived outer membrane vesicles (OMVs) in tubulointerstitial inflammation in DKD. Methods: Gut microbiota in diabetes mellitus rats was manipulated by microbiota depletion and fecal microbiota transplantation to explore its role in tubulointerstitial inflammation. To check the direct effects of OMVs, fecal bacterial extracellular vesicles (fBEVs) were administrated to mice orally and HK-2 cells in vitro. For mechanistic investigations, HK-2 cells were treated with small interfering RNA against caspase-4 and fBEVs pre-neutralized by polymyxin B. Results: By performing gut microbiota manipulation, it was confirmed that gut microbiota mediated tubulointerstitial inflammation in DKD. In diabetic rats, gut microbiota-derived OMVs were increased and were clearly detected in distant renal tubulointerstitium. Diabetic fBEVs directly administered by gavage translocated into tubular epithelial cells and induced tubulointerstitial inflammation and kidney injury. In vitro, OMVs were internalized through various endocytic pathways and triggered cellular inflammatory response. Mechanistically, it was revealed that OMVs-derived lipopolysaccharide induced tubular inflammation, which was mediated by the activation of the caspase-11 pathway. Conclusions: Increased OMVs due to dysbiosis translocated through leaky gut barrier into distant tubulointerstitium and induced cellular inflammation and renal tubulointerstitial injury in DKD. These findings enrich the mechanism understanding of how gut microbiota and its releasing OMVs influence the development and progression of kidney disease.

Roles of bacterial extracellular vesicles in systemic diseases

“…A significantly higher concentration of BEVs was observed in patients with T2DM than in the healthy population among stool, serum, and urine ( Nah et al, 2019 ). In diabetes animal model, intestinal microbiota-derived OMVs are also increased ( Chen et al, 2023 ). Furthermore, gut microbe-derived EVs were reported to permeate the intestinal barrier and enter the bloodstream followed by distribution to distant metabolic organs (e.g., adipose tissue, liver, and skeletal muscle), where they trigger insulin resistance and damage glucose metabolism ( Choi et al, 2015 ; Nah et al, 2019 ; Bittel et al, 2021 ).…”

Kidney tea [Orthosiphon aristatus (Blume) Miq.] improves diabetic nephropathy via regulating gut microbiota and ferroptosis

“…DN patients exhibited dysbiosis in the gut microbiota, manifested by increased levels of Lactobacillus , Megaphaera and Sutterella , as well as decreased levels of Lachnochlostridium and Roseburia ( Du et al, 2021 ). Recent research has demonstrated that gut microbiota-derived outer membrane vesicles can promote DN progression by activating tubulointerstitial inflammation ( Chen et al, 2023 ). Notably, the diversity of the gut viruses was significantly reduced in DN patients ( Fan et al, 2023 ).…”

Guild-level signature of gut microbiome for diabetic kidney disease

“…In recent years, increasing attention has been focused on the role of the gut microbiota in human health, with growing evidence suggesting its involvement in the pathogenesis of DKD ( 12 , 13 ). Dysbiotic gut microbiota in DKD patients often exhibits an increase in pathogenic bacteria and a decrease in beneficial bacteria, resulting in an abnormal colony structure dominated by Gram-negative facultative anaerobic bacteria ( 14 ).…”