Dysregulation of the Lipidome and Gut Microbiome Advances the Progression of Diabetic Nephropathy After Chronic High-Fat Diet Feeding

The high-fat Western diet (HFD) contributes to obesity, which affects type 2 diabetes (T2D) pathophysiology. About one-third of individuals with T2D develop diabetic nephropathy (DN), which can progress to end-stage renal disease. This study aimed to elucidate the role of inflammation in the progression of DN after chronic HFD feeding using a multi-omics approach. We hypothesize that HFD deteriorates renal function by stimulating renal and systemic inflammation through alterations in bioactive lipid mediators and the gut microbiome. Young (12 weeks old) and aged (>40 weeks old) male and female T2DN rats, an established non-obese T2D model, were placed on a normal fat diet (NFD) or HFD for 12 weeks. Renal cortical tissue was collected at the endpoint for lipidomic analysis. Fecal samples were collected in the final week of the study using an aseptic technique for microbiome analysis. Kidney injury was assessed via albuminuria measurement and histological analysis. An unpaired t-test was used for all statistical comparisons; data was represented as ± standard error of the mean, and n=5 for all groups. A significant increase in albuminuria was observed in young HFD males and aged HFD females when compared to their NFD counterparts (Alb/Cre:0.67 ± 0.20 vs 3.12 ± 0.85, p=0.02 and 2.63 ± 0.73 vs 7.14 ± 1.46, p=0.02). Young HFD-fed females showed increased cortical fibrosis (3.7 ± 0.5 vs 6.7 ± 0.8 % area, p=0.03), while aged HFD females had higher kidney injury molecule-1 staining and medullary protein casts (0.8 ± 0.2 vs 1.8 ± 0.2 % area, p=0.01 and 1.9 ± 0.7 vs 4.8 ± 0.8 % area, p=0.02). In young male T2DN rats fed HFD, lipidomic analysis revealed a significant decrease of omega-3-fatty acids, eicosapentaenoic acid and docosahexaenoic acid (33,845 ± 8,200 vs 10,913 ± 2,655, p=0.04 and 123,294 ± 31,121 vs 40,394 ± 9,002 pg/50mg tissue, p=0.04, respectively), thereby reduced the pro-resolution bioactive lipid mediators. Aged HFD male rats revealed significant increases in arachidonic acid (AA) and AA-derived eicosanoids, 5-Hydroxyeicosatetraenoic acid (5-HETE) and Leukotriene B4, metabolites known to cause sustained persistent inflammation (AA: 600,202 ± 67,626 vs 1,133,727 ± 164,904 pg/50mg tissue, p=0.02). The HFD female-aged rats showed significant increases in metabolites known to be involved in renal oxidative stress and inflammation, 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE (426.4 ± 113.2 vs 1,117 ± 238.9, p=0.03 and 294.6 ± 85.21 vs 743.6 ± 129. 7, p=0.02 pg/50mg tissue, respectively). Additionally, HFD affected the gut microbiota of aged males, where significant decreases in alpha diversity and the relative abundance of Bacteroides were observed, which correlates with gut microbiota dysbiosis. However, these observations may have been due to a lack of some anti-inflammatory and short-chain fatty acids-producing microbes, namely Flavonifractor, Ruthenibacterium, Limosilactobacillus, and Longicatena, found in the young animals but were not present in the aged ones. The study demonstrated that alterations in bioactive lipid mediators and gut microbiota may contribute to the progression of HFD-exacerbated DN. R01 DK129227, R01 DK135644, I01 BX004024, R00 HL153686 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.