Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Abstract

BackgroundThe intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear.MethodsTo investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks.ResultsWe found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks.ConclusionWe firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

Integrative ATAC‐seq and RNA‐seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin

“…The dysfunction of DN in our study is compatible with previous studies using RNA‐seq demonstrating that glucolipid metabolic disorders characterized by insulin resistance, glucolipid toxicity, oxidative stress, and dysbacteriosis have become a very common metabolic defect closely associated with DN 7,14–19 . Previous research results by 16S rRNA gene sequencing on fecal samples suggested that DAPA improved DN possibly associated with the effect on the bile acid homeostasis and its antioxidation effect 13 . In theory, changed metabolism induced by altered microbiome composition can enter circulation and thereby impact peripheral tissue metabolism.…”

“…Due to failed energy utilization, multiple degradation pathways were activated and gene expression pathways were inhibited, as our conjoint analysis of ATAC‐seq and RNA‐seq data in CG vs Controls and two conjoint analyses reversed pathway results also all showed. After DAPA administration, we observed that the weight in TG gradually increased consistent with previous research, 9,12,13 despite studies showed that DAPA could reduce body weight in wt mice. We suppose that weight gains after DAPA intervention, the sign of disease status improvement, appear to manifest as improved energy utilization and increased gene expression suggested by several enrichment results in TG versus CG.…”

Empagliflozin attenuates liver fibrosis in high‐fat diet/streptozotocin‐induced mice by modulating gut microbiota

“…18,24 However, the mechanisms by which SGLT2 inhibitors attenuate liver fibrosis, especially in addition to their hypoglycemic effects, remain unclear and need to be further explored. In the past decade, many studies have found that SGLT2 inhibitors can improve various diseases, such as diabetic kidney disease 25 and atherosclerosis, 14 by modulating gut microbiota, suggesting that gut microbiota might also play an important role in their alleviation of liver fibrosis. The intestinal flora is now considered a novel virtual metabolic organ that maintains homeostasis in the host.…”

Gut microbiota microbial metabolites in diabetic nephropathy patients: far to go

“…In experimental models of diabetes, microbiota-derived phenyl sulfate (PS) is associated with the progression of albuminuria ( Kikuchi et al., 2019 ). Several recent studies have shown that regulating gut microbiota dysbiosis and improving intestinal barrier function can effectively reduce uremic toxin levels and serum proinflammatory mediators [such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-18], thereby delaying the progression of DN ( Han et al., 2023 ; Shi et al., 2023 ; Wang et al., 2023 ; Wu et al., 2023 ). These studies indicate that gut microbiota disorders play an essential role in the development of DN, and further exploration is needed to diagnose or treat DN by targeting the composition of gut microbiota ( Figure 1 ).…”

“…Diabetic nephropathy (DN) is one of the common microvascular complications, characterized by structural and functional damage to the kidneys ( Wu and Huang, 2023 ). Clinical manifestations include massive proteinuria, hypertension, and edema, and it is one of the main causes of end-stage renal disease (ESRD) ( Wu et al., 2023 ). At present, the diagnosis of DN depends on a decreased glomerular filtration rate (GFR) or increased urinary albumin excretion (UAE), but these changes are not unique to DN, and the diagnostic sensitivity and specificity in the preclinical stage of diabetic kidney damage are also limited ( Oshima et al., 2021 ).…”