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Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota.

ABSTRACT: The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics, probiotics, postbiotics, fecal microbial transplantation (FMT), and engineering bacteria and phages, are potential microbiota-based therapies for DN. Furthermore, novel diabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, may affect the progression of DN partly through gut microbiota. In the current review, we mainly summarize the evidence concerning the gut-kidney axis in the advancement of DN and discuss therapies targeting the gut microbiota, expecting to provide new insight into the clinical treatment of DN.

SUBMITTER: Ni Y

PROVIDER: S-EPMC9827797 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota.

Ni Yinhua Y Zheng Liujie L Nan Sujie S Ke Lehui L Fu Zhengwei Z Jin Juan J

Acta biochimica et biophysica Sinica 20221001 10

The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics ...[more]

PMID: 36239349

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Project description:BackgroundThe correlation between diabetic nephropathy (DN) and gut microbiota (GM) has been suggested in numerous animal experiments and cross-sectional studies. However, a causal association between GM and DN has not been ascertained.MethodsThis research adopted MR analysis to evaluate the causal link between GM and DN derived from data acquired through publicly available genome-wide association studies (GWAS). The study utilized the inverse variance weighted (IVW) approach to assess causal association between GM and DN. Four additional methods including MR-Egger, weighted median, weighted mode, and simple mode were employed to ensure comprehensive analysis and robust results. The Cochran's Q test and the MR-Egger method were conducted to identify heterogeneity and horizontal pleiotropy, respectively. The leave-one-out approach was utilized to evaluate the stability of MR results. Finally, a reverse MR was performed to identify the reverse causal association between GM and DN.ResultsAccording to IVW analysis, Class Verrucomicrobiae (p = 0.003), Order Verrucomicrobiales (p = 0.003), Family Verrucomicrobiaceae (p = 0.003), Genus Akkermansia (p = 0.003), Genus Catenibacterium (p = 0.031), Genus Coprococcus 1 (p = 0.022), Genus Eubacterium hallii group (p = 0.018), and Genus Marvinbryantia (p = 0.023) were associated with a higher risk of DN. On the contrary, Class Actinobacteria (p = 0.037), Group Eubacterium ventriosum group (p = 0.030), Group Ruminococcus gauvreauii group (p = 0.048), Order Lactobacillales (p = 0.045), Phylum Proteobacteria (p = 0.017) were associated with a lower risk of DN. The sensitivity analysis did not identify any substantial pleiotropy or heterogeneity in the outcomes. We found causal effects of DN on 11 GM species in the reverse MR analysis. Notably, Phylum Proteobacteria and DN are mutually causalities.ConclusionThis study identified the causal association between GM and DN with MR analysis, which may enhance the understanding of the intestinal-renal axis and provide novel potential targets for early non-invasive diagnosis and treatment of DN.

Project description:Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and poses significant threats to individuals with diabetes. The concept of gut-kidney axis has gained increasing attention in recent years and the in the occurrence and development of DN, alterations in the gut microbiota also plays a crucial and indispensable role. However, the specific causal relationships between various gut microbial communities and DN, as well as the underlying molecular mechanisms, remains unclear. This study utilized data from genome-wide association studies. After screening for qualified instrumental variables, mendelian randomization causal analyses were performed by inverse variance weighting, MR-Egger, weighted median, weighted mode and MR-RAPS methods. Additionally, sensitivity analyses such as heterogeneity, multiplicity, and the direction of the causal effect were carried out to ensure that the results were robust. After identifying significant gut microbiota, protein-proteomics mediation analysis was conducted on potential 3282 plasma proteins to determine those with mediating effects. Finally, Reactome enrichment analysis was performed to ascertain metabolic or signaling pathways with mediating effects. Mendelian randomization analysis indicated associations between 21 gut microbiota and DN. After adjusting significance levels, Catenibacterium and Parasutterella were found to have causal effects on the onset of DN. Subsequently, we identified 22 plasma proteins with mediating effects, along with 27 metabolic or signaling pathways including activated propionic acid metabolism. Increased in the abundance of Catenibacterium and Parasutterella intestinal bacteria are causative factors for DN. More importantly, the underlying mechanism by which the increased abundance of Catenibacterium and Parasutterella intestinal bacteria lead to DN were revealed, providing a blueprint for the involvement of gut-kidney axis in the pathogenesis of DN and paving the way for future studies.

Project description:ObjectiveEmerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM).MethodsWe used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results.ResultsIt was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy.ConclusionsAt the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Project description:Over recent years, the prevalence of diabetes has been on the rise, paralleling improvements in living standards. Diabetic nephropathy (DN), a prevalent complication of diabetes, has also exhibited a growing incidence. While some clinical studies and reviews have hinted at a link between diabetic nephropathy and gut microbiota (GM), the nature of this connection, specifically its causative nature, remains uncertain. Investigating the causal relationship between diabetic nephropathy and gut microbiota holds the promise of aiding in disease screening and identifying novel biomarkers. In this study, we employed a two-sample Mendelian randomization analysis. Our dataset encompassed 4,111 DN patients from the GWAS database, juxtaposed with 308,539 members forming a control group. The aim was to pinpoint specific categories within the vast spectrum of the 211 known gut microbiota types that may have a direct causal relationship with diabetic nephropathy. Rigorous measures, including extensive heterogeneity and sensitivity analyses, were implemented to mitigate the influence of confounding variables on our experimental outcomes. Ultimately, our comprehensive analysis revealed 15 distinct categories of gut microbiota that exhibit a causal association with diabetic nephropathy. In summary, the phyla Bacteroidota and Verrucomicrobiae, the families Peptostreptococcaceae and Veillonellaceae, the genus Akkermansia, and the species Catenibacterium, Lachnoclostridium, Parasutterella, along with the orders Bacteroidales and Verrucomicrobiales, and the class Bacteroidetes were identified as correlates of increased risk for DN. Conversely, the family Victivallaceae, the species Eubacterium coprostanoligenes, and the Clostridium sensu stricto 1 group were found to be associated with a protective effect against the development of DN.These findings not only provide valuable insights but also open up novel avenues for clinical research, offering fresh directions for potential treatments.

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Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota.

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Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota.

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