Characteristics of Serum Metabolites and Gut Microbiota in Diabetic Kidney Disease

Abstract

Disturbance of circulating metabolites and disorders of the gut microbiota are involved in the progression of diabetic kidney disease (DKD). However, there is limited research on the relationship between serum metabolites and gut microbiota, and their involvement in DKD. In this study, using an experimental DKD rat model induced by combining streptozotocin injection and unilateral nephrectomy, we employed untargeted metabolomics and 16S rRNA gene sequencing to explore the relationship between the metabolic profile and the structure and function of gut microbiota. Striking alterations took place in 140 serum metabolites, as well as in the composition and function of rat gut microbiota. These changes were mainly associated with carbohydrate, lipid, and amino acid metabolism. In these pathways, isomaltose, D-mannose, galactonic acid, citramalic acid, and prostaglandin B2 were significantly upregulated. 3-(2-Hydroxyethyl)indole, 3-methylindole, and indoleacrylic acid were downregulated and were the critical metabolites in the DKD model. Furthermore, the levels of these three indoles were restored after treatment with the traditional Chinese herbal medicine Tangshen Formula. At the genera level, g_Eubacterium_nodatum_group, g_Lactobacillus, and g_Faecalibaculum were most involved in metabolic disorders in the progression of DKD. Notably, the circulating lipid metabolites had a strong relationship with DKD-related parameters and were especially negatively related to the mesangial matrix area. Serum lipid indices (TG and TC) and UACR were directly associated with certain microbial genera. In conclusion, the present research verified the anomalous circulating metabolites and gut microbiota in DKD progression. We also identified the potential metabolic and microbial targets for the treatment of DKD.

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

“…The gut microbiota has a symbiotic relationship with the host, involving energy metabolism, regulating the gut barrier, and maintaining immune responses (7). Many studies have consistently demonstrated (8)(9)(10)(11)(12) that changes in the composition of gut microbiota regulate the development of diabetes by inducing continuous low-grade inflammation and mediating the therapeutic effects of some type 2 diabetes mellitus(T2DM)drugs (13)(14)(15).…”

Gut microbiota and its metabolites – molecular mechanisms and management strategies in diabetic kidney disease

“…16S rDNA, metagenomics, and mass spectrometry can be utilized to explore the diversity, composition, and function of gut microbiota as well as microbiota-related serum metabolites in patients with DKD. Interaction studies between plasma metabolomics and gut microbiome in experimental DKD mouse/rat model provided evidence for the gut-metabolism-kidney axis, and verified the involvement of gut microbiota and circulating metabolites in DKD progression (15,16). DKD patients displayed dysbiosis with composition, richness and diversity in gut microbiota (17)(18)(19).…”

“…Tryptophan is decomposed by bacterial tryptophanase into indole, which is a compound responsible for intercellular signal transduction, participating in the gene expression of intestinal epithelium connections and anti-inflammatory factors in intestinal epithelial cells, as well as maintaining host-microbiota homeostasis on the mucosa surface (51). As downstream critical metabolites, 3-(2-Hydroxyethyl) indole, 3-methylindole, and indoleacrylic acid were downregulated in the DKD model and were reinstated after treatment with Tangshen Formula (15). Some compounds produced by tryptophan metabolism are ligands for the aryl hydrocarbon receptor (AhR) and could induce AhR conformational changes.…”

Ginsenoside Compound K Ameliorates Development of Diabetic Kidney Disease through Inhibiting TLR4 Activation Induced by Microbially Produced Imidazole Propionate

“…Advances in previous metabolomics have discovered thousands of microbe-derived metabolites, some of which have been detected within host tissues, acting as communicator between host and microbiota. It has been reported that trimethylamine N-oxide (TMAO), polyphenols, protein-bound uremic toxins, and other metabolites had aggravated the progression of DKD [ 25 ]. However, there is no evidence to exclude the effect of IMP on DKD.…”

“…For instance, as it comes to DKD, it commonly appears that Lactobacillus and Akkermansia reduce, leading to the decrease in short-chain fatty acids (SCFAs) [ 32 ]; conversely, Bacteroides , Paraprevotella , Oscillibacter , and Lachnoclostridium rise, leading to the increase in TMAO, LPS, phenyl sulfate (PS), and indoxyl sulfate (IS). SCFAs have been reported to have multiple beneficial regulatory roles in DKD through inhibiting oxidative stress and inflammation to recover renal function [ 25 , 33 ]. On the contrary, TMAO, LPS, PS, and IS have been suggested to contribute to renal dysfunction by activating the renin–angiotensin–aldosterone system (RAAS) and the endothelin system, and then inducing insulin resistance, inflammation, oxidative stress, and fibrosis [ 34 , 35 ].…”