Interaction between Plasma Metabolomics and Intestinal Microbiome in db/db Mouse, an Animal Model for Study of Type 2 Diabetes and Diabetic Kidney Disease

Abstract

Evidence has demonstrated that either metabolites or intestinal microbiota are involved in the pathogenesis of type 2 diabetes (T2D) and diabetic kidney disease (DKD). To explore the interaction between plasma metabolomics and intestinal microbiome in the progress of T2D-DKD, in the current study, we analyzed metabolomics in the plasma of db/db mice with liquid chromatography–mass spectrometry and also examined intestinal prokaryotes and entire gut microbiome dysbiosis at the genus level with both 16S rDNA and metagenomic sequencing techniques. We found that Negativibacillus and Rikenella were upregulated, while Akkermansia, Candidatus, Erysipelatoclostridium and Ileibacterium were downregulated in the colon of db/db mice compared with non-diabetic controls. In parallel, a total of 91 metabolites were upregulated, while 23 were downregulated in the plasma of db/db mice. The top five upregulated metabolites included D-arabinose 5-phosphate, estrone 3-sulfate, L-theanine, 3′-aenylic acid and adenosine 5′-monophosphate, and the five most significantly downregulated metabolites were aurohyocholic acid sodium salt, calcium phosphorylcholine chloride, tauro-alpha-muricholic acid sodium salt, galactinol and phosphocholine. These plasma metabolites were interacted with intestinal microbiomes, which are mainly involved in the pathways related to the biosynthesis of unsaturated fatty acids, fatty acid elongation, steroid biosynthesis, and D-arginine and D-ornithine metabolism. In the differential metabolites, N-acetyl-L-ornithine, ornithine and L-kyn could be metabolized by the correspondingly differential ontology genes in the intestinal metagenome. The current study thereby provides evidence for a gut–metabolism–kidney axis in the metabolism of db/db mice, in which the gut microbiome and circulating metabolomics interact, and suggests that information from this axis may contribute to our understanding of T2D and DKD pathogenesis.

Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study

“…By studying the interaction between the gut microbiome and plasma metabolomics in an experimental model of DN in mice, evidence supporting the existence of the gut-kidney axis has been found. This study confirmed the involvement of gut microbiota and circulating metabolites in the progression of DN ( 41 , 42 ). It is noteworthy that imbalanced gut microbiota is found in DN patients’ fecal samples where there is an increased presence of Proteobacteria , Verrucomicrobia and Fusobacteria ( 43 ).…”

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).…”

Metabolomic profiles in serum and urine uncover novel biomarkers in children with nephrotic syndrome

“…The kidney is the main organ for extensive metabolization and clearance of small molecules. Therefore, metabolomics is a precious approach in the research of kidney diseases, for example diabetic kidney disease, CKD and gout renal injury 18,34,35 . Changes in the serum or urine metabolites concentration may result from impaired kidney functions and can be used as predictors of kidney diseases.…”