Gut Microbiota-Dependent Trimethylamine-N-oxide and Serum Biomarkers in Patients with T2DM and Advanced CKD

Abstract

Trimethylamine-N-oxide (TMAO) is a product of dietary, gut microbiome, and tissues metabolism. Elevated blood TMAO levels are associated with heart attack, stroke and chronic kidney disease (CKD). The purpose of our study was to investigate the gut microbiota associated with trimethylamine (TMA) production, the precursor of TMAO, and the serum levels of TMAO and inflammatory biomarkers associated with type 2 diabetes mellitus (T2DM) and CKD. Twenty adults with T2DM and advanced CKD and 20 healthy adults participated in the study. Analyses included anthropometric and metabolic parameters, characterization of TMA producing gut microbiota, and concentrations of TMAO, lipopolysaccharides (LPS) endotoxin, zonulin (Zo) gut permeability marker, and serum inflammatory and endothelial dysfunction biomarkers. Diversity of the gut microbiota was identified by amplification of V3–V4 regions of the 16S ribosomal RNA genes and DNA sequencing. TMAO was quantified by Mass Spectrometry and serum biomarkers by ELISA. The significance of measurements justified by statistical analysis. The gut microbiome in T2DM-CKD patients exhibited a higher incidence of TMA-producing bacteria than control, p < 0.05. The serum levels of TMAO in T2DM-CKD patients were significantly higher than controls, p < 0.05. TMAO showed a positive correlation with Zo and LPS, inflammatory and endothelial dysfunction biomarkers. A positive correlation was observed between Zo and LPS in T2DM-CKD subjects. An increased abundance of TMA-producing bacteria in the gut microbiota of T2DM-CKD patients together with excessive TMAO and increased gut permeability might impact their risk for cardiovascular disease through elevation of chronic inflammation and endothelial dysfunction.

Gut microbiota signatures and lipids metabolism profiles by exposure to polyene phosphatidylcholine

“…First, Cho CE et al revealed that TMAO production potential is detected in Firmicutes but is absent in Bacteroidetes in healthy volunteers when consuming food rich in TMAO . Furthermore, other report showed that there was a higher TMAO‐producing bacteria ratio and TMAO levels in patients with diabetes mellitus type 2 and chronic kidney disease (T2DM‐CKD) . This present evidence has been proved again that gut microbiota plays an obligatory role for TMAO formation from diet rich in choline and TMAO.…”

Gut microbiota and cardiovascular disease: opportunities and challenges

“…High TMAO production can consequently affect lipids [41] and lead to a 43% higher CAD risk due to the reduction of RCT and alteration in bile acid transport, composition, and pool size [92,93,99]. TMAO is also associated with C-reactive protein (CRP) and endothelial dysfunction in the setting of increased gut permeability and is related to increased serum levels of LPS endotoxin [100]. In addition, it can also lead to calcium release and platelet hyperreactivity [101], which can affect CAD development.…”

“…TMA production has been found in 102 genomes covering 36 species, and TMA producers include Firmicutes, Proteobacteria, Actinobacteria, and absent in Bacteroidetes [95]. Firmicutes including Anaerococcus, Clostridium, Desulfitobacterium, Enterococcus, Streptococcus, and Proteobacteria including Dseulfovibrio, Enterobacter, Escherichia, Klebsiella, Proteus, Pseudomonas, Actinobacter, and Citrobacter have been associated with TMA production [100]. One study found that 8 species from Firmicutes and Proteobacteria consumed > 60% of choline for TMA production: Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathawayi, C. sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri, and Edwardsiella tarda [103].…”

“…Therefore, their role in the immune system needs to be further investigated. The gut microbiome-derived TMAO can also affect our immune system by activating TXNIP-NLRP3 inflammasomes [138], leading to the expression of inflammatory markers such as TNF-α, IL-6 [100,139], IL-18, and IL-1B [138] that can boost plaque development in arteries by generating cholesterol-packed foamy macrophages, ultimately resulting in CAD [140] (Fig. 2).…”

Gut microbial-related metabolite trimethylamine-N-oxide and its precursor L-carnitine are associated with spontaneous preterm birth: a nested case-control study

“…The growing recognition of a contributory role of gut microbiota to health and disease promises that great efforts have devoted to define the cause-effect between gut microbiota and preterm birth [6][7][8][9]. Moreover, experimental and clinical studies have demonstration that TMAO synthesized by the intestinal microbiota is involved in the progression of atherosclerosis, cardiovascular disease, type 2 diabetes, vitamin D deficiency, chronic kidney disease, non-alcoholic fatty liver disease [10][11][12]. Those adverse impacts induced by microbial-related metabolite TMAO may directly affect the physical condition of pregnant women and birth outcomes [13,14].…”