Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.

Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner–Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.