MiRNA-gene regulatory network in gnotobiotic mice stimulated by dysbiotic gut microbiota transplanted from a genetically obese child

Abstract

Gut microbiota (GM) dysbiosis has been considered a pathogenic origin of many chronic diseases. In our previous trial, a shift in GM structure caused by a complex fiber-rich diet was associated with the health improvement of obese Prader-Willi syndrome (PWS) children. The pre- and post-intervention GMs (pre- and post-group, respectively) from one child were then transplanted into gnotobiotic mice, which resulted in significantly different physiological phenotypes, each of which was similar to the phenotype of the corresponding GM donor. This study was designed to investigate the miRNA-gene regulatory networks involved in causing these phenotypic differences. Using the post-group as a reference, we systematically identified and annotated the differentially expressed (DE) miRNAs and genes in the colon and liver of the pre-group in the second and fourth weeks after GM inoculation. Most of the significantly enriched GO terms and KEGG pathways were observed in the liver and were in the second week after GM transplantation. We screened 23 key genes along with their 73 miRNA regulators relevant to the host phenotype changes and constructed a network. The network contained 92 miRNA-gene regulation relationships, 51 of which were positive, and 41 of which were negative. Both the colon and liver had upregulated pro-inflammatory genes, and genes involved in fatty acid oxidation, lipolysis, and plasma cholesterol clearance were downregulated in only the liver. These changes were consistent with lipid and cholesterol accumulation in the host and with a high inflammation level. In addition, the colon showed an impacted glucagon-like peptide 1 (GLP-1) signaling pathway, while the liver displayed decreased insulin receptor signaling pathway activity. These molecular changes were mainly found in the second week, 2 weeks before changes in body fat occurred. This time lag indicated that GM dysbiosis might initially induce cholesterol and lipid metabolism-related miRNA and gene expression disorder and then lead to lipid accumulation and obesity development, which implicates a causative role of GM dysbiosis in obesity development rather than a result of obesity. This study provides fundamental molecular information that elucidates how dysbiotic GM increases host inflammation and disturbs host lipid and glucose metabolism.