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.
Highlights
There is increasing evidence to suspect the pathogenic role of gut microbiota (GM) dysbiosis in many diseases, in gastrointestinal and metabolic disorders (Lynch and Pedersen, 2016)
By combining miRNA and mRNA sequencing data of the colon and liver, this study found that dysbiotic GM changed the expression of miRNAs and their target genes involved in host lipid and cholesterol metabolism, glucose homeostasis and inflammation, which indicated that host miRNAs and genes were important in mediating the effect of the GM and in turn impacting host phenotypes
We first screened the differentially expressed (DE) miRNAs responding to the dysbiotic GM, sought their targeted DE genes, and tracked the key GM members and the biological functions closely correlated with these miRNAs/genes
Summary
There is increasing evidence to suspect the pathogenic role of GM dysbiosis in many diseases, in gastrointestinal and metabolic disorders (Lynch and Pedersen, 2016). Evidence and data analysis suggested that the poor clinical status of the PWS children before the intervention was related to dysbiotic GM. To validate this suspicion, the pre- and post-intervention GMs from an intervened PWS child were transplanted into two randomized groups (pre- and post-group, respectively) of genetically identical germ-free male C57BL/6J mice. The pre-group had a higher inflammation level and more fat accumulation than the post-group (Zhang et al, 2015; Wang et al, 2018) This animal experiment demonstrated the effect of the disturbance of dysbiotic GM on host health.
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