๐ก Type 2 diabetes mellitus (T2DM) is associated with altered immune response, gut microbiota composition, and microbial function. This study aimed to investigate the intricate relationship among retinoic acid-inducible gene-I-like receptors (RLRs) signaling pathway, gut microbiota, microbial tryptophan metabolites, inflammation, and the prolonged course of T2DM.
๐ Methods : Fourteen T2DM patients and seven healthy controls were enrolled. Stool samples were subjected to 16S rRNA amplicon sequencing and untargeted metabolomics. RNA sequencing (RNA-seq) was conducted on peripheral blood samples. C57BL/6J specific pathogen-free (SPF) mice were used to establish an animal model of T2DM.
๐ Key Findings
๐ Reduced Probiotic Abundance: Prolonged T2DM was associated with a decrease in probiotic abundance in the intestinal microbiome, including ๐๐ข๐ค๐ต๐ฆ๐ณ๐ฐ๐ช๐ฅ๐ฆ๐ด ๐ข๐ฏ๐ฅ ๐๐ข๐ฆ๐ค๐ข๐ญ๐ช๐ฃ๐ข๐ค๐ต๐ฆ๐ณ๐ช๐ถ๐ฎ.
๐ Skatole Production Decline: The reduced abundance of probiotics led to a decline in skatole production, a microbial tryptophan derivative.
๐ Activation of RLRs Signaling Pathway: Low abundances of probiotics triggered the inflammatory response by activating the RLRs signaling pathway, as evidenced by increased TANK expression levels.
๐ NF-ฮบB Activation and Inflammatory Damage: Activation of TANK in the colon tissue activated NFฮบB2, resulting in inflammatory damage to the liver, kidney, and colon.
๐ Association with Blood Glucose Levels: Dysbiosis and reduced skatole production were associated with increased blood glucose levels, potentially mediated by downregulation of glucagon-like peptide-1 (GLP1) expression.
๐ Impact on Lipid Metabolism: Dysbiosis, particularly a decrease in butyrate-producing bacteria like Alistipes, was associated with altered lipid metabolism, emphasizing the potential regulatory role of gut microbes in host lipid metabolism.
๐ Role of lncRNAs: Long non-coding RNAs (lncRNAs), such as TANK-012 and RELA-005, were identified as potential regulators in the interplay between the RLRs signaling pathway and inflammation.
๐ The study unveils a complex interplay involving hyperglycemia, altered probiotic abundance, microbial tryptophan metabolism, inflammation, and prolonged T2DM. Dysbiosis and reduced skatole production contribute to inflammation, potentially impacting blood glucose levels and lipid metabolism. Activation of the RLRs signaling pathway and downstream NF-ฮบB activation highlight the intricate relationship among gut microbes, inflammation, and T2DM progression.
๐ Implications and Future Directions
๐ Targeted Therapeutic Approaches: Understanding the role of specific microbes and their small molecules in T2DM provides avenues for targeted therapeutic interventions, potentially using probiotics or microbial-derived compounds.
๐ Mechanistic Insights Needed: Future research should address limitations, including the small sample size, by employing mechanistic studies, genetically modified animals, and fecal microbiota transplantation to unravel the precise mechanisms involved.
๐ This study elucidates the complex connections among the RLRs signaling pathway, gut microbiota, and inflammation in the context of prolonged T2DM. Findings underscore the potential impact of dysbiosis on metabolic and inflammatory processes, opening avenues for targeted interventions in the treatment of T2DM. The identified role of lncRNAs adds a layer of complexity to the regulatory network, warranting further exploration.
Link to the article : http://tinyurl.com/bdexpcx7
