Postbiotic potential of SCFAs on metaflammation and gut microbiota alteration in diabetes

Gut microbiota regulate host metabolism via its fermentation products, mainly short-chain fatty acids (SCFAs), i.e., acetate, propionate, and butyrate. Although butyrate is studied for its anti-inflammatory, anti-obesity, and anti-diabetic effects, propionate alone and in combination with acetate or butyrate is not well reported. In this study, we have shown the combinatorial effect of propionate with acetate or butyrate in the regulation of diabetes characteristics, liver metabolism, and inflammation via SCFA receptors and gut microbiota modulation. Diabetes was induced by high-fat diet administration for 4 months and was followed by oral administration of SCFAs for 1 month. Although propionate and butyrate alone showed reduced diabetic characteristics, a combination of propionate with acetate or butyrate more significantly regulated insulin downstream pathway molecules, i.e., liver X receptor (LXR), sterol regulatory element binding protein 1c (SREBP1c), glucose transporter type 4 (GLUT4), and peroxisome-proliferator-activated receptor alpha (PPARα), and enhanced the expression of SCFA receptors, i.e., G-protein-coupled receptor 41 (GPR41), GPR43, and GPR109 in the liver. They increased microbial richness and evenness along with the restoration of probiotic bacterial strains, healthy bacteria, as well as butyrate producers, mainly, Lactobacillus, Oscillospira, Barnesiella, Rikenellaceae_RC9_gut_group and Lachnospiraceae_NK4B4_group, Roseburia, Eubacteria, and Akkermensia. In conclusion, propionate in the presence of acetate or butyrate exerts beneficial effects on liver metabolism and inflammation via SCFA receptor modulation and gut microbiota alteration in the case of HFDinduced diabetic mice.