Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes

Abstract Long-term intake of a high-fat diet (HFD) induces gut microbiota dysbiosis associated with inflammation and is linked to metabolic abnormalities and depressive-like behaviors. The soluble form of sialic acid-binding Ig-like lectin-9 (s-Siglec-9) exhibits therapeutic effects against inflammatory diseases, and exercise is known to have antidepressant effects. However, the effects of s-Siglec-9 on HFD-induced depressive-like behaviors, alone or in combination with exercise, remain unclear. In this study, we investigated the therapeutic effects of s-Siglec-9 combined with exercise in mice with HFD-induced metabolic dysfunction. Mice were fed an HFD ad libitum for 8 weeks, and interventions were conducted during the final 4 weeks. The induction of the anti-inflammatory phenotype by s-Siglec-9 was also investigated using primary microglia. The results revealed significant suppression of depressive-like behaviors in the intervention groups compared with the group fed only the HFD, with the effect being greater in the s-Siglec-9 with exercise group. Histological analyses showed reduced microglial activation and astrogliosis in the hippocampus and hypothalamus, together with increased hippocampal neurogenesis. Gut microbiota analysis showed a decrease in inflammatory bacterial genera and an increase in short-chain fatty acid-producing bacterial genera in the intervention groups. In vitro, s-Siglec-9 promoted a shift in primary microglia toward an anti-inflammatory and neurotrophic M2-like state in the presence of monocyte chemoattractant protein-1 and chondroitin sulfate proteoglycans. Our study suggests the potential of combining administration of an anti-inflammatory substance with exercise as a therapeutic strategy for metabolic abnormalities accompanied by depressive-like behaviors, potentially involving coordinated changes across gut microbiota, inflammatory, and neural systems.