Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes
5 affiliations
- 1Department of Rehabilitation Medicine, Nagoya City University Graduate School of Medical Sciences , Nagoya ,
- 2Department of Physical Therapy, Toyohashi SOZO University School of Health Sciences , Toyohashi
- 3Department of Neuroimmune System, National Center for Geriatrics and Gerontology , Obu ,
- 4Department of Physical Therapy, Nagoya Aoi University Faculty of Medical Science , Nagoya ,
- 5Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences , Tokushima ,
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.
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BibTeX
@article{matsubara2026soluble,
title = {{Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes}},
author = {Kohki Matsubara and Shintaro Tsukada and Shinnosuke Koketsu and Kazuto Ishida and Akihito Yamamoto and Yoshino Ueki},
journal = {PNAS Nexus},
year = {2026},
month = oct,
doi = {10.1093/pnasnexus/pgag340},
url = {https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag340/8867931},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes
AU - Kohki Matsubara
AU - Shintaro Tsukada
AU - Shinnosuke Koketsu
AU - Kazuto Ishida
AU - Akihito Yamamoto
AU - Yoshino Ueki
PY - 2026
DA - 2026/10/06
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag340
UR - https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag340/8867931
AB - 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.
SN - 2752-6542
ER -