{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Rehabilitation Medicine, Nagoya City University Graduate School of Medical Sciences , Nagoya ,",
    "Department of Physical Therapy, Toyohashi SOZO University School of Health Sciences , Toyohashi",
    "Department of Neuroimmune System, National Center for Geriatrics and Gerontology , Obu ,",
    "Department of Physical Therapy, Nagoya Aoi University Faculty of Medical Science , Nagoya ,",
    "Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences , Tokushima ,"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kohki Matsubara",
      "orcid": "0000-0001-8120-5304"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shintaro Tsukada"
    },
    {
      "affs": [
        2
      ],
      "name": "Shinnosuke Koketsu"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Kazuto Ishida",
      "orcid": "0009-0007-9875-7851"
    },
    {
      "affs": [
        4
      ],
      "name": "Akihito Yamamoto",
      "orcid": "0000-0002-9206-1243"
    },
    {
      "affs": [
        0
      ],
      "name": "Yoshino Ueki"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0jv55zf2hb3e2.bib",
  "cited_by": 0,
  "doi": "10.1093/pnasnexus/pgag340",
  "fulltext_url": null,
  "id": "0jv55zf2hb3e2",
  "issns": [
    "2752-6542"
  ],
  "landing_url": "https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag340/8867931",
  "language": null,
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Gut microbiota and health"
    ]
  ],
  "openalex": "W7220703313",
  "pdf_url": "https://academic.oup.com/pnasnexus/advance-article-pdf/doi/10.1093/pnasnexus/pgag340/71618519/pgag340.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-06",
  "publisher": "Oxford University Press (OUP)",
  "ris": "https://research.draconitic.com/paper/0jv55zf2hb3e2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "10.1093/pnasnexus/pgag340",
      "source": "crossref",
      "url": "https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag340/8867931"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Gut microbiota and health",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes",
  "title_text": "Soluble Siglec-9 combined with exercise ameliorates HFD-induced metabolic and depressive-like phenotypes with gut-brain axis changes",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/0jv55zf2hb3e2",
  "venue": "PNAS Nexus",
  "versions": []
}