{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T02:26:10Z","timestamp":1787624770530,"version":"build-2736575974"},"reference-count":68,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["JP21H03356"],"award-info":[{"award-number":["JP21H03356"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inflammatory bowel disease (IBD) is associated with severe systemic complications, including cachexia, anemia, and renal dysfunction, which represent a significant unmet medical need. The gut microbial metabolite indole-3-acetic acid (IAA) is known to be reduced in IBD; however, its therapeutic potential remains unclear. This study aimed to determine whether oral supplementation with IAA could ameliorate intestinal inflammation and its associated systemic complications. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we administered oral IAA and evaluated a comprehensive panel of clinical, metabolic, renal, and hematological parameters. Systemic health status was assessed using Principal Component Analysis (PCA). IAA administration significantly ameliorated DSS-induced colitis, reducing the Disease Activity Index (DAI) (3.88 vs. 3.13; p &lt; 0.05) and significantly attenuating colon shortening (5.0 cm vs. 5.78 cm; p &lt; 0.05) compared to the DSS-alone group. Crucially, it markedly suppressed systemic complications: IAA ameliorated DSS-induced cachexia (\u0394Body weight, \u22123.27 g vs. \u22121.83 g; p &lt; 0.05), an effect independent of food intake (N.S.). Furthermore, IAA mitigated early-stage renal dysfunction, as evidenced by a significant reduction in plasma Creatinine (Cr) levels (0.12 mg\/dL vs. 0.10 mg\/dL; p = 0.05), and reversed the decline in plasma iron levels associated with anemia (45.75 \u03bcg\/dL vs. 63.50 \u03bcg\/dL; p &lt; 0.05). PCA revealed that IAA induced a distinct recovery profile, significantly improving the systemic health index without fully restoring the original homeostatic state. Oral IAA exerts pleiotropic effects on both intestinal inflammation and systemic complications. Its food intake-independent anti-cachectic mechanism represents a novel therapeutic paradigm for IBD-associated wasting. These findings position IAA as a promising candidate for microbial metabolite-based therapy aimed at reprogramming, rather than merely restoring, systemic homeostasis in IBD.<\/jats:p>","DOI":"10.3390\/ijms262311260","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:41:58Z","timestamp":1763728918000},"page":"11260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Gut Microbial Metabolite Indole-3-Acetic Acid Reprograms Systemic Homeostasis and Ameliorates IBD-Associated Cachexia Independent of Food Intake"],"prefix":"10.3390","volume":"26","author":[{"given":"Ayame","family":"Tomii","sequence":"first","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Takei","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9416-8098","authenticated-orcid":false,"given":"Keisuke","family":"Yoshikiyo","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan"},{"name":"Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0939-0098","authenticated-orcid":false,"given":"Hidehisa","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan"},{"name":"Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"Estuary Research Center, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"},{"name":"Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00535-021-01784-1","article-title":"Evidence-based clinical practice guidelines for inflammatory bowel disease 2020","volume":"56","author":"Nakase","year":"2021","journal-title":"J. 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