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Recent evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs) exert anticancer effects and may hold promise as therapeutic adjuvants. In this study, we investigated the potential of a physiologically relevant mixture of SCFAs to enhance the efficacy of 5-FU against CRC. Using a combination of 2D monolayer cultures, 3D models, and the in vivo chicken chorioallantoic membrane (CAM) assay, we demonstrated that SCFAs positively affect the antitumor effects of low-dose 5-FU. SCFAs contributed to the inhibition of CRC cell growth, proliferation, survival, and migration, with an overall increase of the anti-tumour effects observed across the different models. The combined treatment led to a significant reduction in tumour size in the CAM assay, contributing for an improvement of the effects of 5-FU alone. To our knowledge, this is the first report showing that physiologically relevant SCFA combinations can be harnessed to improve the therapeutic index of 5-FU in CRC, in a context-dependent manner. These findings support the development of microbiota-targeted co-adjuvant strategies to optimize CRC chemotherapy, reduce treatment toxicity, and improve patient outcomes, which is important given the clinical interest in microbiome-chemotherapy interactions.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10565-026-10147-6","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T16:16:41Z","timestamp":1769271401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut microbiota metabolites positively impacts chemotherapy effects in colorectal cancer"],"prefix":"10.1007","volume":"42","author":[{"given":"Sara","family":"Gomes","sequence":"first","affiliation":[]},{"given":"Sara","family":"Granja","sequence":"additional","affiliation":[]},{"given":"Luana A.","family":"Os\u00f3rio","sequence":"additional","affiliation":[]},{"given":"Ruth E.","family":"Mackay","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[]},{"given":"Elisabete","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Preto","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"key":"10147_CR1","doi-asserted-by":"publisher","first-page":"329","DOI":"10.6004\/jnccn.2021.0012","volume":"19","author":"AB Benson","year":"2021","unstructured":"Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen Y-J, Ciombor KK, et al. 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