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Their clinical relevance is currently underestimated, even though their imbalance has been associated with an increased risk of neurodegeneration over the lifespan. We studied the detrimental effects elicited by dietary consumption of the plant-derived \u03b2-sitosterol \u03b2-\n                      <jats:sc>d<\/jats:sc>\n                      -glucoside (BSSG), known to be associated with the occurrence of ALS-PDC, to elucidate its potential mechanism of action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Zebrafish larvae and adults, as well as mice, were treated with BSSG administered directly in the water or via customized food pellet, respectively. Since the intestine was identified as the primary target tissue, its morphological and functional characteristics were assessed, together with transcriptional profiling and gut microbiota sequencing. Ex vivo analysis of zebrafish gut contractility was applied to evaluate intestinal neuromuscular responses. Mutant and transgenic zebrafish lines were used to explore a potential BSSG mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>BSSG induced intestinal inflammation in both zebrafish and mouse models. This previously unknown effect was evidenced by gut dysmotility and inflammatory response. Transcriptomic analyses revealed increased expression of inflammation-related genes in the intestine of both zebrafish and mice, while preliminary gut microbiota analyses suggested the onset of dysbiosis. Transgenic and mutant zebrafish lines, depleted of genes involved in glucocorticoids synthesis and activity, evidenced that BSSG likely interacts with the glucocorticoid receptor, potentially impairing its canonical anti-inflammatory activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified novel pathways altered by dietary BSSG exposure. This molecule appears to initially induce gut inflammation, leading to changes in intestinal morphology and function, and may contribute to neurodegeneration through disruption of the well-known gut\u2013brain axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01249-8","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T08:29:49Z","timestamp":1777883389000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b2-Sitosterol \u03b2-d-glucoside (BSSG) triggers intestinal inflammation in zebrafish and mouse models prior to neurodegeneration onset"],"prefix":"10.1186","volume":"33","author":[{"given":"Francesca","family":"Terrin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Faggin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Bizzotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Santinello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Cerantola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Borsato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Fabris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Scarso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Licitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziano","family":"Guella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Sales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Cagnin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Treu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bubacco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cecilia","family":"Giron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Plotegher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Dalla Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"1249_CR1","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1093\/brain\/84.4.642","volume":"84","author":"A Hirano","year":"1961","unstructured":"Hirano A, Kurland LT, Krooth RS, Lessell S. 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