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There is no clear consensus as to the second\u2010line therapy for IESS. Ketogenic diet (KD) has emerged as an effective treatment for certain drug\u2010resistant epilepsies and in many cases of IESS. Understanding the mechanism of action of the KD in IESS will allow for harnessing the power of the KD and discovering novel therapeutics for IESS. In this review, we will summarize the current state of knowledge of the action of the KD in IESS derived from animal models. We emphasize the importance of the KD in altering respiration to cause brain acidosis. In addition, we review recent data implicating altered gut microbiome and the tryptophan\u2013serotonin\u2013kynurenine pathway in KD animals with infantile epileptic spasms syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>Infantile Epileptic Spasms Syndrome is a serious seizure condition in babies, often resistant to standard drugs, failing in half of cases. Animal studies helped unravel multiple mechanisms through which a high\u2010fat, low\u2010carb ketogenic diet can control seizures, including altering gut bacteria, reducing inflammation, balancing brain chemicals, boosting mitochondrial function, or adjusting breathing to slightly acidify the brain. These findings could lead to new, targeted therapies that are simpler to use and more accessible for families facing this challenging condition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70168","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:38:23Z","timestamp":1761763103000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ketogenic diet for infantile epileptic spasms"],"prefix":"10.1002","author":[{"given":"Morris H.","family":"Scantlebury","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Clinical Neuroscience, Cumming School of Medicine University of 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