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Methods: Female rats were supplemented with CSE (250 mg\/kg\/day) over seven days, and plasma samples were collected at baseline, day 4, and day 7 for untargeted metabolomic profiling using LC-ESI-QTOF. Results: A total of 244 plasma metabolites were identified, while 180 were detected in the CSE. Among these, only 21 compounds were consistently detected in both the CSE and the plasma at baseline and day 7. Notably, just three compounds, caffeine, theobromine, and N-isovaleroylglycine, were bioavailable, detected only in plasma after supplementation on day 7, confirming their absorption and systemic distribution. Pathways related to caffeine metabolism, glycerophospholipid biosynthesis, nicotinate, and nicotinamide metabolism were significantly upregulated, indicating enhanced lipid metabolism and energy homeostasis. Conversely, reductions were observed in pathways involving tryptophan, glutathione, arginine, and proline, pointing to shifts in amino acid metabolism and antioxidant defense mechanisms. Network analysis revealed significant changes in the cholinergic synapse, retrograde endocannabinoid signaling, and glutamatergic synapse pathways, which are crucial for cellular communication and neurotransmission. Conclusions: The observed metabolic reconfiguration demonstrates CSE\u2019s rapid modulation of the metabolome, highlighting the bioavailability of its key components. These findings suggest potential mechanisms for CSE as a functional food ingredient with health-promoting effects, potentially supporting cognitive function and metabolic health through energy metabolism, neurotransmission, and lipid signaling pathways.<\/jats:p>","DOI":"10.3390\/nu17050885","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T05:41:51Z","timestamp":1741066911000},"page":"885","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Untargeted Metabolomics and Chemometrics Elucidate Dynamic Plasma Profile Changes Induced by Cocoa Shell in Female Rats"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7442-1586","authenticated-orcid":false,"given":"David","family":"Ramiro-Cortijo","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 2, 28029 Madrid, Spain"},{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-1290","authenticated-orcid":false,"given":"Miguel","family":"Rebollo-Hernanz","sequence":"additional","affiliation":[{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Department of Agricultural Chemistry and Food Science, Faculty of Science, Universidad Aut\u00f3noma de Madrid, C\/Francisco Tom\u00e1s y Valiente, 7, 28049 Madrid, Spain"},{"name":"Institute of Food Science Research (CIAL, UAM-CSIC), Universidad Aut\u00f3noma de Madrid, C\/Nicol\u00e1s Cabrera, 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6483-8289","authenticated-orcid":false,"given":"Pilar","family":"Rodr\u00edguez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 2, 28029 Madrid, Spain"},{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2216-5335","authenticated-orcid":false,"given":"Santiago","family":"Ruvira","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 2, 28029 Madrid, Spain"},{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Arribas","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 2, 28029 Madrid, Spain"},{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9834-639X","authenticated-orcid":false,"given":"Maria","family":"Martin-Cabrejas","sequence":"additional","affiliation":[{"name":"Food, Oxidative Stress and Cardiovascular Health (FOSCH) Research Group, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Department of Agricultural Chemistry and Food Science, Faculty of Science, Universidad Aut\u00f3noma de Madrid, C\/Francisco Tom\u00e1s y Valiente, 7, 28049 Madrid, Spain"},{"name":"Institute of Food Science Research (CIAL, UAM-CSIC), Universidad Aut\u00f3noma de Madrid, C\/Nicol\u00e1s Cabrera, 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nirmal, N.P., Khanashyam, A.C., Mundanat, A.S., Shah, K., Babu, K.S., Thorakkattu, P., Al-Asmari, F., and Pandiselvam, R. 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