{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:18:21Z","timestamp":1788779901787,"version":"build-2803163510"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer\u2019s Disease (AD) is the most common cause of dementia among elderly individuals worldwide, leading to a strong motor-cognitive decline and consequent emotional distress and codependence. It is traditionally characterized by amyloidogenic pathway formation of senile plaques, and recent studies indicate that dysbiosis is also an important factor in AD\u2019s pathology. To overcome dysbiosis, probiotics\u2014as kefir\u2014have shown to be a great therapeutic alternative for Alzheimer\u2019s disease. In this present work, we explored kefir as a probiotic and a metabolite source as a modulator of microbiome and amyloidogenic pathway, using a <jats:italic>Drosophila melanogaster<\/jats:italic> model for AD (AD-like flies)<jats:italic>.<\/jats:italic> Kefir microbiota composition was determined through 16S rRNA sequencing, and the metabolome of each fraction (hexane, dichloromethane, ethyl acetate, and n-butanol) was investigated. After treatment, flies had their survival, climbing ability, and vacuolar lesions accessed. Kefir and fraction treated flies improved their climbing ability survival rate and neurodegeneration index. In conclusion, we show that kefir <jats:italic>in natura<\/jats:italic>, as well as its fractions may be promising therapeutic source against AD, modulating amyloidogenic related pathways.<\/jats:p>","DOI":"10.1038\/s41598-021-90749-8","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T10:16:36Z","timestamp":1622110596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Kefir metabolites in a fly model for Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"11","author":[{"given":"Let\u00edcia Leandro","family":"Batista","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena Mares","family":"Malta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heitor Cappato","family":"Guerra Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiza Diniz Ferreira","family":"Borges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lays Oliveira","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9ssica Regina","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamiris Sabrina","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Venturini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallyandra","family":"Padilha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"da Costa Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Foued Salmen","family":"Espindola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ueira-Vieira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"90749_CR1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","volume":"396","author":"G Livingston","year":"2020","unstructured":"Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413\u2013446 (2020).","journal-title":"Lancet"},{"key":"90749_CR2","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","volume":"25","author":"CA Lane","year":"2018","unstructured":"Lane, C. A., Hardy, J. & Schott, J. M. Alzheimer\u2019s disease. Eur. J. Neurol. 25, 59\u201370 (2018).","journal-title":"Eur. J. Neurol."},{"key":"90749_CR3","first-page":"353","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy, J. & Selokoe, D. The amyloid hypothesis of Alzheimer \u2019s disease. Amyloid Int. J. Exp. Clin. Investig. 297, 353\u2013357 (2002).","journal-title":"Amyloid Int. J. Exp. Clin. Investig."},{"key":"90749_CR4","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3389\/fncel.2013.00153","volume":"7","author":"S Bhattacharjee","year":"2013","unstructured":"Bhattacharjee, S. & Lukiw, W. Alzheimer\u2019s disease and the microbiome. Front. Cell. Neurosci. 7, 153 (2013).","journal-title":"Front. Cell. Neurosci."},{"key":"90749_CR5","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1038\/s41598-017-02587-2","volume":"7","author":"L Bonfili","year":"2017","unstructured":"Bonfili, L. et al. Microbiota modulation counteracts Alzheimer\u2019s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci. Rep. 7, 2426 (2017).","journal-title":"Sci. Rep."},{"key":"90749_CR6","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3233\/JAD-190872","volume":"73","author":"M Sun","year":"2020","unstructured":"Sun, M. et al. A Review of the Brain-Gut-Microbiome Axis and the Potential Role of Microbiota in Alzheimer\u2019s Disease. J. Alzheimers. Dis. 73, 849\u2013865 (2020).","journal-title":"J. Alzheimers. Dis."},{"key":"90749_CR7","doi-asserted-by":"publisher","first-page":"4528","DOI":"10.1523\/JNEUROSCI.5924-09.2010","volume":"30","author":"R Morales","year":"2010","unstructured":"Morales, R. et al. Molecular cross talk between misfolded proteins in animal models of Alzheimer\u2019s and prion diseases. J. Neurosci. 30, 4528\u20134535 (2010).","journal-title":"J. Neurosci."},{"key":"90749_CR8","doi-asserted-by":"publisher","first-page":"8642","DOI":"10.18632\/aging.102352","volume":"11","author":"Q Gao","year":"2019","unstructured":"Gao, Q. et al. Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: A potential therapeutic approach for Alzheimer\u2019s disease. Aging 11, 8642 (2019).","journal-title":"Aging"},{"key":"90749_CR9","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1186\/1742-2094-9-150","volume":"9","author":"MA Erickson","year":"2012","unstructured":"Erickson, M. A. et al. Lipopolysaccharide impairs amyloid beta efflux from brain: Altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood\u2013brain barrier. J. Neuroinflammation 9, 150 (2012).","journal-title":"J. Neuroinflammation"},{"key":"90749_CR10","doi-asserted-by":"publisher","first-page":"3769","DOI":"10.1007\/s00018-017-2550-9","volume":"74","author":"S Westfall","year":"2017","unstructured":"Westfall, S. et al. Microbiome, probiotics and neurodegenerative diseases: Deciphering the gut brain axis. Cell. Mol. Life Sci. 74, 3769\u20133787 (2017).","journal-title":"Cell. Mol. Life Sci."},{"issue":"1","key":"90749_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/fermentation3010001","volume":"3","author":"Stravos Plessas","year":"2016","unstructured":"Plessas, S., Nouska, C., Mantzourani, I. & Kourkoutas, Y. Microbiological exploration of different types of kefir grains. 1\u201310 (2017) https:\/\/doi.org\/10.3390\/fermentation3010001.","journal-title":"Fermentation"},{"key":"90749_CR12","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/1471-0307.12473","volume":"71","author":"J Dong","year":"2018","unstructured":"Dong, J., Liu, B., Jiang, T., Liu, Y. & Chen, L. The biofilm hypothesis: The formation mechanism of Tibetan kefir grains. Int. J. Dairy Technol. 71, 44\u201350 (2018).","journal-title":"Int. J. Dairy Technol."},{"key":"90749_CR13","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.foodchem.2019.01.010","volume":"282","author":"FG Amorim","year":"2019","unstructured":"Amorim, F. G. et al. Identification of new bioactive peptides from Kefir milk through proteopeptidomics: Bioprospection of antihypertensive molecules. Food Chem. 282, 109\u2013119 (2019).","journal-title":"Food Chem."},{"key":"90749_CR14","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1080\/10408398.2018.1428168","volume":"59","author":"DH Kim","year":"2019","unstructured":"Kim, D. H., Jeong, D., Kim, H. & Seo, K. H. Modern perspectives on the health benefits of kefir in next generation sequencing era: Improvement of the host gut microbiota. Crit. Rev. Food Sci. Nutr. 59, 1782\u20131793 (2019).","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"90749_CR15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1055\/s-2008-1060361","volume":"115","author":"S Cenesiz","year":"2008","unstructured":"Cenesiz, S., Devrim, A. K., Kamber, U. & Sozmen, M. The effect of kefir on glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) levels in mice with colonic abnormal crypt formation (ACF) induced by azoxymethane (AOM). Dtsch. Tierarztl. Wochenschr. 115, 15\u201319 (2008).","journal-title":"Dtsch. Tierarztl. Wochenschr."},{"key":"90749_CR16","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.idairyj.2014.10.004","volume":"43","author":"Z Chen","year":"2015","unstructured":"Chen, Z. et al. Chemical and physical characteristics and antioxidant activities of the exopolysaccharide produced by Tibetan ke fi r grains during milk fermentation. Int. Dairy J. 43, 15\u201321 (2015).","journal-title":"Int. Dairy J."},{"key":"90749_CR17","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.ijantimicag.2004.09.020","volume":"25","author":"KL Rodrigues","year":"2005","unstructured":"Rodrigues, K. L., Gaudino Caputo, L. R., Tavares Carvalho, J. C., Evangelista, J. & Schneedorf, J. M. Antimicrobial and healing activity of kefir and kefiran extract. Int. J. Antimicrob. Agents 25, 404\u2013408 (2005).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"90749_CR18","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.ijfoodmicro.2012.04.014","volume":"157","author":"H-H Hsieh","year":"2012","unstructured":"Hsieh, H.-H., Wang, S.-Y., Chen, T.-L., Huang, Y.-L. & Chen, M.-J. Effects of cow\u2019s and goat\u2019s milk as fermentation media on the microbial ecology of sugary kefir grains. Int. J. Food Microbiol. 157, 73\u201381 (2012).","journal-title":"Int. J. Food Microbiol."},{"key":"90749_CR19","doi-asserted-by":"crossref","unstructured":"Anwar, M. M., Ali, O. S. M., Laila Ahmed, R., Badawi, A. M. & Eltablawy, N. A. The effect of using kefir grains and mesenchymal stem cells in LPS-induced Alzheimer\u2019s disease neuroinflammatory model. Neurobiol. Rev. electr\u00f3nica (2019).","DOI":"10.25009\/eb.v10i25.2568"},{"key":"90749_CR20","unstructured":"Anwar, M. M., Ali, O. S. M., Laila Ahmed, R., Badawi, A. M. & Eltablawy, N. A. Regulation of miRNA-124, nuclear factor-Kappa B and \u03b2-Catenin expression in response to novel therapeutic protocol in LPS induced Alzheimer\u2019s disease in rats. Bone 1, 17\u201319 (2018)."},{"key":"90749_CR21","unstructured":"Ton, A. M. M. et al. Oxidative Stress and Dementia in Alzheimer\u2019s Patients: Effects of Synbiotic Supplementation. Oxid. Med. Cell. Longev. 2020, (2020)."},{"key":"90749_CR22","doi-asserted-by":"publisher","first-page":"134","DOI":"10.2741\/4798","volume":"25","author":"NT Tue","year":"2020","unstructured":"Tue, N. T., Dat, T. Q., Ly, L. L., Anh, V. D. & Yoshida, H. Insights from Drosophila melanogaster model of Alzheimer\u2019s disease. Front. Biosci. - Landmark 25, 134\u2013146 (2020).","journal-title":"Front. Biosci. - Landmark"},{"key":"90749_CR23","doi-asserted-by":"crossref","unstructured":"Jeon, Y., Lee, J. H., Choi, B., Won, S. Y. & Cho, K. S. Genetic dissection of Alzheimer\u2019s disease using Drosophila models. Int. J. Mol. Sci. 21, (2020).","DOI":"10.3390\/ijms21030884"},{"key":"90749_CR24","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1534\/genetics.115.179457","volume":"201","author":"L McGurk","year":"2015","unstructured":"McGurk, L., Berson, A. & Bonini, N. M. Drosophila as an in vivo model for human neurodegenerative disease. Genetics 201, 377\u2013402 (2015).","journal-title":"Genetics"},{"key":"90749_CR25","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1111\/jnc.12446","volume":"127","author":"S Lenz","year":"2013","unstructured":"Lenz, S., Karsten, P., Schulz, J. B. & Voigt, A. Drosophila as a screening tool to study human neurodegenerative diseases. J. Neurochem. 127, 453\u2013460 (2013).","journal-title":"J. Neurochem."},{"key":"90749_CR26","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1080\/21691401.2018.1458731","volume":"46","author":"Susan Westfall","year":"2018","unstructured":"Westfall, S., Lomis, N. & Prakash, S. A novel polyphenolic prebiotic and probiotic formulation have synergistic effects on the gut microbiota influencing Drosophila melanogaster physiology. Artif. Cells, Nanomedicine Biotechnol. 46, 441\u2013455 (2018).","journal-title":"Artificial Cells, Nanomedicine, and Biotechnology"},{"key":"90749_CR27","doi-asserted-by":"publisher","first-page":"79","DOI":"10.3920\/BM2019.0086","volume":"11","author":"FHP Tan","year":"2020","unstructured":"Tan, F. H. P. et al. Lactobacillus probiotics improved the gut microbiota profile of a Drosophila melanogaster Alzheimer\u2019s disease model and alleviated neurodegeneration in the eye. Benef. Microbes 11, 79\u201389 (2020).","journal-title":"Benef. Microbes"},{"key":"90749_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0214985","volume":"14","author":"S Westfall","year":"2019","unstructured":"Westfall, S., Lomis, N. & Prakash, S. A novel synbiotic delays Alzheimer\u2019s disease onset via combinatorial gut-brain-axis signaling in Drosophila melanogaster. PLoS ONE 14, 1\u201324 (2019).","journal-title":"PLoS ONE"},{"key":"90749_CR29","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jsb.2005.06.006","volume":"151","author":"R Khurana","year":"2005","unstructured":"Khurana, R. et al. Mechanism of thioflavin T binding to amyloid fibrils. J. Struct. Biol. 151, 229\u2013238 (2005).","journal-title":"J. Struct. Biol."},{"key":"90749_CR30","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1017\/S0022029912000179","volume":"79","author":"A Londero","year":"2012","unstructured":"Londero, A., Hamet, M. F., De Antoni, G. L., Garrote, G. L. & Abraham, A. G. Kefir grains as a starter for whey fermentation at different temperatures: Chemical and microbiological characterisation. J. Dairy Res. 79, 262\u2013271 (2012).","journal-title":"J. Dairy Res."},{"key":"90749_CR31","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1017\/S0954422416000275","volume":"30","author":"DD Rosa","year":"2017","unstructured":"Rosa, D. D. et al. Milk kefir: Nutritional, microbiological and health benefits. Nutr. Res. Rev. 30, 82\u201396 (2017).","journal-title":"Nutr. Res. Rev."},{"key":"90749_CR32","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s12602-014-9168-0","volume":"6","author":"B Nielsen","year":"2014","unstructured":"Nielsen, B., G\u00fcrakan, G. C. & Unl\u00fc, G. Kefir: A multifaceted fermented dairy product. Probiotics Antimicrob. Proteins 6, 123\u2013135 (2014).","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"90749_CR33","doi-asserted-by":"publisher","DOI":"10.1128\/mSystems.00052-16","author":"Aaron M. Walsh","year":"2016","unstructured":"Walsh, A. M. et al. Microbial Succession and Flavor Production in the Fermented Dairy Beverage Kefir. mSystems 1, (2016).","journal-title":"Applied and Environmental Science"},{"key":"90749_CR34","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.3168\/jds.2014-9065","volume":"98","author":"N Korsak","year":"2015","unstructured":"Korsak, N. et al. Evaluation of the microbiota of kefir samples using metagenetic analysis targeting the 16S and 26S ribosomal DNA fragments. J. Dairy Sci. 98, 3684\u20133689 (2015).","journal-title":"J. Dairy Sci."},{"key":"90749_CR35","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1080\/08905436.2016.1200987","volume":"30","author":"NR Zamberi","year":"2016","unstructured":"Zamberi, N. R. et al. 16S Metagenomic Microbial Composition Analysis of Kefir Grain using MEGAN and BaseSpace. Food Biotechnol. 30, 219\u2013230 (2016).","journal-title":"Food Biotechnol."},{"key":"90749_CR36","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.fm.2015.01.017","volume":"49","author":"C Garofalo","year":"2015","unstructured":"Garofalo, C. et al. Bacteria and yeast microbiota in milk kefir grains from different Italian regions. Food Microbiol. 49, 123\u2013133 (2015).","journal-title":"Food Microbiol."},{"key":"90749_CR37","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.fm.2012.03.011","volume":"31","author":"AMO Leite","year":"2012","unstructured":"Leite, A. M. O. et al. Assessment of the microbial diversity of Brazilian kefir grains by PCR-DGGE and pyrosequencing analysis. Food Microbiol. 31, 215\u2013221 (2012).","journal-title":"Food Microbiol."},{"key":"90749_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12032-017-1044-9","volume":"34","author":"M Sharifi","year":"2017","unstructured":"Sharifi, M. et al. Kefir: A powerful probiotics with anticancer properties. Med. Oncol. 34, 1\u20137 (2017).","journal-title":"Med. Oncol."},{"key":"90749_CR39","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.clnu.2015.07.018","volume":"35","author":"FR Maciel","year":"2016","unstructured":"Maciel, F. R. et al. Immunomodulation and nitric oxide restoration by a probiotic and its activity in gut and peritoneal macrophages in diabetic rats. Clin. Nutr. 35, 1066\u20131072 (2016).","journal-title":"Clin. Nutr."},{"key":"90749_CR40","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.toxicon.2018.11.296","volume":"157","author":"E El Golli-Bennour","year":"2019","unstructured":"El Golli-Bennour, E., Timoumi, R., Koroit, M., Bacha, H. & Abid-Essefi, S. Protective effects of kefir against zearalenone toxicity mediated by oxidative stress in cultured HCT-116 cells. Toxicon 157, 25\u201334 (2019).","journal-title":"Toxicon"},{"key":"90749_CR41","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1381612826666200304145224","volume":"26","author":"EC Vasquez","year":"2020","unstructured":"Vasquez, E. C., Aires, R., Ton, A. M. M. & Amorim, F. G. New insights on the beneficial effects of the probiotic kefir on vascular dysfunction in cardiovascular and neurodegenerative diseases. Curr. Pharm. Des. 26, 2 (2020).","journal-title":"Curr. Pharm. Des."},{"key":"90749_CR42","doi-asserted-by":"publisher","DOI":"10.1007\/s41207-020-0141-x","author":"F. Ben Taheur","year":"2020","unstructured":"Taheur, F. Ben, Mansour, C. & Chaieb, K. Inhibitory effect of kefir on Aspergillus growth and mycotoxin production. Euro-Mediterranean J. Environ. Integr. 5, (2020).","journal-title":"Euro-Mediterranean J. Environ"},{"key":"90749_CR43","doi-asserted-by":"publisher","first-page":"103588","DOI":"10.1016\/j.jff.2019.103588","volume":"63","author":"MSR Rajoka","year":"2019","unstructured":"Rajoka, M. S. R. et al. Characterization and anti-tumor activity of exopolysaccharide produced by Lactobacillus kefiri isolated from Chinese kefir grains. J. Funct. Foods 63, 103588 (2019).","journal-title":"J. Funct. Foods"},{"key":"90749_CR44","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s12032-015-0722-8","volume":"33","author":"F Jalali","year":"2016","unstructured":"Jalali, F., Sharifi, M. & Salehi, R. Kefir induces apoptosis and inhibits cell proliferation in human acute erythroleukemia. Med. Oncol. 33, 7 (2016).","journal-title":"Med. Oncol."},{"key":"90749_CR45","doi-asserted-by":"publisher","first-page":"787","DOI":"10.5851\/kosfa.2016.36.6.787","volume":"36","author":"DH Kim","year":"2016","unstructured":"Kim, D. H. et al. Antimicrobial activity of kefir against various food pathogens and spoilage bacteria. Korean J. Food Sci. Anim. Resour. 36, 787\u2013790 (2016).","journal-title":"Korean J. Food Sci. Anim. Resour."},{"key":"90749_CR46","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/1471-0307.12346","volume":"71","author":"T \u015eanli","year":"2018","unstructured":"\u015eanli, T., Akal, H. C., Yeti\u015femiyen, A. & Hayaloglu, A. A. Influence of adjunct cultures on angiotensin-converting enzyme (ACE)-inhibitory activity, organic acid content and peptide profile of kefir. Int. J. Dairy Technol. 71, 131\u2013139 (2018).","journal-title":"Int. J. Dairy Technol."},{"key":"90749_CR47","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.foodcont.2016.01.023","volume":"65","author":"J Miao","year":"2016","unstructured":"Miao, J. et al. Inhibitory effects of a novel antimicrobial peptide from kefir against Escherichia coli. Food Control 65, 63\u201372 (2016).","journal-title":"Food Control"},{"key":"90749_CR48","doi-asserted-by":"publisher","first-page":"3480","DOI":"10.3168\/jds.S0022-0302(05)73032-0","volume":"88","author":"A Quir\u00f3s","year":"2005","unstructured":"Quir\u00f3s, A., Hern\u00e1ndez-Ledesma, B., Ramos, M., Amigo, L. & Recio, I. Angiotensin-converting enzyme inhibitory activity of peptides derived from caprine kefir. J. Dairy Sci. 88, 3480\u20133487 (2005).","journal-title":"J. Dairy Sci."},{"key":"90749_CR49","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.3233\/JAD-200436","volume":"76","author":"H Kaur","year":"2020","unstructured":"Kaur, H. et al. Effects of Probiotic Supplementation on Short Chain Fatty Acids in the App NL-G-F Mouse Model of Alzheimer\u2019s Disease. J. Alzheimer\u2019s Dis. 76, 1083\u20131102 (2020).","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"90749_CR50","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/mnfr.201700505","volume":"62","author":"YT Tung","year":"2018","unstructured":"Tung, Y. T. et al. Kefir Peptides Prevent Hyperlipidemia and Obesity in High-Fat-Diet-Induced Obese Rats via Lipid Metabolism Modulation. Mol. Nutr. Food Res. 62, 2 (2018).","journal-title":"Mol. Nutr. Food Res."},{"key":"90749_CR51","doi-asserted-by":"crossref","unstructured":"Akbari, E. et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer\u2019s disease: A randomized, double-blind and controlled trial. Front. Aging Neurosci. 8, 2 (2016).","DOI":"10.3389\/fnagi.2016.00256"},{"key":"90749_CR52","doi-asserted-by":"publisher","DOI":"10.1021\/ac5005103","author":"GAN Gowda","year":"2014","unstructured":"Gowda, G. A. N. & Raftery, D. Quantitating Metabolites in Protein Precipitated Serum Using NMR Spectroscopy. https:\/\/doi.org\/10.1021\/ac5005103 (2014).","journal-title":"Quantitating Metabolites in Protein Precipitated Serum Using NMR Spectroscopy."},{"key":"90749_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1472-6882-14-88","volume":"14","author":"X Wang","year":"2014","unstructured":"Wang, X. et al. Effects of curcuminoids identified in rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer\u2019s disease Drosophila models. BMC Complement. Altern. Med. 14, 1\u201314 (2014).","journal-title":"BMC Complement. Altern. Med."},{"key":"90749_CR54","doi-asserted-by":"publisher","first-page":"99274","DOI":"10.18632\/oncotarget.20062","volume":"8","author":"WYV Chiu","year":"2017","unstructured":"Chiu, W. Y. V., Koon, A. C., Ngo, J. C. K., Chan, H. Y. E. & Lau, K.-F. GULP1\/CED-6 ameliorates amyloid-\u03b2 toxicity in a Drosophila model of Alzheimer\u2019s disease. Oncotarget 8, 99274 (2017).","journal-title":"Oncotarget"},{"key":"90749_CR55","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.3762\/bjoc.9.313","volume":"9","author":"L Valgimigli","year":"2013","unstructured":"Valgimigli, L. et al. 3-pyridinols and 5-pyrimidinols: Tailor-made for use in synergistic radical-trapping co-antioxidant systems. Beilstein J. Org. Chem. 9, 2781\u20132792 (2013).","journal-title":"Beilstein J. Org. Chem."},{"key":"90749_CR56","first-page":"1015","volume":"7","author":"R Tundis","year":"2012","unstructured":"Tundis, R. et al. Antioxidant and anti-cholinesterase activity of Globularia meridionalis extracts and isolated constituents. Nat. Prod. Commun. 7, 1015\u20131020 (2012).","journal-title":"Nat. Prod. Commun."},{"key":"90749_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0304-4165(02)00338-0","volume":"1573","author":"T Kayashima","year":"2002","unstructured":"Kayashima, T. & Katayama, T. Oxalic acid is available as a natural antioxidant in some systems. Biochim. Biophys. Acta - Gen. Subj. 1573, 1\u20133 (2002).","journal-title":"Biochim. Biophys. Acta - Gen. Subj."},{"key":"90749_CR58","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.jbiosc.2011.08.005","volume":"112","author":"Y Ishihara","year":"2011","unstructured":"Ishihara, Y. et al. Antioxidant properties of rare sugar D-allose: Effects on mitochondrial reactive oxygen species production in Neuro2A cells. J. Biosci. Bioeng. 112, 638\u2013642 (2011).","journal-title":"J. Biosci. Bioeng."},{"key":"90749_CR59","first-page":"233","volume":"3","author":"A Maimulyanti","year":"2015","unstructured":"Maimulyanti, A. & Prihadi, A. R. Chemical composition, phytochemical and antioxidant activity from extract of Etlingera elatior flower from Indonesia. J. Pharmacogn. Phytochem. 3, 233\u2013238 (2015).","journal-title":"J. Pharmacogn. Phytochem."},{"key":"90749_CR60","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.intimp.2014.01.017","volume":"19","author":"S. Y. Park","year":"2014","unstructured":"Park, S. Y. et al. Ethyl linoleate from garlic attenuates lipopolysaccharide-induced pro-inflammatory cytokine production by inducing heme oxygenase-1 in RAW264.7 cells. Int. Immunopharmacol. 19, 253\u2013261 (2014).","journal-title":"Int. Immunopharmacol."},{"key":"90749_CR61","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1007\/s11064-018-2587-7","volume":"43","author":"Y Nishimura","year":"2018","unstructured":"Nishimura, Y. et al. Lauric Acid Alleviates Neuroinflammatory Responses by Activated Microglia: Involvement of the GPR40-Dependent Pathway. Neurochem. Res. 43, 1723\u20131735 (2018).","journal-title":"Neurochem. Res."},{"key":"90749_CR62","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1002\/ffj.3610","volume":"35","author":"H. Servi","year":"2020","unstructured":"Servi, H., Sen, A. & Dogan, A. Chemical composition and biological activities of endemic Tripleurospermum conoclinium (Boiss. & Balansa) Hayek essential oils. Flavour Fragr. J. 35, 713\u2013721 (2020).","journal-title":"Flavour Fragr. J."},{"key":"90749_CR63","doi-asserted-by":"crossref","unstructured":"Riccobono, L. et al. Chemical composition of volatile and fixed oils from of Salvia argentea L. (Lamiaceae) growing wild in Sicily. Nat. Prod. Res. 30, 25\u201334 (2016).","DOI":"10.1080\/14786419.2015.1030742"},{"key":"90749_CR64","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.2217\/fmb-2018-0185","volume":"13","author":"Y Kong","year":"2018","unstructured":"Kong, Y., Jiang, B. & Luo, X. Gut microbiota influences Alzheimer\u2019s disease pathogenesis by regulating acetate in Drosophila model. Future Microbiol. 13, 1117\u20131128 (2018).","journal-title":"Future Microbiol."},{"key":"90749_CR65","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.3233\/JAD-170020","volume":"60","author":"L Zhang","year":"2017","unstructured":"Zhang, L. et al. Altered Gut Microbiota in a Mouse Model of Alzheimer\u2019s Disease. J. Alzheimer\u2019s Dis. 60, 1241\u20131257 (2017).","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"90749_CR66","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1080\/14737175.2018.1400909","volume":"18","author":"L Ho","year":"2018","unstructured":"Ho, L. et al. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer\u2019s disease-type beta-amyloid neuropathological mechanisms. Expert Rev. Neurother. 18, 83\u201390 (2018).","journal-title":"Expert Rev. Neurother."},{"key":"90749_CR67","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/jmf.2013.2968","volume":"17","author":"K Youn","year":"2014","unstructured":"Youn, K. et al. Oleic acid and linoleic acid from tenebrio molitor larvae inhibit BACE1 activity in vitro: Molecular docking studies. J. Med. Food 17, 284\u2013289 (2014).","journal-title":"J. Med. Food"},{"key":"90749_CR68","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.bbalip.2012.12.003","volume":"1831","author":"E. Lee","year":"2013","unstructured":"Lee, E. et al. Effect of conjugated linoleic acid, \u03bc-calpain inhibitor, on pathogenesis of Alzheimer\u2019s disease. Biochim. Biophys. Acta - Mol. Cell Biol. Lipids 1831, 709\u2013718 (2013).","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids"},{"key":"90749_CR69","doi-asserted-by":"publisher","first-page":"6246","DOI":"10.1016\/j.arabjc.2020.05.035","volume":"13","author":"SR Kareti","year":"2020","unstructured":"Kareti, S. R. & Subash, P. In silico exploration of anti-Alzheimer\u2019s compounds present in methanolic extract of Neolamarckia cadamba bark using GC\u2013MS\/MS. Arab. J. Chem. 13, 6246\u20136255 (2020).","journal-title":"Arab. J. Chem."},{"key":"90749_CR70","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/j.1750-3639.2010.00449.x","volume":"21","author":"Z Amtul","year":"2011","unstructured":"Amtul, Z., Westaway, D., Cechetto, D. F. & Rozmahel, R. F. Oleic acid ameliorates amyloidosis in cellular and mouse models of alzheimer\u2019s disease. Brain Pathol. 21, 321\u2013329 (2011).","journal-title":"Brain Pathol."},{"key":"90749_CR71","doi-asserted-by":"crossref","unstructured":"Polis, B., Gurevich, V., Assa, M. & Samson, A. O. Norvaline restores the BBB integrity in a mouse model of alzheimer\u2019s disease. Int. J. Mol. Sci. 20, (2019).","DOI":"10.3390\/ijms20184616"},{"key":"90749_CR72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnagi.2020.00226","volume":"12","author":"CH Lin","year":"2020","unstructured":"Lin, C. H. et al. Lactulose and melibiose attenuate MPTP-induced parkinson\u2019s disease in mice by inhibition of oxidative stress, reduction of neuroinflammation and up-regulation of autophagy. Front. Aging Neurosci. 12, 1\u201311 (2020).","journal-title":"Front. Aging Neurosci."},{"key":"90749_CR73","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.neuro.2015.03.009","volume":"48","author":"GC Lee","year":"2015","unstructured":"Lee, G. C. et al. The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment. Neurotoxicology 48, 120\u2013130 (2015).","journal-title":"Neurotoxicology"},{"key":"90749_CR74","doi-asserted-by":"publisher","first-page":"3008","DOI":"10.1039\/C8FO00643A","volume":"9","author":"H Che","year":"2018","unstructured":"Che, H. et al. A comparative study of EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine on A\u03b242 induced cognitive deficiency in a rat model of Alzheimer\u2019s disease. Food Funct. 9, 3008\u20133017 (2018).","journal-title":"Food Funct."},{"key":"90749_CR75","doi-asserted-by":"crossref","unstructured":"Ewing, B., Hillier, L., Wendl, M. C. & Green, P. Base-Calling of Automated Sequencer Traces Using Phred . I . Accuracy Assessment. 175\u2013185 (2005).","DOI":"10.1101\/gr.8.3.175"},{"key":"90749_CR76","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1093\/bioinformatics\/btr507","volume":"27","author":"T Mago\u010d","year":"2011","unstructured":"Mago\u010d, T. & Salzberg, S. L. FLASH: Fast length adjustment of short reads to improve genome assemblies. Bioinformatics 27, 2957\u20132963 (2011).","journal-title":"Bioinformatics"},{"key":"90749_CR77","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1093\/bioinformatics\/btq461","volume":"26","author":"RC Edgar","year":"2010","unstructured":"Edgar, R. C. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26, 2460\u20132461 (2010).","journal-title":"Bioinformatics"},{"key":"90749_CR78","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/nmeth.2604","volume":"10","author":"RC Edgar","year":"2013","unstructured":"Edgar, R. C. UPARSE: Highly accurate OTU sequences from microbial amplicon reads. Nat. Methods 10, 996\u2013998 (2013).","journal-title":"Nat. Methods"},{"key":"90749_CR79","doi-asserted-by":"publisher","first-page":"2194","DOI":"10.1093\/bioinformatics\/btr381","volume":"27","author":"RC Edgar","year":"2011","unstructured":"Edgar, R. C., Haas, B. J., Clemente, J. C., Quince, C. & Knight, R. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27, 2194\u20132200 (2011).","journal-title":"Bioinformatics"},{"key":"90749_CR80","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1093\/nar\/29.1.126","volume":"29","author":"A Bernal","year":"2001","unstructured":"Bernal, A., Ear, U. & Kyrpides, N. Genomes OnLine Database (GOLD): A monitor of genome projects world-wide. Nucleic Acids Res. 29, 126\u2013127 (2001).","journal-title":"Nucleic Acids Res."},{"key":"90749_CR81","doi-asserted-by":"crossref","unstructured":"Nilsson, R. H. et al. Towards a unified paradigm for sequence-based identification of fungi. 5271\u20135277 (2013).","DOI":"10.1111\/mec.12481"},{"key":"90749_CR82","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1093\/nar\/gkn879","volume":"37","author":"J.R. Cole","year":"2009","unstructured":"Cole, J. R. et al. The Ribosomal Database Project\u202f: improved alignments and new tools for rRNA analysis. 37, 141\u2013145 (2009)","journal-title":"Nucleic Acids Res ."},{"key":"90749_CR83","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.1128\/AEM.03006-05","volume":"72","author":"TZ DeSantis","year":"2006","unstructured":"DeSantis, T. Z. et al. Greengenes, a Chimera-Checked 16S rRNA Gene Database and Workbench Compatible with ARB. Appl. Environ. Microbiol. 72, 5069\u20135072 (2006).","journal-title":"Appl. Environ. Microbiol."},{"key":"90749_CR84","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.neuropharm.2016.10.020","volume":"113","author":"L Penazzi","year":"2017","unstructured":"Penazzi, L. et al. DMSO modulates CNS function in a preclinical Alzheimer\u2019s disease model. Neuropharmacology 113, 434\u2013444 (2017).","journal-title":"Neuropharmacology"},{"key":"90749_CR85","doi-asserted-by":"publisher","first-page":"2618","DOI":"10.1021\/acschemneuro.7b00344","volume":"8","author":"A Kumar","year":"2017","unstructured":"Kumar, A. & Darreh-Shori, T. DMSO: A mixed-competitive inhibitor of human acetylcholinesterase. ACS Chem. Neurosci. 8, 2618\u20132625 (2017).","journal-title":"ACS Chem. Neurosci."},{"key":"90749_CR86","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1073\/pnas.87.4.1471","volume":"87","author":"TL Krause","year":"1990","unstructured":"Krause, T. L. & Bittner, G. D. Rapid morphological fusion of severed myelinated axons by polyethylene glycol. Proc. Natl. Acad. Sci. 87, 1471\u20131475 (1990).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"90749_CR87","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1089\/0897715041651097","volume":"21","author":"J Luo","year":"2004","unstructured":"Luo, J., Borgens, R. & Shi, R. Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. J. Neurotrauma 21, 994\u20131007 (2004).","journal-title":"J. Neurotrauma"},{"key":"90749_CR88","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1097\/NEN.0b013e3181a72605","volume":"68","author":"DC Baptiste","year":"2009","unstructured":"Baptiste, D. C. et al. Systemic polyethylene glycol promotes neurological recovery and tissue sparing in rats after cervical spinal cord injury. J. Neuropathol. Exp. Neurol. 68, 661\u2013676 (2009).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"90749_CR89","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb3004s114","author":"O. Fiehn","year":"2016","unstructured":"Fiehn, O. Metabolomics by gas chromatography-mass spectrometry: Combined targeted and untargeted profiling. Curr. Protoc. Mol. Biol. (2016).","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"90749_CR90","doi-asserted-by":"publisher","first-page":"E1752","DOI":"10.1073\/pnas.1306220110","volume":"110","author":"Y Cao","year":"2013","unstructured":"Cao, Y., Chtarbanova, S., Petersen, A. J. & Ganetzky, B. Dnr1 mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain. Proc. Natl. Acad. Sci. U. S. A. 110, E1752\u2013E1760 (2013).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90749-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90749-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90749-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T16:09:25Z","timestamp":1675354165000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90749-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,27]]},"references-count":90,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["90749"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-90749-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,27]]},"assertion":[{"value":"19 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11262"}}