5,888
Views
7
CrossRef citations to date
0
Altmetric
Review

Gut microbiome-targeted therapies for Alzheimer’s disease

, , & ORCID Icon
Article: 2271613 | Received 25 May 2023, Accepted 12 Oct 2023, Published online: 07 Nov 2023

References

  • Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):7. doi:10.1038/s41572-021-00269-y.
  • Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement. 2021;17:1966–35. PMID: 34043283. doi:10.1002/alz.12362.
  • 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. 2021;17(3):327–406. PMID: 33756057. doi:10.1002/alz.12328.
  • Khan S, Barve KH, Kumar MS. Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer’s disease. Curr Neuropharmacol. 2020;18:1106–1125. PMID: 32484110. doi:10.2174/1570159x18666200528142429.
  • Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer’s disease. Lancet. 2021;397:1577–1590. doi:10.1016/s0140-6736(20)32205-4.
  • Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, Rongve A, Børte S, Winsvold BS, Drange OK, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–1282. PMID: 34493870. doi:10.1038/s41588-021-00921-z.
  • Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15(9):501–518. PMID: 31367008. doi: 10.1038/s41582-019-0228-7.
  • Wolters FJ, van der Lee S J, Koudstaal PJ, van Duijn CM, Hofman A, Ikram MK, Vernooij MW, Ikram MA. Parental family history of dementia in relation to subclinical brain disease and dementia risk. Neurology. 2017;88(17):1642–1649. PMID: 28356461. doi: 10.1212/wnl.0000000000003871.
  • Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet commission. Lancet. 2020;396(10248):413–446. PMID: 32738937. doi:10.1016/s0140-6736(20)30367-6.
  • FDA. Drugs@FDA: FDA-approved drugs. Aduhelm. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761178.
  • Lythgoe MP, Jenei K, Prasad V. Regulatory decisions diverge over aducanumab for Alzheimer’s disease. Bmj. 2022;e069780. doi:10.1136/bmj-2021-069780.
  • Travagli RA, Browning KN, Camilleri M. Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol. 2020;17(11):673–685. PMID: 32737460. doi: 10.1038/s41575-020-0339-z.
  • Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474:1823–1836. PMID: 28512250. doi:10.1042/bcj20160510.
  • Berg G, Rybakova D, Fischer D, Cernava T, Vergès MC, Charles T, Chen X, Cocolin L, Eversole K, Corral GH, et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome. 2020;8(1):103. PMID: 32605663. doi:10.1186/s40168-020-00875-0.
  • Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, et al. Expert consensus document. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–514. PMID: 24912386. doi:10.1038/nrgastro.2014.66.
  • Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, et al. Expert consensus document: The international scientific association for probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14(8):491–502. PMID: 28611480. doi:10.1038/nrgastro.2017.75.
  • Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K, Scott KP, Holscher HD, Azad MB, Delzenne NM, et al. The International Scientific association for probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nat Rev Gastroenterol Hepatol. 2020;17(11):687–701. PMID: 32826966. doi:10.1038/s41575-020-0344-2.
  • Salminen S, Collado MC, Endo A, Hill C, Lebeer S, Quigley EMM, Sanders ME, Shamir R, Swann JR, Szajewska H, et al. The International Scientific association of probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat Rev Gastroenterol Hepatol. 2021;18(9):649–667. PMID: 33948025. doi:10.1038/s41575-021-00440-6.
  • Cammarota G, Ianiro G, Tilg H, Rajilić-Stojanović M, Kump P, Satokari R, Sokol H, Arkkila P, Pintus C, Hart A, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569–580. PMID: 28087657. doi:10.1136/gutjnl-2016-313017.
  • Cryan JF, O’Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19:179–194. PMID: 31753762. doi:10.1016/S1474-4422(19)30356-4.
  • Chandra S, Sisodia SS, Vassar RJ. The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored. Mol Neurodegener. 2023;18:9. PMID: 36721148. doi:10.1186/s13024-023-00595-7.
  • Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D, Kim DK, Kim HJ, Choi H, Hyun DW, et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut. 2020;69(2):283–294. PMID: 31471351. doi:10.1136/gutjnl-2018-317431.
  • Xiao L, Feng Q, Liang S, Sonne SB, Xia Z, Qiu X, Li X, Long H, Zhang J, Zhang D, et al. A catalog of the mouse gut metagenome. Nat Biotechnol. 2015;33(10):1103–1108. PMID: 26414350. doi:10.1038/nbt.3353.
  • Parizadeh M, Arrieta MC. The global human gut microbiome: genes, lifestyles, and diet. Trends Mol Med. 2023;29:789–801. PMID: 37516570. doi:10.1016/j.molmed.2023.07.002.
  • Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer’s disease. Sci Rep. 2017;7(1):10411. PMID: 28874832. doi:10.1038/s41598-017-11047-w.
  • Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6(1):30028. PMID: 27443609. doi:10.1038/srep30028.
  • Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, Gottel N, Zhang X, Butovsky O, Gilbert JA, et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019;216:1542–1560. PMID: 31097468. doi:10.1084/jem.20182386.
  • Dodiya HB, Frith M, Sidebottom A, Cao Y, Koval J, Chang E, Sisodia SS. Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer’s transgenic mice. Sci Rep. 2020;10(1):8183. PMID: 32424118. doi: 10.1038/s41598-020-64797-5.
  • Agirman G, Hsiao EY. SnapShot: The microbiota-gut-brain axis. Cell. 2021;184(9):2524–2524.e2521. PMID: 33930299. doi: 10.1016/j.cell.2021.03.022.
  • Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6(4):193–201. PMID: 20234358. doi: 10.1038/nrneurol.2010.17.
  • Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–472. PMID: 29196460. doi:10.1083/jcb.201709069.
  • Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–172. PMID: 33318676. doi: 10.1038/s41582-020-00435-y.
  • Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–977. PMID: 26030851. doi:10.1038/nn.4030.
  • Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, Ben-Yehuda H, David E, Zelada Gonzalez F, Perrin P, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Sci. 2016;353(6301):aad8670. PMID: 27338705. doi:10.1126/science.aad8670.
  • Thion MS, Low D, Silvin A, Chen J, Grisel P, Schulte-Schrepping J, Blecher R, Ulas T, Squarzoni P, Hoeffel G, et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2018;172(3):500–516 e516. PMID: 29275859. doi:10.1016/j.cell.2017.11.042.
  • Mossad O, Batut B, Yilmaz B, Dokalis N, Mezo C, Nent E, Nabavi LS, Mayer M, Maron FJM, Buescher JM, et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat Neurosci. 2022;25(3):295–305. PMID: 35241804. doi:10.1038/s41593-022-01027-3.
  • Dodiya HB, Lutz HL, Weigle IQ, Patel P, Michalkiewicz J, Roman-Santiago CJ, Zhang CM, Liang Y, Srinath A, Zhang X, et al. Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia. J Exp Med. 2022;219(1). PMID: 34854884. doi: 10.1084/jem.20200895.
  • Mezo C, Dokalis N, Mossad O, Staszewski O, Neuber J, Yilmaz B, Schnepf D, de Aguero MG, Ganal-Vonarburg SC, Macpherson AJ, et al. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. 2020;8(1):119. PMID: 32727612. doi:10.1186/s40478-020-00988-5.
  • Huang Y, Wu J, Zhang H, Li Y, Wen L, Tan X, Cheng K, Liu Y, Pu J, Liu L, et al. The gut microbiome modulates the transformation of microglial subtypes. Mol Psychiatry. 2023;28(4):1611–1621. PMID: 36914812. doi:10.1038/s41380-023-02017-y.
  • Seo DO, O’Donnell D, Jain N, Ulrich JD, Herz J, Li Y, Lemieux M, Cheng J, Hu H, Serrano JR, et al. ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Sci. 2023;379(6628):eadd1236. PMID: 36634180. doi:10.1126/science.add1236.
  • De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164(4):603–615. PMID: 26871627. doi: 10.1016/j.cell.2015.12.056.
  • Endo F, Kasai A, Soto JS, Yu X, Qu Z, Hashimoto H, Gradinaru V, Kawaguchi R, Khakh BS. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Sci. 2022;378(6619):eadc9020. PMID: 36378959. doi: 10.1126/science.adc9020.
  • Ferrari-Souza JP, Ferreira PCL, Bellaver B, Tissot C, Wang YT, Leffa DT, Brum WS, Benedet AL, Ashton NJ, De Bastiani MA, et al. Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease. Mol Psychiatry. 2022;27(11):4781–4789. PMID: 35948658. doi:10.1038/s41380-022-01716-2.
  • Mann CN, Devi SS, Kersting CT, Bleem AV, Karch CM, Holtzman DM, Gallardo G. Astrocytic α2-Na + /K + ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model. Sci Transl Med. 2022;14(632):eabm4107. PMID: 35171651. doi: 10.1126/scitranslmed.abm4107.
  • Wang M, Cao J, Gong C, Amakye WK, Yao M, Ren J. Exploring the microbiota-Alzheimer’s disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation. Brain Behav Immun. 2021;96:227–238. PMID: 34111528. doi:10.1016/j.bbi.2021.06.003.
  • Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22(6):586–597. PMID: 27158906. doi:10.1038/nm.4106.
  • Sanmarco LM, Wheeler MA, Gutierrez-Vazquez C, Polonio CM, Linnerbauer M, Pinho-Ribeiro FA, Li Z, Giovannoni F, Batterman KV, Scalisi G, et al. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes. Nature. 2021;590(7846):473–479. PMID: 33408417. doi:10.1038/s41586-020-03116-4.
  • Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med. 2016;22(5):516–523. PMID: 27019327. doi:10.1038/nm.4068.
  • Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun. 2015;6(1):7967. PMID: 26284939. doi: 10.1038/ncomms8967.
  • Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276–1290.e1217. PMID: 28602351. doi:10.1016/j.cell.2017.05.018.
  • Kim K, Wang X, Ragonnaud E, Bodogai M, Illouz T, DeLuca M, McDevitt RA, Gusev F, Okun E, Rogaev E, et al. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nat Commun. 2021;12(1):2185. PMID: 33846335. doi:10.1038/s41467-021-22479-4.
  • Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn MB, Hu H, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023;615(7953):668–677. PMID: 36890231. doi:10.1038/s41586-023-05788-0.
  • Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang H, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29(10):787–803. PMID: 31488882. doi:10.1038/s41422-019-0216-x.
  • Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145–155. PMID: 28092661. doi: 10.1038/nn.4476.
  • Ahmed H, Leyrolle Q, Koistinen V, Karkkainen O, Laye S, Delzenne N, Hanhineva K. Microbiota-derived metabolites as drivers of gut–brain communication. Gut Microbes. 2022;14(1):2102878. PMID: 35903003. doi: 10.1080/19490976.2022.2102878.
  • Marizzoni M, Cattaneo A, Mirabelli P, Festari C, Lopizzo N, Nicolosi V, Mombelli E, Mazzelli M, Luongo D, Naviglio D, et al. Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimer’s disease. J Alzheimers Dis. 2020;78(2):683–697. PMID: 33074224. doi:10.3233/JAD-200306.
  • MahmoudianDehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G, Louie G, Kueider-Paisley A, Moseley MA, Thompson JW, et al. Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease—an emerging role for gut microbiome. Alzheimers Dement. 2019;15(1):76–92. PMID: 30337151. doi:10.1016/j.jalz.2018.07.217.
  • Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, Asthana S, Blennow K, Zetterberg H, Bendlin BB, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther. 2018;10:124. PMID: 30579367. doi:10.1186/s13195-018-0451-2.
  • Madeira C, Vargas-Lopes C, Brandao CO, Reis T, Laks J, Panizzutti R, Ferreira ST. Elevated glutamate and glutamine levels in the cerebrospinal fluid of patients with probable Alzheimer’s disease and depression. Front Psychiatry. 2018;9:561. PMID: 30459657. doi:10.3389/fpsyt.2018.00561.
  • Colombo AV, Sadler RK, Llovera G, Singh V, Roth S, Heindl S, Sebastian Monasor L, Verhoeven A, Peters F, Parhizkar S, et al. Microbiota-derived short chain fatty acids modulate microglia and promote Abeta plaque deposition. Elife. 2021;10. PMID: 33845942. doi:10.7554/eLife.59826.
  • Erny D, Dokalis N, Mezo C, Castoldi A, Mossad O, Staszewski O, Frosch M, Villa M, Fuchs V, Mayer A, et al. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab. 2021;33(11):2260–2276 e2267. PMID: 34731656. doi:10.1016/j.cmet.2021.10.010.
  • Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469–1480 e1412. PMID: 27912057. doi:10.1016/j.cell.2016.11.018.
  • Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother. 2018;18:83–90. PMID: 29095058. doi:10.1080/14737175.2018.1400909.
  • Fernando W, Martins IJ, Morici M, Bharadwaj P, Rainey-Smith SR, Lim WLF, Martins RN. Sodium butyrate reduces brain amyloid-β levels and improves cognitive memory performance in an Alzheimer’s disease transgenic mouse model at an early disease stage. J Alzheimers Dis. 2020;74(1):91–99. PMID: 31958090. doi: 10.3233/JAD-190120.
  • Jiang Y, Li K, Li X, Xu L, Yang Z. Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice. Chem Biol Interact. 2021;341:109452. PMID: 33785315. doi:10.1016/j.cbi.2021.109452.
  • Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid β peptide in APPswe transgenic mice. Neurobiol Dis. 2003;14(1):133–145. PMID: 13678674. doi: 10.1016/s0969-9961(03)00069-x.
  • Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:8843–8853. PMID: 16192374. doi:10.1523/JNEUROSCI.2868-05.2005.
  • Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol. 2017;133(2):155–175. PMID: 28025715. doi: 10.1007/s00401-016-1662-x.
  • Bonfili L, Cecarini V, Berardi S, Scarpona S, Suchodolski JS, Nasuti C, Fiorini D, Boarelli MC, Rossi G, Eleuteri AM. Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci Rep. 2017;7(1):2426. PMID: 28546539. doi: 10.1038/s41598-017-02587-2.
  • Bonfili L, Cecarini V, Cuccioloni M, Angeletti M, Berardi S, Scarpona S, Rossi G, Eleuteri AM. SLAB51 probiotic formulation activates SIRT1 pathway promoting antioxidant and neuroprotective effects in an AD mouse model. Mol Neurobiol. 2018;55(10):7987–8000. PMID: 29492848. doi: 10.1007/s12035-018-0973-4.
  • Lee HJ, Hwang YH, Kim DH. Lactobacillus plantarum C29-Fermented soybean (DW2009) alleviates memory impairment in 5XFAD transgenic mice by regulating microglia activation and gut microbiota composition. Mol Nutr Food Res. 2018;62(20):e1800359. PMID: 30152045. doi: 10.1002/mnfr.201800359.
  • Lee HJ, Lee KE, Kim JK, Kim DH. Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice. Sci Rep. 2019;9(1):11814. PMID: 31413350. doi: 10.1038/s41598-019-48342-7.
  • Bonfili L, Cecarini V, Gogoi O, Berardi S, Scarpona S, Angeletti M, Rossi G, Eleuteri AM. Gut microbiota manipulation through probiotics oral administration restores glucose homeostasis in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2020;87:35–43. PMID: 31813629. doi:10.1016/j.neurobiolaging.2019.11.004.
  • Cecarini V, Bonfili L, Gogoi O, Lawrence S, Venanzi FM, Azevedo V, Mancha-Agresti P, Drumond MM, Rossi G, Berardi S, et al. Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study. Aging (Albany NY). 2020;12(16):15995–16020. PMID: 32855357. doi:10.18632/aging.103900.
  • Kaur H, Golovko S, Golovko MY, Singh S, Darland DC, Combs CK. Effects of probiotic supplementation on short chain fatty acids in the AppNL-G-F mouse model of Alzheimer’s disease. J Alzheimers Dis. 2020;76:1083–1102. PMID: 32623399. doi:10.3233/jad-200436.
  • Kaur H, Nagamoto-Combs K, Golovko S, Golovko MY, Klug MG, Combs CK. Probiotics ameliorate intestinal pathophysiology in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2020;92:114–134. PMID: 32417748. doi:10.1016/j.neurobiolaging.2020.04.009.
  • Ou Z, Deng L, Lu Z, Wu F, Liu W, Huang D, Peng Y. Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease. Nutr Diabetes. 2020;10(1):12. PMID: 32321934. doi: 10.1038/s41387-020-0115-8.
  • Sun J, Xu J, Yang B, Chen K, Kong Y, Fang N, Gong T, Wang F, Ling Z, Liu J. Effect of Clostridium butyricum against microglia-mediated neuroinflammation in Alzheimer’s disease via regulating gut microbiota and metabolites butyrate. Molecular Nutrition Food Res. 2020;64(2):e1900636. PMID: 31835282. doi: 10.1002/mnfr.201900636.
  • Wang F, Xu T, Zhang Y, Zheng T, He Y, He F, Jiang Y. Long-term combined administration of Bifidobacterium bifidum TMC3115 and Lactobacillus plantarum 45 alleviates spatial memory impairment and gut dysbiosis in APP/PS1 mice. FEMS Microbiol Lett. 2020;367. PMID: 32239209. doi:10.1093/femsle/fnaa048.
  • Wang QJ, Shen YE, Wang X, Fu S, Zhang X, Zhang YN, Wang RT. Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice. Aging (Albany NY). 2020;12(1):628–649. PMID: 31907339. doi: 10.18632/aging.102645.
  • Wu Q, Li Q, Zhang X, Ntim M, Wu X, Li M, Wang L, Zhao J, Li S. Treatment with Bifidobacteria can suppress Aβ accumulation and neuroinflammation in APP/PS1 mice. PeerJ. 2020;8:e10262. PMID: 33194428. doi:10.7717/peerj.10262.
  • Cao J, Amakye WK, Qi C, Liu X, Ma J, Ren J. Bifidobacterium lactis Probio-M8 regulates gut microbiota to alleviate Alzheimer’s disease in the APP/PS1 mouse model. Eur J Nutr. 2021;60(7):3757–3769. PMID: 33796919. doi: 10.1007/s00394-021-02543-x.
  • Go J, Chang DH, Ryu YK, Park HY, Lee IB, Noh JR, Hwang DY, Kim BC, Kim KS, Lee CH. Human gut microbiota Agathobaculum butyriciproducens improves cognitive impairment in LPS-induced and APP/PS1 mouse models of Alzheimer’s disease. Nutr Res. 2021;86:96–108. PMID: 33551257. doi:10.1016/j.nutres.2020.12.010.
  • Guilherme MDS, Nguyen VTT, Reinhardt C, Endres K. Impact of gut microbiome manipulation in 5xFAD mice on Alzheimer’s disease-like pathology. Microorganisms. 2021;9(4):815. PMID: 33924322. doi: 10.3390/microorganisms9040815.
  • Huang HJ, Chen JL, Liao JF, Chen YH, Chieu MW, Ke YY, Hsu CC, Tsai YC, Hsieh-Li HM. Lactobacillus plantarum PS128 prevents cognitive dysfunction in Alzheimer’s disease mice by modulating propionic acid levels, glycogen synthase kinase 3 beta activity, and gliosis. BMC Complement Med Ther. 2021;21(1):259. PMID: 34627204. doi: 10.1186/s12906-021-03426-8.
  • Kaur H, Nookala S, Singh S, Mukundan S, Nagamoto-Combs K, Combs CK. Sex-dependent effects of intestinal microbiome Manipulation in a mouse model of Alzheimer’s disease. Cells. 2021;10(9):2370. PMID: 34572019. doi: 10.3390/cells10092370.
  • Kim H, Kim S, Park SJ, Park G, Shin H, Park MS, Kim J. Administration of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI improves cognitive and memory function in the mouse model of Alzheimer’s disease. Front Aging Neurosci. 2021;13:709091. PMID: 34421576. doi:10.3389/fnagi.2021.709091.
  • Sun M, Bao W, Huang C, Xia Z, Zhang C, Wang G, Wang R, Li J, Roux S, Li Q, et al. A novel probiotic Formula, BIOCG, Protects against Alzheimer’s-related cognitive deficits via regulation of dendritic spine dynamics. Curr Alzheimer Res. 2021;18:558–572. PMID: 34674621. doi:10.2174/1567205018666211022091110.
  • Abdelhamid M, Zhou C, Ohno K, Kuhara T, Taslima F, Abdullah M, Jung CG, Michikawa M. Probiotic Bifidobacterium breve prevents memory impairment through the Reduction of both amyloid-β production and microglia activation in APP Knock-in mouse. J Alzheimers Dis. 2022;85:1555–1571. PMID: 34958017. doi:10.3233/jad-215025.
  • Bonfili L, Cuccioloni M, Gong C, Cecarini V, Spina M, Zheng Y, Angeletti M, Eleuteri AM. Gut microbiota modulation in Alzheimer’s disease: Focus on lipid metabolism. Clin Nutr. 2022;41:698–708. PMID: 35158177. doi:10.1016/j.clnu.2022.01.025.
  • Ohno K, Abdelhamid M, Zhou C, Jung CG, Michikawa M. Bifidobacterium breve MCC1274 supplementation Increased the plasma levels of metabolites with potential anti-oxidative activity in APP Knock-in mice. J Alzheimers Dis. 2022;89(4):1413–1425. PMID: 36057824. doi: 10.3233/jad-220479.
  • Webberley TS, Masetti G, Bevan RJ, Kerry-Smith J, Jack AA, Michael DR, Thomas S, Glymenaki M, Li J, McDonald JAK, et al. The impact of probiotic supplementation on cognitive, Pathological and metabolic markers in a transgenic mouse model of Alzheimer’s disease. Front Neurosci. 2022;16:843105. PMID: 35685773. doi:10.3389/fnins.2022.843105.
  • Ye T, Yuan S, Kong Y, Yang H, Wei H, Zhang Y, Jin H, Yu Q, Liu J, Chen S, et al. Effect of probiotic fungi against cognitive impairment in mice via regulation of the fungal microbiota–gut–brain axis. J Agric Food Chem. 2022;70(29):9026–9038. PMID: 35833673. doi:10.1021/acs.jafc.2c03142.
  • Webberley TS, Bevan RJ, Kerry-Smith J, Dally J, Michael DR, Thomas S, Rees M, Morgan JE, Marchesi JR, Good MA, et al. Assessment of Lab4P probiotic effects on cognition in 3xTg-AD Alzheimer’s disease model mice and the SH-SY5Y neuronal cell line. Int J Mol Sci. 2023;24(5):4683. PMID: 36902113. doi:10.3390/ijms24054683.
  • Zhu G, Zhao J, Wang G, Chen W. Bifidobacterium breve HNXY26M4 attenuates cognitive deficits and neuroinflammation by regulating the gut–brain axis in APP/PS1 mice. J Agric Food Chem. 2023;71(11):4646–4655. PMID: 36888896. doi: 10.1021/acs.jafc.3c00652.
  • Liu Y, Sheng Y, Pan Q, Xue Y, Yu L, Tian F, Zhao J, Zhang H, Zhai Q, Chen W. Identification of the key physiological characteristics of Lactobacillus plantarum strains for ulcerative colitis alleviation. Food Funct. 2020;11(2):1279–1291. PMID: 31984399. doi: 10.1039/c9fo02935d.
  • Beck LC, Masi AC, Young GR, Vatanen T, Lamb CA, Smith R, Coxhead J, Butler A, Marsland BJ, Embleton ND, et al. Strain-specific impacts of probiotics are a significant driver of gut microbiome development in very preterm infants. Nature Microbiology. 2022;7(10):1525–1535. PMID: 36163498. doi:10.1038/s41564-022-01213-w.
  • Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, Hamidi GA, Salami M. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind and controlled trial. Front Aging Neurosci. 2016;8:256. PMID: 27891089. doi:10.3389/fnagi.2016.00256.
  • Agahi A, Hamidi GA, Daneshvar R, Hamdieh M, Soheili M, Alinaghipour A, Esmaeili Taba SM, Salami M. Does severity of Alzheimer’s disease contribute to its responsiveness to modifying gut microbiota? A double blind clinical trial. Front Neurol. 2018;9:662. PMID: 30158897. doi:10.3389/fneur.2018.00662.
  • Leblhuber F, Steiner K, Schuetz B, Fuchs D, Gostner JM. Probiotic supplementation in patients with Alzheimer’s dementia - an Explorative intervention study. Curr Alzheimer Res. 2018;15:1106–1113. PMID: 30101706. doi:10.2174/1389200219666180813144834.
  • Hwang YH, Park S, Paik JW, Chae SW, Kim DH, Jeong DG, Ha E, Kim M, Hong G, Park SH, et al. Efficacy and safety of Lactobacillus plantarum C29-Fermented soybean (DW2009) in individuals with Mild cognitive impairment: A 12-week, multi-center, randomized, double-blind, placebo-controlled clinical trial. Nutrients. 2019;11(2):305. PMID: 30717153. doi:10.3390/nu11020305.
  • Kobayashi Y, Kinoshita T, Matsumoto A, Yoshino K, Saito I, Xiao JZ. Bifidobacterium Breve A1 supplementation Improved cognitive decline in older adults with Mild cognitive impairment: An Open-label, single-arm study. J Prev Alzheimers Dis. 2019;6:70–75. PMID: 30569089. doi:10.14283/jpad.2018.32.
  • Kobayashi Y, Kuhara T, Oki M, Xiao JZ. Effects of Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: a randomised, double-blind, placebo-controlled trial. Benef Microbes. 2019;10(5):511–520. PMID: 31090457. doi: 10.3920/bm2018.0170.
  • Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E, Tajabadi-Ebrahimi M, Asemi Z. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer’s disease: A randomized, double-blind, controlled trial. Clin Nutr. 2019;38:2569–2575. PMID: 30642737. doi:10.1016/j.clnu.2018.11.034.
  • Xiao J, Katsumata N, Bernier F, Ohno K, Yamauchi Y, Odamaki T, Yoshikawa K, Ito K, Kaneko T. Probiotic Bifidobacterium breve in improving cognitive functions of older adults with Suspected Mild cognitive impairment: A randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2020;77:139–147. PMID: 32623402. doi:10.3233/jad-200488.
  • Bernier F, Ohno K, Katsumata N, Shimizu T, Xiao J. Association of plasma hemoglobin A1c with improvement of cognitive functions by probiotic Bifidobacterium breve supplementation in healthy adults with Mild cognitive impairment. J Alzheimers Dis. 2021;81:493–497. PMID: 33814441. doi:10.3233/jad-201488.
  • Akhgarjand C, Vahabi Z, Shab-Bidar S, Etesam F, Djafarian K. Effects of probiotic supplements on cognition, anxiety, and physical activity in subjects with mild and moderate Alzheimer’s disease: A randomized, double-blind, and placebo-controlled study. Front Aging Neurosci. 2022;14:1032494. PMID: 36389063. doi:10.3389/fnagi.2022.1032494.
  • Asaoka D, Xiao J, Takeda T, Yanagisawa N, Yamazaki T, Matsubara Y, Sugiyama H, Endo N, Higa M, Kasanuki K, et al. Effect of probiotic Bifidobacterium breve in improving cognitive function and preventing brain atrophy in older patients with Suspected Mild cognitive impairment: Results of a 24-week randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2022;88:75–95. PMID: 35570493. doi:10.3233/jad-220148.
  • Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell. 2019;179(2):312–339. PMID: 31564456. doi: 10.1016/j.cell.2019.09.001.
  • Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam study. Ann Neurol. 1997;42(5):776–782. PMID: 9392577. doi: 10.1002/ana.410420514.
  • Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr., Ashe KH, et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron. 2004;43:633–645. PMID: 15339646. doi:10.1016/j.neuron.2004.08.013.
  • Calon F, Lim GP, Morihara T, Yang F, Ubeda O, Salem N Jr., Frautschy SA, Cole GM. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer’s disease. Eur J Of Neuroscience. 2005;22(3):617–626. PMID: 16101743. doi: 10.1111/j.1460-9568.2005.04253.x.
  • Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr., Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25(12):3032–3040. PMID: 15788759. doi: 10.1523/jneurosci.4225-04.2005.
  • Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H. Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice. Neurobiol Dis. 2006;23:563–572. PMID: 16765602. doi:10.1016/j.nbd.2006.04.013.
  • Arendash GW, Jensen MT, Salem N Jr., Hussein N, Cracchiolo J, Dickson A, Leighty R, Potter H. A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer’s transgenic mice. Neuroscience. 2007;149(2):286–302. PMID: 17904756. doi: 10.1016/j.neuroscience.2007.08.018.
  • Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-β and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci. 2007;27(16):4385–4395. PMID: 17442823. doi: 10.1523/jneurosci.0055-07.2007.
  • Hooijmans CR, Rutters F, Dederen PJ, Gambarota G, Veltien A, van Groen T, Broersen LM, Lütjohann D, Heerschap A, Tanila H, et al. Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western diet (TWD). Neurobiol Dis. 2007;28:16–29. PMID: 17720508. doi:10.1016/j.nbd.2007.06.007.
  • Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer’s disease (AD): relevance to AD prevention. J Neurosci. 2007;27(52):14299–14307. PMID: 18160637. doi: 10.1523/jneurosci.3593-07.2007.
  • Hooijmans CR, der Zee CE V, Dederen PJ, Brouwer KM, Reijmer YD, van Groen T, Broersen LM, Lütjohann D, Heerschap A, Kiliaan AJ. DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice. Neurobiol Dis. 2009;33(3):482–498. PMID: 19130883. doi: 10.1016/j.nbd.2008.12.002.
  • Perez SE, Berg BM, Moore KA, He B, Counts SE, Fritz JJ, Hu YS, Lazarov O, Lah JJ, Mufson EJ. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects. J Neurosci Res. 2010;88:1026–1040. PMID: 19859965. doi:10.1002/jnr.22266.
  • Arsenault D, Julien C, Tremblay C, Calon F. DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice. PloS One. 2011;6(2):e17397. PMID: 21383850. doi: 10.1371/journal.pone.0017397.
  • Fiol-DeRoque MA, Gutierrez-Lanza R, Terés S, Torres M, Barceló P, Rial RV, Verkhratsky A, Escribá PV, Busquets X, Rodríguez JJ. Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer’s disease following 2-hydroxy-DHA treatment. Biogerontology. 2013;14(6):763–775. PMID: 24114505. doi: 10.1007/s10522-013-9461-4.
  • Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Kiosea NC, Nazari S, Chen PP, Nothias F, et al. Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris water maze with aging. J Neurosci. 2014;34(21):7124–7136. PMID: 24849348. doi:10.1523/jneurosci.3439-13.2014.
  • Torres M, Price SL, Fiol-Deroque MA, Marcilla-Etxenike A, Ahyayauch H, Barceló-Coblijn G, Terés S, Katsouri L, Ordinas M, López DJ, et al. Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer’s disease. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2014;1838(6):1680–1692. PMID: 24374316. doi:10.1016/j.bbamem.2013.12.016.
  • Hosono T, Mouri A, Nishitsuji K, Jung CG, Kontani M, Tokuda H, Kawashima H, Shibata H, Suzuki T, Nabehsima T, et al. Arachidonic or docosahexaenoic acid diet prevents memory impairment in Tg2576 mice. J Alzheimers Dis. 2015;48:149–162. PMID: 26401936. doi:10.3233/jad-150341.
  • Teng E, Taylor K, Bilousova T, Weiland D, Pham T, Zuo X, Yang F, Chen PP, Glabe CG, Takacs A, et al. Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization. Neurobiol Dis. 2015;82:552–560. PMID: 26369878. doi:10.1016/j.nbd.2015.09.002.
  • Raefsky SM, Furman R, Milne G, Pollock E, Axelsen P, Mattson MP, Shchepinov MS. Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid beta-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2018;66:165–176. PMID: 29579687. doi:10.1016/j.neurobiolaging.2018.02.024.
  • Hoffman JD, Yanckello LM, Chlipala G, Hammond TC, McCulloch SD, Parikh I, Sun S, Morganti JM, Green SJ, Lin AL. Dietary inulin alters the gut microbiome, enhances systemic metabolism and reduces neuroinflammation in an APOE4 mouse model. PloS One. 2019;14(8):e0221828. PMID: 31461505. doi: 10.1371/journal.pone.0221828.
  • Sun J, Liu S, Ling Z, Wang F, Ling Y, Gong T, Fang N, Ye S, Si J, Liu J. Fructooligosaccharides Ameliorating cognitive deficits and neurodegeneration in APP/PS1 transgenic mice through modulating gut microbiota. J Agric Food Chem. 2019;67(10):3006–3017. PMID: 30816709. doi: 10.1021/acs.jafc.8b07313.
  • Chang Y-H, Hoffman J, Yanckello L, McCulloch S, Lin P, Lane A, Chlipala G, Green S, Lin A-L. Apolipoprotein E Genotype-dependent nutrigenetic effects to prebiotic inulin for reducing risk for Alzheimer’s disease in a mouse model. Curr Dev Nutr. 2020;4:1197–1197. doi:10.1093/cdn/nzaa057_013.
  • Han D, Li Z, Liu T, Yang N, Li Y, He J, Qian M, Kuang Z, Zhang W, Ni C, et al. Prebiotics regulation of intestinal microbiota attenuates cognitive dysfunction induced by surgery stimulation in APP/PS1 mice. Aging Dis. 2020;11:1029–1045. PMID: 33014520. doi:10.14336/ad.2020.0106.
  • Park YH, Shin SJ, Kim HS, Hong SB, Kim S, Nam Y, Kim JJ, Lim K, Kim JS, Kim JI, et al. Omega-3 fatty acid-type docosahexaenoic acid protects against Aβ-mediated mitochondrial deficits and pathomechanisms in Alzheimer’s disease-related animal model. Int J Mol Sci. 2020;21(11):3879. PMID: 32486013. doi:10.3390/ijms21113879.
  • Wu S, Zhang J, Jiang C, Wang S, Que R, An L. Up-regulation of neprilysin mediates the protection of fructo-oligosaccharides against Alzheimer’s disease. Food Funct. 2020;11(7):6565–6572. PMID: 32644062. doi: 10.1039/d0fo00161a.
  • Bie N, Li J, Li C, Lian R, Qin L, Wang C. Protective effect and mechanism of docosahexaenoic acid on the cognitive function in female APP/PS1 mice. Food Funct. 2021;12(22):11435–11448. PMID: 34676845. doi: 10.1039/d1fo01922h.
  • Liu Q, Xi Y, Wang Q, Liu J, Li P, Meng X, Liu K, Chen W, Liu X, Liu Z. Mannan oligosaccharide attenuates cognitive and behavioral disorders in the 5xFAD Alzheimer’s disease mouse model via regulating the gut microbiota-brain axis. Brain Behav Immun. 2021;95:330–343. PMID: 33839232. doi:10.1016/j.bbi.2021.04.005.
  • Badesso S, Cartas-Cejudo P, Espelosin M, Santamaria E, Cuadrado-Tejedor M, Garcia-Osta A. Docosahexaenoic acid ameliorates contextual fear memory deficits in the Tg2576 Alzheimer’s disease mouse model: Cellular and molecular correlates. Pharmaceutics. 2022;15(1):82. PMID: 36678710. doi: 10.3390/pharmaceutics15010082.
  • Xiao M, Xiang W, Chen Y, Peng N, Du X, Lu S, Zuo Y, Li B, Hu Y, Li X. DHA ameliorates cognitive ability, reduces amyloid deposition, and nerve fiber production in Alzheimer’s disease. Front Nutr. 2022;9:852433. PMID: 35782939. doi:10.3389/fnut.2022.852433.
  • Zussy C, John R, Urgin T, Otaegui L, Vigor C, Acar N, Canet G, Vitalis M, Morin F, Planel E, et al. Intranasal administration of Nanovectorized docosahexaenoic acid (DHA) improves cognitive function in two complementary mouse models of Alzheimer’s disease. Antioxid (Basel). 2022;11(5):838. PMID: 35624701. doi:10.3390/antiox11050838.
  • Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. ω-3 fatty acid treatment in 174 patients with Mild to moderate Alzheimer disease: OmegAD study. Arch Neurol. 2006;63(10):1402–1408. PMID: 17030655. doi: 10.1001/archneur.63.10.1402.
  • Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res (N Y). 2006;56:159–164. PMID: 16905216. doi:10.1016/j.neures.2006.06.010.
  • Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, Stewart R, Huang SY. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Progress In Neuro-Psychopharmacology And Biological Psychiatry. 2008;32(6):1538–1544. PMID: 18573585. doi: 10.1016/j.pnpbp.2008.05.015.
  • Freund-Levi Y, Basun H, Cederholm T, Faxén-Irving G, Garlind A, Grut M, Vedin I, Palmblad J, Wahlund LO, Eriksdotter-Jönhagen M. Omega-3 supplementation in mild to moderate Alzheimer’s disease: effects on neuropsychiatric symptoms. Int J Geriat Psychiatry. 2008;23(2):161–169. PMID: 17582225. doi: 10.1002/gps.1857.
  • Vedin I, Cederholm T, Freund Levi Y, Basun H, Garlind A, Faxén Irving G, Jönhagen ME, Vessby B, Wahlund LO, Palmblad J. Effects of docosahexaenoic acid–rich n−3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008;87(6):1616–1622. PMID: 18541548. doi: 10.1093/ajcn/87.6.1616.
  • Freund-Levi Y, Hjorth E, Lindberg C, Cederholm T, Faxen-Irving G, Vedin I, Palmblad J, Wahlund LO, Schultzberg M, Basun H, et al. Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer’s disease: the OmegAD study. Dement Geriatr Cogn Disord. 2009;27(5):481–490. PMID: 19439966. doi:10.1159/000218081.
  • Irving GF, Freund-Levi Y, Eriksdotter-Jönhagen M, Basun H, Brismar K, Hjorth E, Palmblad J, Vessby B, Vedin I, Wahlund LO, et al. Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer’s disease: the omega-3 Alzheimer’s disease study. J American Geriatrics Society. 2009;57(1):11–17. PMID: 19054188. doi:10.1111/j.1532-5415.2008.02055.x.
  • Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR Jr., Weiner M, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. Jama. 2010;304(17):1903–1911. PMID: 21045096. doi:10.1001/jama.2010.1510.
  • Vedin I, Cederholm T, Freund-Levi Y, Basun H, Hjorth E, Irving GF, Eriksdotter-Jönhagen M, Schultzberg M, Wahlund LO, Palmblad J. Reduced prostaglandin F2α release from blood mononuclear leukocytes after oral supplementation of ω3 fatty acids: the OmegAD study. J Lipid Res. 2010;51(5):1179–1185. PMID: 19965584. doi: 10.1194/jlr.M002667.
  • Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, Howe PR. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107(11):1682–1693. PMID: 21929835. doi: 10.1017/s0007114511004788.
  • Vedin I, Cederholm T, Freund-Levi Y, Basun H, Garlind A, Irving GF, Eriksdotter-Jönhagen M, Wahlund LO, Dahlman I, Palmblad J, et al. Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study. PloS One. 2012;7(4):e35425. PMID: 22545106. doi: 10.1371/journal.pone.0035425.
  • Faxén-Irving G, Freund-Levi Y, Eriksdotter-Jönhagen M, Basun H, Hjorth E, Palmblad J, Vedin I, Cederholm T, Wahlund LO. Effects on transthyretin in plasma and cerebrospinal fluid by DHA-Rich n – 3 fatty acid supplementation in patients with Alzheimer’s disease: The OmegAD study. J Alzheimers Dis. 2013;36(1):1–6. PMID: 23563245. doi: 10.3233/jad-121828.
  • Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacol (Berl). 2013;225(3):605–612. PMID: 22932777. doi: 10.1007/s00213-012-2848-0.
  • Freund Levi Y, Vedin I, Cederholm T, Basun H, Faxén Irving G, Eriksdotter M, Hjorth E, Schultzberg M, Vessby B, Wahlund LO, et al. Transfer of omega-3 fatty acids across the blood–brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with a lzheimer’s disease: the O meg AD study. J Intern Med. 2014;275(4):428–436. PMID: 24410954. doi:10.1111/joim.12166.
  • Freund-Levi Y, Vedin I, Hjorth E, Basun H, Faxén Irving G, Schultzberg M, Eriksdotter M, Palmblad J, Vessby B, Wahlund LO, et al. Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer’s disease: the OmegAD study. JAD. 2014;42(3):823–831. PMID: 24934544. doi:10.3233/jad-132042.
  • Mahmoudi MJ, Hedayat M, Sharifi F, Mirarefin M, Nazari N, Mehrdad N, Ghaderpanahi M, Tajalizadekhoob Y, Badamchizade Z, Larijani B, et al. Effect of low dose ω-3 poly unsaturated fatty acids on cognitive status among older people: a double-blind randomized placebo-controlled study. J Diabetes Metab Disord. 2014;13(1):34. PMID: 24507770. doi:10.1186/2251-6581-13-34.
  • Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. JAD. 2014;38(1):111–120. PMID: 24077434. doi:10.3233/jad-130722.
  • Eriksdotter M, Vedin I, Falahati F, Freund-Levi Y, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Cederholm T, et al. Plasma fatty acid profiles in relation to cognition and gender in Alzheimer’s disease patients during Oral Omega-3 fatty acid supplementation: The OmegAD study. J Alzheimers Dis. 2015;48:805–812. PMID: 26402079. doi:10.3233/jad-150102.
  • Fiala M, Halder RC, Sagong B, Ross O, Sayre J, Porter V, Bredesen DE. ω-3 supplementation increases amyloid-β phagocytosis and resolvin D1 in patients with minor cognitive impairment. FASEB J. 2015;29(7):2681–2689. PMID: 25805829. doi: 10.1096/fj.14-264218.
  • Phillips MA, Childs CE, Calder PC, Rogers PJ. No effect of Omega-3 fatty acid supplementation on cognition and mood in individuals with cognitive impairment and probable Alzheimer’s disease: A Randomised controlled trial. Int J Mol Sci. 2015;16:24600–24613. PMID: 26501267. doi:10.3390/ijms161024600.
  • Wang X, Hjorth E, Vedin I, Eriksdotter M, Freund-Levi Y, Wahlund LO, Cederholm T, Palmblad J, Schultzberg M. Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study. J Lipid Res. 2015;56:674–681. PMID: 25616438. doi:10.1194/jlr.P055418.
  • Karimi M, Vedin I, Freund Levi Y, Basun H, Faxén Irving G, Eriksdotter M, Wahlund LO, Schultzberg M, Hjorth E, Cederholm T, et al. DHA-rich n–3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study. Am J Clin Nutr. 2017;106(4):1157–1165. PMID: 28855224. doi:10.3945/ajcn.117.155648.
  • Zhang YP, Miao R, Li Q, Wu T, Ma F. Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with Mild cognitive impairment: A 12-month randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2017;55(2):497–507. PMID: 27716665. doi: 10.3233/jad-160439.
  • Schwarz C, Wirth M, Gerischer L, Grittner U, Witte AV, Köbe T, Flöel A. Effects of Omega-3 fatty acids on resting cerebral perfusion in patients with Mild cognitive impairment: A randomized controlled trial. J Prev Alzheimers Dis. 2018;5:26–30. PMID: 29405229. doi:10.14283/jpad.2017.23.
  • Zhang YP, Lou Y, Hu J, Miao R, Ma F. DHA supplementation improves cognitive function via enhancing Aβ-mediated autophagy in Chinese elderly with mild cognitive impairment: a randomised placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2018;89(4):382–388. PMID: 29142143. doi: 10.1136/jnnp-2017-316176.
  • Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, et al. Homocysteine status modifies the treatment effect of Omega-3 fatty acids on cognition in a randomized clinical trial in Mild to moderate Alzheimer’s disease: The OmegAD study. J Alzheimers Dis. 2019;69(1):189–197. PMID: 30958356. doi:10.3233/jad-181148.
  • Tofiq A, Zetterberg H, Blennow K, Basun H, Cederholm T, Eriksdotter M, Faxén-Irving G, Hjorth E, Jernerén F, Schultzberg M, et al. Effects of peroral Omega-3 fatty acid supplementation on cerebrospinal fluid biomarkers in patients with Alzheimer’s disease: A randomized controlled trial—the OmegAD study. J Alzheimers Dis. 2021;83(3):1291–1301. PMID: 34420949. doi:10.3233/jad-210007.
  • Lin PY, Cheng C, Satyanarayanan SK, Chiu LT, Chien YC, Chuu CP, Lan TH, Su KP. Omega-3 fatty acids and blood-based biomarkers in Alzheimer’s disease and mild cognitive impairment: A randomized placebo-controlled trial. Brain Behav Immun. 2022;99:289–298. PMID: 34755655. doi:10.1016/j.bbi.2021.10.014.
  • El Gaamouch F, Chen F, Ho L, Lin HY, Yuan C, Wong J, Wang J. Benefits of dietary polyphenols in Alzheimer’s disease. Front Aging Neurosci. 2022;14:1019942. PMID: 36583187. doi:10.3389/fnagi.2022.1019942.
  • Huang TL, Zandi PP, Tucker KL, Fitzpatrick AL, Kuller LH, Fried LP, Burke GL, Carlson MC. Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology. 2005;65(9):1409–1414. PMID: 16275829. doi: 10.1212/01.wnl.0000183148.34197.2e.
  • Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N Jr., Calon F, Plourde M. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J Neurochem. 2014;129:516–526. PMID: 24345162. doi:10.1111/jnc.12640.
  • Deng SM, Chen CJ, Lin HL, Cheng IH. The beneficial effect of synbiotics consumption on Alzheimer’s disease mouse model via reducing local and systemic inflammation. Iubmb Life. 2022;74:748–753. PMID: 34962691. doi:10.1002/iub.2589.
  • Westfall S, Lomis N, Prakash S. A novel synbiotic delays Alzheimer’s disease onset via combinatorial gut-brain-axis signaling in Drosophila melanogaster. PloS One. 2019;14:e0214985. PMID: 31009489. doi:10.1371/journal.pone.0214985.
  • Abbasi A, Rad AH, Ghasempour Z, Sabahi S, Kafil HS, Hasannezhad P, Rahbar Saadat Y, Shahbazi N. The biological activities of postbiotics in gastrointestinal disorders. Crit Rev Food Sci Nutr. 2022;62(22):1–22. PMID: 33715539. doi: 10.1080/10408398.2021.1895061.
  • Zhang T, Zhang W, Feng C, Kwok LY, He Q, Sun Z. Stronger gut microbiome modulatory effects by postbiotics than probiotics in a mouse colitis model. NPJ Sci Food. 2022;6(1):53. PMID: 36379940. doi: 10.1038/s41538-022-00169-9.
  • Sabahi S, Homayouni Rad A, Aghebati-Maleki L, Sangtarash N, Ozma MA, Karimi A, Hosseini H, Abbasi A. Postbiotics as the new frontier in food and pharmaceutical research. Crit Rev Food Sci Nutr. 2022;1–28. PMID: 35348016. doi:10.1080/10408398.2022.2056727.
  • Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1755. author reply 1755-1756 PMID: 23160295. doi:10.1038/ajg.2012.251.
  • Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854–859. PMID: 13592638.
  • van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415. PMID: 23323867. doi:10.1056/NEJMoa1205037.
  • Allegretti JR, Mullish BH, Kelly C, Fischer M. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. Lancet. 2019;394(10196):420–431. PMID: 31379333. doi: 10.1016/s0140-6736(19)31266-8.
  • WHO. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product. 2022.
  • Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fåk F, Jucker M, Lasser T, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7(1):41802. PMID: 28176819. doi:10.1038/srep41802.
  • Sun J, Xu J, Ling Y, Wang F, Gong T, Yang C, Ye S, Ye K, Wei D, Song Z, et al. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl Psychiatry. 2019;9(1):189. PMID: 31383855. doi:10.1038/s41398-019-0525-3.
  • Shen H, Guan Q, Zhang X, Yuan C, Tan Z, Zhai L, Hao Y, Gu Y, Han C. New mechanism of neuroinflammation in Alzheimer’s disease: The activation of NLRP3 inflammasome mediated by gut microbiota. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109884. PMID: 32032696. doi:10.1016/j.pnpbp.2020.109884.
  • Kim N, Jeon SH, Ju IG, Gee MS, Do J, Oh MS, Lee JK. Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain Behav Immun. 2021;98:357–365. PMID: 34500036. doi:10.1016/j.bbi.2021.09.002.
  • Valeri F, Dos Santos Guilherme M, He F, Stoye NM, Schwiertz A, Endres K. Impact of the age of cecal material transfer donors on Alzheimer’s disease pathology in 5xFAD mice. Microorganisms. 2021;9(12):2548. PMID: 34946148. doi: 10.3390/microorganisms9122548.
  • Bi W, Cai S, Hang Z, Lei T, Wang D, Wang L, Du H. Transplantation of feces from mice with Alzheimer’s disease promoted lung cancer growth. Biochem Biophys Res Commun. 2022;600:67–74. PMID: 35196629. doi:10.1016/j.bbrc.2022.01.078.
  • Elangovan S, Borody TJ, Holsinger RMD. Fecal microbiota transplantation reduces pathology and improves cognition in a mouse model of Alzheimer’s disease. Cells. 2022;12(1):119. PMID: 36611911. doi: 10.3390/cells12010119.
  • Hang Z, Cai S, Lei T, Zhang X, Xiao Z, Wang D, Li Y, Bi W, Yang Y, Deng S, et al. Transfer of tumor-bearing mice intestinal flora can ameliorate cognition in Alzheimer’s disease mice. J Alzheimers Dis. 2022;86(3):1287–1300. PMID: 35180124. doi:10.3233/jad-215495.
  • Kim JE, Roh YJ, Choi YJ, Lee SJ, Jin YJ, Song HJ, Seol AY, Son HJ, Hong JT, Hwang DY. Dysbiosis of fecal microbiota in Tg2576 mice for Alzheimer’s disease during pathological constipation. Int J Mol Sci. 2022;23(23):14928. PMID: 36499254. doi: 10.3390/ijms232314928.
  • Soriano S, Curry K, Wang Q, Chow E, Treangen TJ, Villapol S. Fecal microbiota transplantation derived from Alzheimer’s disease mice worsens brain trauma outcomes in wild-type controls. Int J Mol Sci. 2022;23(9):4476. PMID: 35562867. doi: 10.3390/ijms23094476.
  • Wang F, Gu Y, Xu C, Du K, Zhao C, Zhao Y, Liu X. Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice. Front Aging Neurosci. 2022;14:858130. PMID: 35966768. doi:10.3389/fnagi.2022.858130.
  • Fujii Y, Nguyen TTT, Fujimura Y, Kameya N, Nakamura S, Arakawa K, Morita H. Fecal metabolite of a gnotobiotic mouse transplanted with gut microbiota from a patient with Alzheimer’s disease. Biosci Biotechnol Biochem. 2019;83:2144–2152. PMID: 31327302. doi:10.1080/09168451.2019.1644149.
  • Hazan S. Rapid improvement in Alzheimer’s disease symptoms following fecal microbiota transplantation: a case report. J Int Med Res. 2020;48(6):300060520925930. PMID: 32600151. doi: 10.1177/0300060520925930.
  • Park SH, Lee JH, Shin J, Kim JS, Cha B, Lee S, Kwon KS, Shin YW, Choi SH. Cognitive function improvement after fecal microbiota transplantation in Alzheimer’s dementia patient: a case report. Curr Med Res Opin. 2021;37:1739–1744. PMID: 34289768. doi:10.1080/03007995.2021.1957807.
  • Hou Q, Zhao F, Liu W, Lv R, Khine WWT, Han J, Sun Z, Lee YK, Zhang H. Probiotic-directed modulation of gut microbiota is basal microbiome dependent. Gut Microbes. 2020;12(1):1736974. PMID: 32200683. doi: 10.1080/19490976.2020.1736974.
  • Smillie CS, Sauk J, Gevers D, Friedman J, Sung J, Youngster I, Hohmann EL, Staley C, Khoruts A, Sadowsky MJ, et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host & Microbe. 2018;23(2):229–240 e225. PMID: 29447696. doi:10.1016/j.chom.2018.01.003.
  • Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16(1):35–56. PMID: 30262901. doi: 10.1038/s41575-018-0061-2.
  • Arora S, Santiago JA, Bernstein M, Potashkin JA. Diet and lifestyle impact the development and progression of Alzheimer’s dementia. Front Nutr. 2023;10:1213223. PMID: 37457976. doi:10.3389/fnut.2023.1213223.
  • van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, van de Rest O. The Mediterranean, Dietary approaches to stop hypertension (DASH), and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer’s disease—A review. Adv Nutr. 2019;10(6):1040–1065. PMID: 31209456. doi: 10.1093/advances/nmz054.
  • Wieckowska-Gacek A, Mietelska-Porowska A, Wydrych M, Wojda U. Western diet as a trigger of Alzheimer’s disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing Res Rev. 2021;70:101397. PMID: 34214643. doi:10.1016/j.arr.2021.101397.
  • Dhana K, Franco OH, Ritz EM, Ford CN, Desai P, Krueger KR, Holland TM, Dhana A, Liu X, Aggarwal NT, et al. Healthy lifestyle and life expectancy with and without Alzheimer’s dementia: population based cohort study. BMJ. 2022;377:e068390. PMID: 35418416. doi:10.1136/bmj-2021-068390.
  • Barnes LL, Dhana K, Liu X, Carey VJ, Ventrelle J, Johnson K, Hollings CS, Bishop L, Laranjo N, Stubbs BJ, et al. Trial of the MIND diet for prevention of cognitive decline in older persons. N Engl J Med. 2023;389(7):602–611. PMID: 37466280. doi:10.1056/NEJMoa2302368.
  • Pellegrini C, Fornai M, D’Antongiovanni V, Antonioli L, Bernardini N, Derkinderen P. The intestinal barrier in disorders of the central nervous system. Lancet Gastroenterol Hepatol. 2023;8:66–80. PMID: 36334596. doi:10.1016/S2468-1253(22)00241-2.
  • Carrasco E, de Las Heras MM G, Gabande-Rodriguez E, Desdin-Mico G, Aranda JF, Mittelbrunn M. The role of T cells in age-related diseases. Nat Rev Immunol. 2022;22(2):97–111. PMID: 34099898. doi: 10.1038/s41577-021-00557-4.