No effective drug treatment is currently available for Alzheimer's disease (AD), highlighting the urgent need to develop efficient therapeutic options. We have developed a formula based on medicine and food homology (MFH) consisting of egg yolk oil, perilla seed oil, raphani seed oil, cinnamon oil, and noni puree (EPRCN), and demonstrated that it can treat AD by alleviating neuroinflammation and oxidative stress. However, whether EPRCN can improve AD by regulating gut microbiota remains unknown.
Objective
The current study aimed to evaluate the effect of EPRCN on regulating gut microbiota and neuroprotection.
Methods
16S rRNA sequencing was used to assess the structure of gut microbiota. Hematoxylin-eosin (HE) staining, qRT-PCR, and ELISA were used to evaluate gut inflammation. Detected indexes associated with cholinergic dysfunction and neuronal damage to investigate the neuroprotective effects of EPRCN.
Results
16S rRNA gene analysis revealed that EPRCN remodeled the gut microbiota, inhibited gut metabolic disorders, and promoted CoA biosynthesis in scopolamine-induced mice. EPRCN can ameliorates gut inflammation by activating the cholinergic anti-inflammatory pathway. The results further indicated that EPRCN improved cholinergic dysfunction by inhibiting the activity of acetylcholinesterase and restoring cholinergic receptors. Additionally, EPRCN administration suppressed the neuronal loss and elevated brain derived neurotrophic factor expression in hippocampus. Correlation analysis found that alteration of several gut microbes was associated with indexes improved by EPRCN.
Conclusions
These findings suggest that EPRCN may serve as a promising dietary intervention for treating AD by regulating the microbiota-gut-brain axis and exerting neuroprotective function.
BondiMWEdmondsECSalmonDP. Alzheimer's disease: past, present, and future. J Int Neuropsychol Soc2017; 23: 818–831.
2.
BrownAJHBradleySJMarshallFH, et al.From structure to clinic: design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease. Cell2021; 184: 5886–5901.e5822.
3.
RogersJLKesnerRP. Cholinergic modulation of the hippocampus during encoding and retrieval of tone/shock-induced fear conditioning. Learn Mem2004; 11: 102–107.
4.
SunQZhangJLiA, et al.Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer's disease. Nat Commun2022; 13: 998.
5.
HerrupK. The contributions of unscheduled neuronal cell cycle events to the death of neurons in Alzheimer's disease. Front Biosci (Elite Ed)2012; 4: 2101–2109.
6.
SochockaMDonskow-ŁysoniewskaKDinizBS, et al.The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer's disease-A critical review. Mol Neurobiol2019; 56: 1841–1851.
XieZLuHYangS, et al.Salidroside attenuates cognitive dysfunction in senescence-accelerated mouse prone 8 (SAMP8) mice and modulates inflammation of the gut-brain axis. Front Pharmacol2020; 11: 568423.
9.
MaLNiYWangZ, et al.Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes2020; 12: 1–19.
10.
NimgampalleMKunaY. Anti-Alzheimer properties of probiotic, Lactobacillus plantarum MTCC 1325 in Alzheimer's disease induced albino rats. J Clin Diagn Res2017; 11: KC01–KC05.
11.
WangZXLianWWHeJ, et al.Cornuside ameliorates cognitive impairments in scopolamine induced AD mice: involvement of neurotransmitter and oxidative stress. J Ethnopharmacol2022; 293: 115252.
12.
BajoRPusilSLópezME, et al.Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease. Sci Rep2015; 5: 9748.
13.
NiHLiuMCaoM, et al.Sinomenine regulates the cholinergic anti-inflammatory pathway to inhibit TLR4/NF-κB pathway and protect the homeostasis in brain and gut in scopolamine-induced Alzheimer's disease mice. Biomed Pharmacother2024; 171: 116190.
14.
SuAYangWZhaoL, et al.Flammulina velutipes polysaccharides improve scopolamine-induced learning and memory impairment in mice by modulating gut microbiota composition. Food Funct2018; 9: 1424–1432.
15.
ChenCLiaoJXiaY, et al.Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Gut2022; 71: 2233–2252.
16.
DaughertyDGoldbergJFischerW, et al.A novel Alzheimer's disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimers Res Ther2017; 9: 50.
17.
PatwardhanAGBelemkarS. An update on Alzheimer's disease: immunotherapeutic agents, stem cell therapy and gene editing. Life Sci2021; 282: 119790.
18.
NgCYJBunHHZhaoY, et al.TCM “Medicine and food homology” in the management of post-COVID disorders. Front Immunol2023; 14: 1234307.
19.
SongDXJiangJG. Hypolipidemic components from medicine food homology species used in China: pharmacological and health effects. Arch Med Res2017; 48: 569–581.
20.
LiM-JXuJ-YZhangH-Y, et al.A medicine and food homology formula prevents cognitive deficits by inhibiting neuroinflammation and oxidative stress via activating AEA–Trpv1–Nrf2 pathway. Inflammopharmacology2024; 32: 3745–3759.
21.
WanCQianWWLiuW, et al.Exopolysaccharide from Lactobacillus rhamnosus ZFM231 alleviates DSS-induced colitis in mice by regulating gut microbiota. J Sci Food Agric2022; 102: 7087–7097.
22.
XiaoHLiHSongH, et al.Shenzao jiannao oral liquid, an herbal formula, ameliorates cognitive impairments by rescuing neuronal death and triggering endogenous neurogenesis in AD-like mice induced by a combination of Aβ42 and scopolamine. J Ethnopharmacol2020; 259: 112957.
23.
CuiHKTangCJGaoY, et al.An integrative analysis of single-cell and bulk transcriptome and bidirectional Mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis. Front Immunol2023; 14: 1289223.
24.
MaYLiYYinR, et al.Therapeutic potential of aromatic plant extracts in Alzheimer's disease: comprehensive review of their underlying mechanisms. CNS Neurosci Ther2023; 29: 2045–2059.
25.
WangDZhangHZengM, et al.Maternal high sugar and fat diet benefits offspring brain function via targeting on the gut-brain axis. Aging (Albany NY)2021; 13: 10240–10274.
26.
Di VincenzoFDel GaudioAPetitoV, et al.Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med2024; 19: 275–293.
27.
YuanMChenXSuT, et al.Supplementation of kiwifruit polyphenol extract attenuates high fat diet induced intestinal barrier damage and inflammation via reshaping gut microbiome. Front Nutr2021; 8: 702157.
28.
WangJZhuXLiY, et al.Jiedu-Yizhi formula alleviates neuroinflammation in AD rats by modulating the gut microbiota. Evid Based Complement Alternat Med2022; 2022: 4023006.
29.
LiuMHuRGuoY, et al.Influence of Lactobacillus reuteri SL001 on intestinal microbiota in AD model mice and C57BL/6 mice. Sheng Wu Gong Cheng Xue Bao2020; 36: 1887–1898.
30.
TanJMcKenzieCPotamitisM, et al.The role of short-chain fatty acids in health and disease. Adv Immunol2014; 121: 91–119.
31.
ZhangMWangYZhaoX, et al.Mechanistic basis and preliminary practice of butyric acid and butyrate sodium to mitigate gut inflammatory diseases: a comprehensive review. Nutr Res2021; 95: 1–18.
32.
XuFYuZLiuY, et al.A high-fat, high-cholesterol diet promotes intestinal inflammation by exacerbating gut microbiome dysbiosis and bile acid disorders in cholecystectomy. Nutrients2023; 15: 3829.
33.
GernerRRKlepschVMacheinerS, et al.NAD metabolism fuels human and mouse intestinal inflammation. Gut2018; 67: 1813–1823.
34.
WinterSEThiennimitrPWinterMG, et al.Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature2010; 467: 426–429.
35.
BäumlerAJSperandioV. Interactions between the microbiota and pathogenic bacteria in the gut. Nature2016; 535: 85–93.
36.
KimGHLeeYCKimTJ, et al.Risk of neurodegenerative diseases in patients with inflammatory bowel disease: a nationwide population-based cohort study. J Crohns Colitis2022; 16: 436–443.
37.
LiALNiWWZhangQM, et al.Effect of cinnamon essential oil on gut microbiota in the mouse model of dextran sodium sulfate-induced colitis. Microbiol Immunol2020; 64: 23–32.
38.
KangwanNPratchayasakulWKongkaewA, et al.Perilla seed oil alleviates gut dysbiosis, intestinal inflammation and metabolic disturbance in obese-insulin-resistant rats. Nutrients2021; 13: 3141.
39.
HestonMBHanslikKLZarbockKR, et al.Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study. Sci Rep2023; 13: 18924.
40.
CocciaMHarrisonOJSchieringC, et al.IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. J Exp Med2012; 209: 1595–1609.
41.
WuYJWangLJiCF, et al.The role of α7nAChR-mediated cholinergic anti-inflammatory pathway in immune cells. Inflammation2021; 44: 821–834.
42.
CasertanoMFryganasCValentinoV, et al.Gut production of GABA by a probiotic formula: an in vitro study. Benef Microbes2024; 15: 67–81.
43.
ZhangFWanYZuoT, et al.Prolonged impairment of short-chain fatty acid and l-isoleucine biosynthesis in gut microbiome in patients with COVID-19. Gastroenterology2022; 162: 548–561.e544.
44.
TerryAVJrBuccafuscoJJ. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther2003; 306: 821–827.
45.
Gil-BeaFJGarcía-AllozaMDomínguezJ, et al.Evaluation of cholinergic markers in Alzheimer's disease and in a model of cholinergic deficit. Neurosci Lett2005; 375: 37–41.
46.
HalderNLalG. Cholinergic system and its therapeutic importance in inflammation and autoimmunity. Front Immunol2021; 12: 660342.
47.
Ferreira-VieiraTHGuimaraesIMSilvaFR, et al.Alzheimer's disease: targeting the cholinergic system. Curr Neuropharmacol2016; 14: 101–115.
48.
Glynn-ServedioBERanolaTS. AChe inhibitors and NMDA receptor antagonists in advanced Alzheimer's disease. Consult Pharm2017; 32: 511–518.
49.
ChoiSJOhSSKimCR, et al.Perilla frutescens extract ameliorates acetylcholinesterase and trimethyltin chloride-induced neurotoxicity. J Med Food2016; 19: 281–289.
50.
MutluMBingolZUcEM, et al.Comprehensive metabolite profiling of cinnamon (Cinnamomum zeylanicum) leaf oil using LC-HR/MS, GC/MS, and GC-FID: determination of antiglaucoma, antioxidant, anticholinergic, and antidiabetic profiles. Life (Basel)2023; 13: 136.
51.
PachauriSDVermaPRDwivediAK, et al.Ameliorative effect of Noni fruit extract on streptozotocin-induced memory impairment in mice. Behav Pharmacol2013; 24: 307–319.
52.
YektaRSadeghiLDehghanG. The inefficacy of donepezil on glycated-AChE inhibition: binding affinity, complex stability and mechanism. Int J Biol Macromol2020; 160: 35–46.
53.
ShamsiAAnwarSMohammadT, et al.MARK4 Inhibited by AChE inhibitors, donepezil and rivastigmine tartrate: insights into Alzheimer's disease therapy. Biomolecules2020; 10: 789.
54.
MarucciGBuccioniMBenDD, et al.Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology2021; 190: 108352.
55.
RandákováAJakubíkJ. Functionally selective and biased agonists of muscarinic receptors. Pharmacol Res2021; 169: 105641.
56.
HernandezCMDineleyKT. Α7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both?Curr Drug Targets2012; 13: 613–622.
57.
RedrobeJPNielsenEChristensenJK, et al.Alpha7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioural changes in a modified continuous Y-maze task in mice. Eur J Pharmacol2009; 602: 58–65.
58.
SinghSAgrawalNGoyalA. Role of alpha-7-nicotinic acetylcholine receptor in Alzheimer's disease. CNS Neurol Disord Drug Targets2024; 23: 384–394.
59.
PrathumsapNOngnokBKhuanjingT, et al.Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats. Life Sci2023; 329: 121971.
60.
SunZKwonJSRenY, et al.Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming. Science2024; 385: adl2992.
61.
JiangZWangJQinY, et al.A nonhuman primate model with Alzheimer's disease-like pathology induced by hippocampal overexpression of human tau. Alzheimers Res Ther2024; 16: 22.
62.
WestMJKawasCHStewartWF, et al.Hippocampal neurons in pre-clinical Alzheimer's disease. Neurobiol Aging2004; 25: 1205–1212.
63.
LazarovOHollandsC. Hippocampal neurogenesis: learning to remember. Prog Neurobiol2016; 138–140: 1–18.
64.
PriceRBDumanR. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry2020; 25: 530–543.
65.
MinDMaoXWuK, et al.Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils. Neurosci Lett2012; 510: 29–33.
66.
WangHZhouLZhengQ, et al.Kai-xin-san improves cognitive impairment in D-gal and Aβ(25–35) induced ad rats by regulating gut microbiota and reducing neuronal damage. J Ethnopharmacol2024; 329: 118161.
67.
ZhangHHuiXWangY, et al.Angong Niuhuang Pill ameliorates cerebral ischemia/reperfusion injury in mice partly by restoring gut microbiota dysbiosis. Front Pharmacol2022; 13: 1001422.
68.
RongZJCaiHHWangH, et al.Ursolic acid ameliorates spinal cord injury in mice by regulating gut microbiota and metabolic changes. Front Cell Neurosci2022; 16: 872935.
69.
BierlyJJPetersonBL. Distribution of donepezil in postmortem casework. J Forensic Leg Med2024; 101: 102625.
70.
ZhangXLianSZhangY, et al.Efficacy and safety of donepezil for mild cognitive impairment: a systematic review and meta-analysis. Clin Neurol Neurosurg2022; 213: 107134.
71.
BabaiSAurichePLe-LouëtH. Comparison of adverse drug reactions with donepezil versus memantine: analysis of the French pharmacovigilance database. Therapie2010; 65: 255–259.
72.
RuangritchankulSChantharitPSrisumaS, et al.Adverse drug reactions of acetylcholinesterase inhibitors in older people living with dementia: a comprehensive literature review. Ther Clin Risk Manag2021; 17: 927–949.
73.
FillitHM. The pharmacoeconomics of Alzheimer's disease. Am J Manag Care2000; 6: S1139–S1144. discussion S1145–1138.
74.
BirksJSMelzerDBeppuH. Donepezil for mild and moderate Alzheimer's disease. Cochrane Database Syst Rev2000; 4: CD001190.
75.
SabbaghMNMathewPBlauA. A randomized double-blind study to assess the skin irritation and sensitization potential of a once-weekly donepezil transdermal delivery system in healthy volunteers. Alzheimer Dis Assoc Disord2023; 37: 290–295.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
