Preventive electroacupuncture ameliorates D-galactose-induced Alzheimer’s disease-like inflammation and memory deficits, probably via modulating the microbiota–gut–brain axis

Document Type : Original Article

Authors

1 College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China

2 Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, Hubei, China

3 Department of Tuina, Shenzhen Traditional Chinese Medicine Hospital

4 The 4th Clinical College of Guangzhou University of Chinese Medicine, Shenzhen, China

5 Hubei Provincial Hospital of TCM, Wuhan, Hubei, China

6 Hubei Province Academy of Traditional Chinese Medicine, Wuhan, Hubei, China

Abstract

Objective(s): We aimed to observe the effects of preventive electroacupuncture (EA) on the microbiota–gut–brain axis and spatial learning and memory deficits and to investigate the possible mechanism using D-galactose (D-gal)-induced aging rats.
Materials and Methods: D-gal was intraperitoneally injected to establish the aging model. We used Morris water maze to detect spatial learning and memory function of rats. RT-PCR was applied to test targeted gut microbes. The expression of zonula occludens-1 (ZO-1) and Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway proteins were detected by Western blotting. ELISA was employed to evaluate the level of lipopolysaccharides (LPS), diamine oxidase (DAO) and S-100β. Additionally, we observed ionized calcium-binding adapter molecule-1 (Iba-1) expression in the hippocampal CA1 area by immunofluorescence.
Results: Morris water maze test showed decreased mean escape latency and increased target quadrant time after EA treatment. The gut microbiota composition has been modified in EA treated rats. Molecular examination indicated that expression of ZO-1 was improved and the the concentration of LPS in blood and hippocampus were reduced in EA treated rats. Further, we observed an inhibition of activated microglia and TLR4/NF-κB pathway in EA groups.
Conclusion: Preventive EA may alleviate the impairments of the microbiota–gut–brain axis and spatial learning and memory in aging, and the mechanism may be related to the inhibition of TLR4/NF-kB signaling pathway. The combination of acupoints GV20 and ST36 can enhance the therapeutic effect in aging rats.

Keywords

References

1. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet 2016; 388:505-517.
2. Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis 2017; 58:1-15.
3. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464:59-65.
4. Torow N, Hornef MW. The neonatal window of opportunity: setting the stage for life-long host-microbial interaction and immune homeostasis. J Immunol 2017; 198:557-563.
5. Lynch SV, Pedersen O. The Human intestinal microbiome in health and disease. N Engl J Med 2016; 375:2369-2379.
6. Cani PD, Knauf C. How gut microbes talk to organs: The role of endocrine and nervous routes. Mol Metab 2016; 5:743-752.
7. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155:1451-1463.
8. García-Peña C, Álvarez-Cisneros T, Quiroz-Baez R, Friedland RP. Microbiota and aging. A review and commentary. Arch Med Res 2017; 48:681-689.
9. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 2016; 21:738-748.
10. Maldonado RF, Sá-Correia I, Valvano MA. Lipopolysaccharide modification in Gram-negative bacteria during chronic infection. FEMS Microbiol Rev 2016; 40:480-493.
11. Zhao Y, Jaber V, Lukiw WJ. Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): Detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol 2017; 7:318-336.
12. Yang X, Yu D, Xue L, Li H, Du J. Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice. Acta Pharm Sin B 2020; 10:475-487.
13. Jin L, Nation RL, Li J, Nicolazzo JA. Species-dependent blood-brain barrier disruption of lipopolysaccharide: Amelioration by colistin in vitro and in vivo. Antimicrob Agents Chemother 2013; 57:4336-4342.
14. Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, et al. GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J Neuro-inflammation 2012; 9:268-286.
15. Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest 2000; 105:497-504.
16. Jiao FZ, Wang Y, Zhang HY, Zhang WB, Wang LW, Gong ZJ. Histone deacetylase 2 inhibitor CAY10683 alleviates lipopolysaccharide induced neuro-inflammation through attenuating TLR4/NF-κB signaling pathway. Neurochem Res 2018; 43:1161-1170.
17. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci 2018; 21:1359-1369.
18. Lukiw WJ. Lipopolysaccharide and inflammatory signaling in Alzheimer’s disease. Front Microbiol 2016; 7:1544.
19. Jia Y, Zhang X, Yu J, Han J, Yu T, Shi J, et al. Acupuncture for patients with mild to moderate Alzheimer’s disease: a randomized controlled trial. BMC Complement Altern Med 2017; 17:556-571.
20. Kan BH, Yu JC, Zhao L, Zhao J, Li Z, Suo YR, et al. Acupuncture improves dendritic structure and spatial learning and memory ability of Alzheimer’s disease mice. Neural Regen Res 2018; 13:1390-1395.
21. Wang H, Wang Q, Liang C, Su M, Wang X, Li H, et al. Acupuncture regulating gut microbiota in abdominal obese rats induced by high-fat diet. Evid Based Complement Alternat Med 2019; 2019:4958294.
22. Gao J, Zhou R, You X, Luo F, He H, Chang X, et al. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-κB pathway. Metab Brain Dis 2016; 31:771-778.
23. Yu CC, Wang Y, Shen F, Kong LH, Wang YW, Zhou H, et al. High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1-42-induced Alzheimer’s disease. Neural Regen Res 2018; 13:1833-1841.
24. Cunningham KE, Turner JR. Myosin light chain kinase: Pulling the strings of epithelial tight junction function. Ann N Y Acad Sci 2012; 1258:34-42.
25. Zhao L, Luo L, Jia W, Xiao J, Huang G, Tian G, et al. Serum diamine oxidase as a hemorrhagic shock biomarker in a rabbit model. PLoS One 2014; 9:e102285.
26. Branca JJV, Maresca M, Morucci G, Mello T, Becatti M, Pazzagli L, et al. Effects of cadmium on ZO-1 tight junction integrity of the blood brain barrier. Int J Mol Sci 2019; 20-??.
27. Aluganti Narasimhulu C, Mitra C, Bhardwaj D, Burge KY, Parthasarathy S. Alzheimer’s disease markers in aged ApoE-PON1 deficient mice. J Alzheimers Dis 2019; 67:1353-1365.
28. Owens T. Toll-like receptors in neurodegeneration. Curr Top Microbiol Immunol 2009; 336:105-120.
29. Gárate I, García-Bueno B, Madrigal JLM, Caso JR, Alou L, Gómez-Lus ML, et al. Toll-like 4 receptor inhibitor TAK-242 decreases neuro-inflammation in rat brain frontal cortex after stress. J Neuro-inflammation 2014; 11:8-32.
30. Azman KF, Zakaria R. D-Galactose-induced accelerated aging model: an overview. Biogerontology 2019; 20:763-782.
31. Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Exp Gerontol 2018; 101:13-36.
32. Yu CC, Wang J, Ye SS, Gao S, Li J, Wang L, et al. Preventive electroacupuncture ameliorates D-galactose-induced Alzheimer’s disease-Like pathology and memory deficits probably via inhibition of GSK3/mTOR signaling pathway. Evid Based Complement Alternat Med 2020; 2020:1428752.
33. Wolf SA, Boddeke HWGM, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol 2017; 79:619-643.
34. Cai M, Lee JH, Yang EJ. Electroacupuncture attenuates cognition impairment via anti-neuro-inflammation in an Alzheimer’s disease animal model. J Neuro-inflammation 2019; 16:264-285.
35. Wang Y, Wang Q, Ren B, Guo T, Qiang J, Cao H, et al. “Olfactory three-needle” enhances spatial learning and memory ability in SAMP8 mice. Behav Neurol 2020; 2020:2893289.
36. Köhler CA, Maes M, Slyepchenko A, Berk M, Solmi M, Lanctôt KL, et al. The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: mechanisms and pathophysiological role in Alzheimer’s disease. Curr Pharm Des 2016; 22:6152-6166.
37. Hu X, Wang T, Jin F. Alzheimer’s disease and gut microbiota. Sci China Life Sci 2016; 59:1006-1023.
38. Zhao Y, Cong L, Jaber V, Lukiw WJ. Microbiome-derived lipopolysaccharide enriched in the perinuclear region of Alzheimer’s disease brain. Front Immunol 2017; 8:1064-1075.
39. Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, et al. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci 2017; 9:195.
40. Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA 2008; 105:17151-17156.
41. Han Y, Zhao T, Cheng X, Zhao M, Gong S-H, Zhao Y-Q, et al. Cortical inflammation is increased in a DSS-induced colitis mouse model. Neurosci Bull 2018; 34:1058-1066.
42. Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS, et al. Chronic intestinal inflammation alters hippocampal neurogenesis. J Neuro-inflammation 2015; 12:65-85.
43. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J 2017; 474:1823-1836.
44. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA 2011; 108 Suppl 1:4586-4591.
45. Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010; 5:e10667.
46. Bier A, Braun T, Khasbab R, Di Segni A, Grossman E, Haberman Y, et al. A High salt diet modulates the gut microbiota and short chain fatty acids production in a salt-sensitive hypertension rat model. Nutrients 2018; 10:1154-1168.
47. Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 2017; 49:60-68.
48. König J, Wells J, Cani PD, García-Ródenas CL, MacDonald T, Mercenier A, et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol 2016; 7:e196.
49. Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke J-D, Serino M, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol 2014; 14:189-249.
50. Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 2009; 206:121-124.
51. Plaza-Díaz J, Ruiz-Ojeda FJ, Vilchez-Padial LM, Gil A. Evidence of the anti-inflammatory effects of probiotics and synbiotics in intestinal chronic diseases. Nutrients 2017; 9:555-579.
52. Athari Nik Azm S, Djazayeri A, Safa M, Azami K, Ahmadvand B, Sabbaghziarani F, et al. Lactobacilli and bifidobacteria ameliorate memory and learning deficits and oxidative stress in β-amyloid (1-42) injected rats. Appl Physiol Nutr Metab 2018; 43:718-726.
53. Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, et al. 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.
54. Wang XM, Lu Y, Wu LY, Yu G, Zhao BX, Hu HY, et al. Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis. World J Gastroenterol 2012; 18:6819-6828.
55. Wei D, Xie L, Zhuang Z, Zhao N, Huang B, Tang Y, et al. Gut microbiota: A new strategy to study the mechanism of electroacupuncture and moxibustion in treating ulcerative colitis. Evid Based Complement Alternat Med 2019; 2019:9730176.
56. Pan Y, Nicolazzo JA. Impact of aging, Alzheimer’s disease and Parkinson’s disease on the blood-brain barrier transport of therapeutics. Adv Drug Deliv Rev 2018; 135:62-74.
57. Bake S, Friedman JA, Sohrabji F. Reproductive age-related changes in the blood brain barrier: Expression of IgG and tight junction proteins. Microvasc Res 2009; 78:413-424.
58. Elahy M, Jackaman C, Mamo JC, Lam V, Dhaliwal SS, Giles C, et al. Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immun Ageing 2015; 12:2.
59. Takechi R, Pallebage-Gamarallage MM, Lam V, Giles C, Mamo JC. Aging-related changes in blood-brain barrier integrity and the effect of dietary fat. Neurodegener Dis 2013; 12:125-135.
60. Branca JJV, Gulisano M, Nicoletti C. Intestinal epithelial barrier functions in ageing. Ageing Res Rev 2019; 54:100938.
61. Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J Neurosci 2015; 35:4942-4952.
62. Chen T, Xiong Y, Long M, Zheng D, Ke H, Xie J, et al. Electro-acupuncture pretreatment at zusanli (ST36) acupoint attenuates lipopolysaccharide-induced inflammation in rats by inhibiting ca influx associated with cannabinoid Cb2 receptors. Inflammation 2019; 42:211-220.
63. Song YF, Pei LX, Chen L, Geng H, Yuan MQ, Xu WL, et al. Electroacupuncture relieves irritable bowel syndrome by regulating IL-18 and gut microbial dysbiosis in a trinitrobenzene sulfonic acid-induced post-inflammatory animal model. Am J Chin Med 2020; 48:77-90.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 3
March 2021
Pages 341-348

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