Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial

Azadeh Agahi, Gholam Ali Hamidi, Reza Daneshvar, Mostafa Hamdieh, Masoud Soheili, Azam Alinaghipour, Seyyed Mohammad Esmaeili Taba, Mahmoud Salami, Azadeh Agahi, Gholam Ali Hamidi, Reza Daneshvar, Mostafa Hamdieh, Masoud Soheili, Azam Alinaghipour, Seyyed Mohammad Esmaeili Taba, Mahmoud Salami

Abstract

Alzheimer's disease (AD) is associated with cognitive dysfunction. Evidence indicates that gut microbiota is altered in the AD and, hence, modifying the gut flora may affect the disease. In the previous clinical research we evaluated the effect of a probiotic combination on the cognitive abilities of AD patients. Since, in addition to pathological disorders, the AD is associated with changes in oxidant/antioxidant and inflammatory/anti-inflammatory biomarkers, the present work was designed to evaluate responsiveness of the inflammatory and oxidative biomarkers to the probiotic treatment. The control (CON) and probiotic (PRO) AD patients were treated for 12 weeks by the placebo and probiotic supplementation, respectively. The patients were cognitively assessed by Test Your Memory (TYM = 50 scores). Also serum concentrations of nitric oxide (NO), glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), 8-hydroxy-2' -deoxyguanosine (8-OHdG) and cytokines (TNF-a, IL-6, and IL-10) were measured. The cognitive test and the serum biomarkers were assessed pre- and post-treatment. According to TYM test 83.5% of the patients showed severe AD. The CON (12.86% ± 8.33) and PRO (-9.35% ± 16.83) groups not differently scored the cognitive test. Not pronounced change percent was found in the serum level of TNF-α (1.67% ± 1.33 vs. -0.15% ± 0.27), IL-6 (0.35% ± 0.17 vs. 2.18% ± 0.15), IL-10 (0.05% ± 0.10 vs. -0.70% ± 0.73), TAC (0.07% ± 0.07 and -0.06% ± 0.03), GSH (0.08% ± 0.05 and 0.04% ± 0.03) NO (0.11% ± 0.06 and 0.05% ± 0.09), MDA (-0.11% ± 0.03 and -0.17% ± 0.03), 8-OHdG (43.25% ± 3.01 and 42.70% ± 3.27) in the CON and PRO groups, respectively. We concluded that the cognitive and biochemical indications in the patients with severe AD are insensitive to the probiotic supplementation. Therefore, in addition to formulation and dosage of probiotic bacteria, severity of disease and time of administration deeply affects results of treatment.

Keywords: Alzheimer's disease; cognition; inflammation; microbiota; oxidative stress; probiotics.

Figures

Figure 1
Figure 1
Summary of patient flow.
Figure 2
Figure 2
The scores of the TYM test achieved by the cognitively intact people and those with Alzheimer's disease (AD). The scores gained by the cognitively intact and AD participants were 44.55 ± 0.37 against 14.51 ± 1.40, respectively. Unpaired student t-test indicated a significant difference between the two groups (***P < 0.0001).
Figure 3
Figure 3
The TYM scores achieved by the patients with moderate and severe Alzheimer's disease (AD); the former group gained 28.7 ± 4.47 score and the latter 10.63 ± 1.35 score. Unpaired student t-test showed a significant difference between the two AD groups (***P < 0.0001).

References

    1. de Souza-Talarico JN, de Carvalho AP, Brucki SM, Nitrini R, Renata Ed, Ferretti-Rebustini L. Dementia and cognitive impairment prevalence and associated factors in indigenous populations: a systematic review. Alz Dis Assoc Dis. (2016) 30:281–7. 10.1097/WAD.0000000000000140
    1. Pennisi M, Crupi R, Paola R, Ontario ML, Bella R, Calabrese EJ, et al. . Inflammasomes, hormesis, and antioxidants in neuroinflammation: role of NRLP3 in Alzheimer disease. J Neurosci Res. (2017) 95:1360–72. 10.1002/jnr.23986
    1. Greene JD, Baddeley AD, Hodges JR. Analysis of the episodic memory deficit in early Alzheimer's disease: evidence from the doors and people test. Neuropsychologia (1996) 34:537–51. 10.1016/0028-3932(95)00151-4
    1. Grönholm-Nyman P, Rinne JO, Laine M. Learning and forgetting new names and objects in MCI and AD. Neuropsychologia (2010) 48:1079–88. 10.1016/j.neuropsychologia.2009.12.008
    1. Alescio-Lautier B, Michel B, Herrera C, Elahmadi A, Chambon C, Touzet C, et al. . Visual and visuospatial short-term memory in mild cognitive impairment and Alzheimer disease: role of attention. Neuropsychologia (2007) 45:1948–60. 10.1016/j.neuropsychologia.2006.04.033
    1. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. (2001) 81:741–66. 10.1152/physrev.2001.81.2.741
    1. Bonda DJ, Wang X, Lee H-G, Smith MA, Perry G, Zhu X. Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass. Neurosci Bull. (2014) 30:243–52. 10.1007/s12264-013-1424-x
    1. Dorey E, Chang N, Liu QY, Yang Z, Zhang W. Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer's disease. Neurosci Bull. (2014) 30:317–30. 10.1007/s12264-013-1422-z
    1. Padurariu M, Ciobica A, Lefter R, Lacramioara Serban I, Stefanescu C, Chirita R. The oxidative stress hypothesis in Alzheimer's disease. Psychiat Danub. (2013) 25: 401–9.
    1. Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease. J Alz Dis. (2013) 35:349–61. 10.3233/JAD-122140
    1. Cooper EL, Ma MJ. Alzheimer Disease: clues from traditional and complementary medicine. J Tradit Complement Med. (2017) 7:380–5. 10.1016/j.jtcme.2016.12.003
    1. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell (2006) 124:837–48. 10.1016/j.cell.2006.02.017
    1. Collins SM, Kassam Z, Bercik P. The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr Opin Microbiol. (2013) 16:240–5. 10.1016/j.mib.2013.06.004
    1. Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr. (2013) 167:374–9. 10.1001/jamapediatrics.2013.497
    1. Bravo JA, Julio-Pieper M, Forsythe P, Kunze W, Dinan TG, Bienenstock J, et al. . Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol. (2012) 12:667–72. 10.1016/j.coph.2012.09.010
    1. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. (2015) 125:926–38. 10.1172/JCI76304
    1. Grenham S, Clarke G, Cryan JF, Dinan TG. Brain–gut–microbe communication in health and disease. Front Physiol. (2011) 2:94. 10.3389/fphys.2011.00094
    1. Davari S, Talaei S, Alaei H. Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome–gut–brain axis. Neuroscience (2013) 240:287–96. 10.1016/j.neuroscience.2013.02.055
    1. D'souza A, Fordjour L, Ahmad A, Cai C, Kumar D, Valencia G, et al. . Effects of probiotics, prebiotics, and synbiotics on messenger RNA expression of caveolin-1, NOS, and genes regulating oxidative stress in the terminal ileum of formula-fed neonatal rats. Pediatr Res. (2010) 67:526. 10.1203/PDR.0b013e3181d4ff2b
    1. Brown J, Pengas G, Dawson K, Brown LA, Clatworthy P. Self administered cognitive screening test (TYM) for detection of Alzheimer's disease: cross sectional study-The 10 item test your memory (TYM) test is simpler and more sensitive for Alzheimer's disease than the mini-mental examination. BMJ (2009) 338:1426. 10.1136/bmj.b2030
    1. 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. 10.3389/fnagi.2016.00256
    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology (1984) 34:939–44. 10.1212/WNL.34.7.939
    1. Jack CR, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. . Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alz Dementia (2011) 7:257–62. 10.1016/j.jalz.2011.03.004
    1. Malaguarnera M, Greco F, Barone G, Gargante MP, Toscano MA. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci. (2007) 52:3259–65. 10.1007/s10620-006-9687-y
    1. Soccol CR, de Souza Vandenberghe LP, Spier MR, Medeiros ABP, Yamaguishi CT, De Dea Lindner J, et al. The potential of probiotics: a review. Food Technol Biotech. (2010) 48:413–34.
    1. Bonfili L, Cecarini V, Cuccioloni M, Angeletti M, Berardi S, Scarpona S, et al. . SLAB51 probiotic formulation activates sirt1 pathway promoting antioxidant and neuroprotective effects in an ad mouse model. Mol Neurobiol. (2018). [Epub ahead of print]. 10.1007/s12035-018-0973-4
    1. Nimgampalle M, Kuna Y. Anti-Alzheimer Properties of Probiotic, Lactobacillus plantarum MTCC 1325 in Alzheimer's Disease induced Albino Rats. J Clin Diagn Res. (2017) 11:Kc01–kc5. 10.7860/JCDR/2017/26106.10428
    1. Butterfield DA, Perluigi M, Sultana R. Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics. Eur J Pharmacol. (2006) 545:39–50. 10.1016/j.ejphar.2006.06.026
    1. Chung Y-C, Jin H-M, Cui Y, Kim DS, Jung JM, Park J-I, et al. Fermented milk of Lactobacillus helveticus IDCC3801 improves cognitive functioning during cognitive fatigue tests in healthy older adults. J Funct Food. (2014) 10:465–74. 10.1016/j.jff.2014.07.007
    1. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem. (1996) 239:70–6.
    1. Beutler E, Gelbart T. Plasma glutathione in health and in patients with malignant disease. J Lab Clin Med. (1985) 105:581–4.
    1. Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radical Bio Med. (1990) 9:515–40.
    1. Tatsch E, Bochi GV, da Silva Pereira R, Kober H, Agertt VA, de Campos MMA, et al. . A simple and inexpensive automated technique for measurement of serum nitrite/nitrate. Clin Biochem. (2011) 44:348–50. 10.1016/j.clinbiochem.2010.12.011
    1. Leblhuber F, Egger M, Schuetz B, Fuchs D. Commentary: effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. (2018) 10:54. 10.3389/fnagi.2018.00054
    1. Chassaing B, Gewirtz AT. Gut microbiota, low-grade inflammation, and metabolic syndrome. Toxicol Pathol. (2014) 42:49–53. 10.1177/0192623313508481
    1. Hu X, Wang T, Jin F. Alzheimer's disease and gut microbiota. Sci China Life Sci. (2016) 59:1006–23. 10.1007/s11427-016-5083-9
    1. Peng X, Meng J, Chi T, Liu P, Man C, Liu S, et al. . Lactobacillus plantarum NDC 75017 alleviates the learning and memory ability in aging rats by reducing mitochondrial dysfunction. Exp Ther Med. (2014) 8:1841–6. 10.3892/etm.2014.2000
    1. Distrutti E, O'Reilly J-A, McDonald C, Cipriani S, Renga B, Lynch MA, et al. . Modulation of intestinal microbiota by the probiotic VSL# 3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS ONE (2014) 9:e106503. 10.1371/journal.pone.0106503
    1. Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Kakhaki RD, Akbari E, et al. . Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr. (2017) 36:1245–9. 10.1016/j.clnu.2016.08.015
    1. Tamtaji OR, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M, et al. . The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. (2017) 36:660–5. 10.1080/07315724.2017.1347074
    1. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. . Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol. (2008) 173:1768–82. 10.2353/ajpath.2008.080528
    1. Eriksson UK, Pedersen NL, Reynolds CA, Hong M-G, Prince JA, Gatz M, et al. . Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer's disease and dementia. J Alz Dis. (2011) 23:361–9. 10.3233/JAD-2010-101671
    1. Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B. Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. J Tech Method Pathol. (1992) 66:223–30.
    1. Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther. (2012) 19:724–33. 10.1038/gt.2011.126
    1. Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. . IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron (2015) 85:519–33. 10.1016/j.neuron.2014.11.020
    1. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, et al. . Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging (2003) 24:915–9. 10.1016/S0197-4580(03)00031-9
    1. Vina J, Lloret A, Orti R, Alonso D. Molecular bases of the treatment of Alzheimer's disease with antioxidants: prevention of oxidative stress. Mol Aspects Med. (2004) 25:117–23. 10.1016/j.mam.2004.02.013
    1. Tramutola A, Lanzillotta C, Perluigi M, Butterfield DA. Oxidative stress, protein modification and Alzheimer disease. Brain Res Bull. (2017) 133:88–96. 10.1016/j.brainresbull.2016.06.005
    1. Kryscio RJ, Abner EL, Caban-Holt A, Lovell M, Goodman P, Darke AK, et al. . Association of antioxidant supplement use and dementia in the prevention of Alzheimer's disease by vitamin e and selenium trial. JAMA Neurol. (2017) 74:567–73. 10.1001/jamaneurol.2016.5778
    1. Brewer GJ. Why vitamin E therapy fails for treatment of Alzheimer disease. J Alz Dis. (2011) 23:361–9. 10.3233/JAD-2010-1238

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