Exploration of Neuroprotective Therapy

Table 6. Summary of included studies evaluating the effects of probiotic supplementation on health-related outcomes in patients with AD.

First author, year of publication, and country	Study design	Participants (baseline sample size and characteristics, withdrawals, and final sample size)	Intervention	Outcomes	Results
Agahi et al. [28] 2018 Iran	Randomized, double-blind, placebo-controlled clinical trial	n = 60 enrolled AD (NINDS-ADRDA, NI-AAA TYM < 45 out of 50) n = 48 (17 ♂ and 31 ♀) included IG n = 25 (7 ♂ and 18 ♀) Age (mean ± SD): 79.70 ± 1.72 years Weight (mean ± SD): 60.12 ± 1.12 kg Height (mean ± SD): 156.77 ± 1.23 cm BMI (mean ± SD): 24.05 ± 1.07 kg/m² CG n = 23 (10 ♂ and 13 ♀) Age (mean ± SD): 80.57 ± 1.79 years Weight (mean ± SD): 60.63 ± 1.26 kg Height (mean ± SD): 156.43 ± 1.86 cm BMI (mean ± SD): 24.44 ± 1.33 kg/m² Withdrawals due to death from aging (n = 12) (CG n = 7, IG n = 5) 25 participants IG 23 participants CG	3 × 10⁹ CFU 1× capsule A + 1× capsule B every other day orally A: Lactobacillus fermentum, Lactobacillus plantarum, Bifidobacterium lactis (Zist Takhmir Company; Tehran, Iran) B: Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium longum (Milad Farmed Company; Tehran, Iran) Placebo 500 mg Maltodextrin 12 weeks	Anthropometry: BMI Cognitive function: TYM (over 50 points) Oxidative stress: TAC GSH MDA NO 8-OHdG Inflammation: IL-6 IL-10 TNF-α	IG vs. GC ↔ BMI ↑ TYM ↔ TAC ↑ GSH ↓ MDA ↓ NO ↓ 8-OHdG * ↑ IL-6 ↓ IL-10 ↓ TNF-α
Akbari et al. [29] 2016 Iran	Randomized, double-blind, placebo-controlled clinical trial	n = 60 (12 ♂ and 48 ♀) AD (NINDS-ADRDA, NI-AAA) IG n = 30 (6 ♂ and 24 ♀) Age (mean ± SD): 77.67 ± 2.62 years Height (mean ± SD): 157.77 ± 2.03 cm Weight (mean ± SD): 59.03 ± 1.99 kg BMI (mean ± SD): 23.77 ± 0.73 kg/m² CG n = 30 (6 ♂ and 24 ♀) Age (mean ± SD): 82.00 ± 1.69 years Height (mean ± SD): 157.43 ± 1.86 cm Weight (mean ± SD): 56.63 ± 2.21 kg BMI (mean ± SD): 22.73 ± 0.68 kg/m² Withdrawals due to death from aging (n = 8) (CG n = 4, IG n = 4) 26 participants IG 26 participants CG	2 × 10⁹ CFU/g strain: Lactobacillus acidophilus Lactobacillus casei Bifidobacterium bifidum Lactobacillus fermentum 200 mL milk + probiotics day orally (Tak Gen Zist Pharmaceutical Company; Tehran, Iran) Placebo: 200 mL milk per day orally 12 weeks	Anthropometry: BMI Cognitive function: MMSE Oxidative stress: MDA CT GSH NO Inflammation: hs-CRP Biochemicals: HOMA-β QUICKI FPG LDL HDL TG VLDL CT	IG vs. CG ↔ BMI * ↑ MMSE ↓ MDA ↔ CT ↔ GSH ↔ NO * ↓ hs-CRP ↓ HOMA-β ↑ QUICKI ↔ FPG ↔ LDL ↔ HDL * ↓ TG * ↓ VLDL ↔ CT
Akhgarjand et al. [30] 2022 Iran	Randomized, double-blind, placebo-controlled clinical trial	n = 90 (48 ♂ and 42 ♀) AD (NINDS-ADRDA, NI-AAA, mild or moderate FAST) IG1: n = 30 (16 ♂ and 14 ♀) Age (mean ± SD): 67.93 ± 7.8 years Weight (mean ± SD): 67.07 ± 6.6 kg BMI (mean ± SD): 23.71 ± 1.4 kg/m² IG2: n = 30 (16 ♂ and 14 ♀) Age (mean ± SD): 67.90 ± 7.9 years Weight (mean + SD): 65.97 ± 7.1 kg BMI (mean ± SD): 79 ± 2.4 kg/m² CG: n = 30 (16 ♂ and 14 ♀) Age (mean ± SD): 67.77 ± 7.9 years Weight (mean ± SD): 62.27 ± 6.8 kg BMI (mean ± SD): 23.93 ± 2.2 kg/m² No withdrawals	1 × 10¹⁵ CFU 2 capsules orally Group 1: Lactobacillus rhamnosus Group 2: Bifidobacterium longum R0175 (Lallemand Company; Canada) Placebo 2 capsules/day of xylitol, maltodextrin, and malic acid orally (Lallemand Company; Canada) 12 weeks	Cognitive function: MMSE CFT Psychological state: GAD-7 Physical condition: BADL → Barthel IADL→ Lawton	IG1 vs. CG * ↑ MMSE * ↑ CFT * ↓ GAD-7 ↔ ABVD * ↑ AIVD IG2 vs. CG * ↑ MMSE * ↑ CFT * ↓ GAD-7 ↔ ABVD * ↑ AIVD
Hsu et al. [31] 2023 Taiwan, China	Randomized, double-blind, active-controlled clinical trial	n = 40 (12 ♂ and 28 ♀) AD (DSM-V, NINCDS-ADRDA, NI-AAA, MMSE 10–25; CDR 0.5–2) (Treatment with donepezil or rivastigmine) IG: n = 20 (4 ♂ and 16 ♀) Age (mean ± SD): 75.4 ± 8.0 years CG: n = 20 (8 ♂ and 12 ♀) Age (mean ± SD): 75.8 ± 7.3 years Withdrawals (n = 8) (CG n = 4, IG n = 4) 16 participants IG 16 participants CG	IG: 1 × 10¹⁰ CFU/day CG¹: 5 × 10⁷ CFU/day 1 capsule daily orally with 5 probiotic strains in equal proportions: Bifidobacterium longum subsp. infantis BLI-02, Bifidobacterium breve Bv-889, Bifidobacterium animalis subsp. lactis CP-9, Bifidobacterium bifidum VDD088, and Lactobacillus plantarum PL-02 (Glac Biotech Co., Ltd.; Tainan, Taiwan, China) 12 weeks	Cognitive function: MMSE ADAS-Cog CDR Oxidative stress: MDA PCC SOD Inflammatory markers: IL-1β IL-10 Physical condition: BADL AD biomarker: BDNF Intestinal microbiota: Strains Hormonal: Cortisol	IG vs. CG ↔ MMSE ↔ ADAS-Cog ↔ CDR * ↓ MDA * ↓ PCC * ↑ SOD * ↓ IL-1 β ↑ IL-10 ↔ ABVD * ↑ BDNF ↑ Bifidobacterium ↑ Lactobacillus ↑ Ruminococcus ↑ Clostridium ↑ Akkermansia ↓ Megamonas * ↓ Cortisol
Tamtaji et al. [32] 2019 Iran	Randomized, double-blind, placebo-controlled clinical trial	n = 90 (gender not specified) AD (NINDS-ADRDA, NI-AAA, Golabchi Welfare Organization, and Madar, Shayestegan, Amin Welfare Organizations) IG probiotics + selenium: n = 27 Age (mean ± SD): 76.2 ± 8.1 years BMI (mean ± SD): 20.7 ± 3.2 kg/m² CG1 selenium: n = 26 Age (mean ± SD): 78.8 ± 10.2 years BMI (mean ± SD): 21.2 ± 1.2 kg/m² CG2 placebo: n = 26 Age (mean ± SD):78.5 ± 8.0 years BMI (mean + SD): 21.5 ± 2.4 kg/m² Withdrawals (n = 11), personal reasons: CG1 n = 4, CG2 n = 4, IG n = 3 27 participants IG 26 participants CG1 26 participants in CG2	2 × 10⁹ CFU/day of each strain + 200 µg/day selenium 1 capsule orally Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium longum (Tak Gen Zist Pharmaceutical Company; Tehran, Iran) Selenium 200 µg/day 1 capsule orally (Naturals Pharmaceutical Company; Coquitlam, Canada) Placebo: starch 1 capsule orally (Tak Gen Zist Pharmaceutical Company; Tehran, Iran) 12 weeks	Cognitive function: MMSE Oxidative stress: CT GSH MDA NO Inflammation: IL-8 TNF-α TGF-β hs-CRP Biochemicals: INS HOMA-IR LDL HDL TG VLDL QUICKI LDLR PPAR-γ	IG vs. CG1 * ↑ MMSE ↓ TNF-α ↔ IL-8 ↔ TGF-β ↓ hs-CRP ↑ TAC ↑ GSH ↔ MDA ↔ NO ↓ INS ↓ HOMA-IR ↓ LDL ↔ HDL ↓ TG ↔ VLDL ↔ QUICKI ↑ LDLR ↑ PPAR-γ

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♂: male; ♀: female; ↑: non-significant increase; ↓: non-significant decrease; ↔: no significant change; * ↑: significant increase; * ↓: significant decrease; 8-OHdG: ultrasensitive 8-hydroxy-2’-deoxyguanosine; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive; BADL: basic activities of daily living; BDNF: brain-derived neurotrophic factor; BMI: body mass index; CDR: Clinical Dementia Rating; CFT: Categorical Verbal Fluency Test; CFU: colony-forming units; CG: control group; DASS-21: anxiety, depression, and stress scale; DSM-V: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; FAST: Functional Assessment Staging Tool; FPG: fasting plasma glucose; GAD-7: Generalized Anxiety Disorder-7; GSH: total glutathione; HOMA-β: Homeostasis Model Assessment of pancreatic β cells; HDL: high-density lipoproteins; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; hs-CRP: high-sensitivity C-reactive protein; IADL: instrumental activities of daily living; IG: intervention group; IL: interleukin; INS: insulin; kg: kilograms; LDL: low-density lipoproteins; LDLR: low-density lipoprotein receptor; m²: square meters; MDA: malondialdehyde; MMSE: Mini-Mental State Examination; NI-AAA: National Institute on Aging and Alzheimer’s Association; NIH TCB: NIH (US National Institutes of Health) cognitive battery; NINDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; NO: nitric oxide; PCC: protein carbonyl content; PPAR-γ: peroxisome proliferator-activated receptor gamma; QUICKI: Quantitative Insulin Sensitivity Check Index; SD: standard deviation; SOD: superoxide dismutase antioxidant; TAC: total antioxidant capacity; TC: total cholesterol; TG: triglycerides; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; TYM: test your memory; VLDL: very-low-density lipoprotein. ¹ Probiotic intake of 5 × 10⁷ CFU is considered insufficient to achieve the benefits described by the International Scientific Association for Probiotics and Prebiotics (2025).

Supplementary materials

The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1004140_sup_1.pdf.

Declarations

Acknowledgments

The authors would like to thank the Neurobiology Research Group at the University of Valladolid and the Department of Cell Biology, Genetics, Histology, and Pharmacology at the University of Valladolid School of Medicine for their collaboration in conducting this review and providing infrastructure.

Author contributions

DFL: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Visualization, Supervision. AMCSM: Data curation, Investigation, Writing—original draft. AMFA: Investigation, Writing—review & editing. BVO: Investigation, Writing—review & editing. JMA: Investigation, Writing—review & editing. GS: Conceptualization, Writing—review & editing, Visualization. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The datasets supporting the findings of this study are available from the corresponding author upon reasonable request.

Funding

The research is funded by the TCUE 2024-2027 Plan, approved by agreement on September 16, 2024, and has been selected within the framework of an operational program co-financed by the European Regional Development Fund (ERDF) and the Regional Government of Castile and León (067/230003 POC). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14:32. [DOI] [PubMed] [PMC]

Dementia [Internet]. WHO: c2026 [cited 2025 Nov 24]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia

Fuentes P. Alzheimer’s disease: A historical note. Rev Chil Neuropsiquiatr. 2003;41:9–12. Spanish. [DOI]

Seabury J, Weinstein J, Varma A, Rosero SJ, Engebrecht C, Arky A, et al. Patient- and Caregiver-Reported Impact of Symptoms in Alzheimer Disease, Mild Cognitive Impairment, and Dementia. Neurol Clin Pract. 2025;15:e200418. [DOI] [PubMed] [PMC]

Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener. 2020;15:40. [DOI] [PubMed] [PMC]

Bello-Corral L, Seco-Calvo J, Celorrio San Miguel M, Garrosa E, Fernández-Lázaro D, Sánchez-Valdeón L. Evaluating the Link Between Cardiovascular Risk and Alzheimer’s Disease: A Comprehensive Case-Control Study in Castilla y León, Spain. Appl Sci. 2025;15:3409. [DOI]

Bello-Corral L, Seco-Calvo J, Molina Fresno A, González AI, Llorente A, Fernández-Lázaro D, et al. Prevalence of ApoE Alleles in a Spanish Population of Patients with a Clinical Diagnosis of Alzheimer’s Disease: An Observational Case-Control Study. Medicina (Kaunas). 2024;60:1941. [DOI] [PubMed] [PMC]

Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal. 2012;2012:756357. [DOI] [PubMed] [PMC]

Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575–90. [DOI] [PubMed] [PMC]

10.

Serra J. Intestinal microbiota. Aten Primaria. 2016;48:345–6. Spanish. [DOI] [PubMed] [PMC]

11.

Kelsen JR, Wu GD. The gut microbiota, environment and diseases of modern society. Gut Microbes. 2012;3:374–82. [DOI] [PubMed] [PMC]

12.

Bajinka O, Tan Y, Abdelhalim KA, Özdemir G, Qiu X. Extrinsic factors influencing gut microbes, the immediate consequences and restoring eubiosis. AMB Express. 2020;10:130. [DOI] [PubMed] [PMC]

13.

Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021;70:1174–82. [DOI] [PubMed] [PMC]

14.

Zheng Y, Bonfili L, Wei T, Eleuteri AM. Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders. Nutrients. 2023;15:4631. [DOI] [PubMed] [PMC]

15.

Zhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L, et al. Gut Microbiota is Altered in Patients with Alzheimer’s Disease. J Alzheimers Dis. 2018;63:1337–46. [DOI] [PubMed]

16.

Loh JS, Mak WQ, Tan LKS, Ng CX, Chan HH, Yeow SH, et al. Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. 2024;9:37. [DOI] [PubMed] [PMC]

17.

Baldi S, Mundula T, Nannini G, Amedei A. Microbiota shaping - the effects of probiotics, prebiotics, and fecal microbiota transplant on cognitive functions: A systematic review. World J Gastroenterol. 2021;27:6715–32. [DOI] [PubMed] [PMC]

18.

Mercado-Monroy J, Falfán-Cortés RN, Muñóz-Pérez VM, Gómez-Aldapa CA, Castro-Rosas J. Probiotics as modulators of intestinal barrier integrity and immune homeostasis: a comprehensive review. J Sci Food Agric. 2025;[Epub ahead of print]. [DOI] [PubMed]

19.

Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018;1693:128–33. [DOI] [PubMed] [PMC]

20.

Gulliver EL, Young RB, Chonwerawong M, D’Adamo GL, Thomason T, Widdop JT, et al. Review article: the future of microbiome-based therapeutics. Aliment Pharmacol Ther. 2022;56:192–208. [DOI] [PubMed] [PMC]

21.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. [DOI] [PubMed] [PMC]

22.

Santos DHM, Magnani AB. Evidence-Based Law: A New Approach to Legal Practice under the Scope of the Pragmatic Methodologies of Evidence-Based Medicine. Beijing Law Rev. 2024;15:1493–504. [DOI]

23.

Brown P, Brunnhuber K, Chalkidou K, Chalmers I, Clarke M, Fenton M, et al. How to formulate research recommendations. BMJ. 2006;333:804–6. [DOI] [PubMed] [PMC]

24.

Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. [DOI] [PubMed] [PMC]

25.

Law M, Stewart D, Pollock N, Letts L, Bosch J, Westmorland M. Guidelines for Critical Review of Qualitative Studies. Hamilton, ON, Canada: McMaster University Occupational Therapy Evidence-Based Practice Research Group; 1998.

26.

Moseley AM, Elkins MR, Van der Wees PJ, Pinheiro MB. Using research to guide practice: The Physiotherapy Evidence Database (PEDro). Braz J Phys Ther. 2020;24:384–91. [DOI] [PubMed] [PMC]

27.

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al.; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [DOI] [PubMed] [PMC]

28.

Agahi A, Hamidi GA, Daneshvar R, Hamdieh M, Soheili M, Alinaghipour A, et al. Does Severity of Alzheimer’s Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial. Front Neurol. 2018;9:662. [DOI] [PubMed] [PMC]

29.

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. [DOI] [PubMed] [PMC]

30.

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. [DOI] [PubMed] [PMC]

31.

Hsu YC, Huang YY, Tsai SY, Kuo YW, Lin JH, Ho HH, et al. Efficacy of Probiotic Supplements on Brain-Derived Neurotrophic Factor, Inflammatory Biomarkers, Oxidative Stress and Cognitive Function in Patients with Alzheimer’s Dementia: A 12-Week Randomized, Double-Blind Active-Controlled Study. Nutrients. 2023;16:16. [DOI] [PubMed] [PMC]

32.

Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N, Kouchaki E, Bahmani F, Aghadavod E, et al. 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;38:2569–75. [DOI] [PubMed]

33.

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9. [DOI] [PubMed] [PMC]

34.

Jack CR Jr, 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. Alzheimers Dement. 2011;7:257–62. [DOI] [PubMed] [PMC]

35.

Probiotics [Internet]. [cited 2025 Nov 29]. Available from: https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/

36.

Mitchell AJ. The Mini-Mental State Examination (MMSE): An Update on Its Diagnostic Validity for Cognitive Disorders. In: Larner AJ, editor. Cognitive screening instruments: A practical approach. Springer-Verlag Publishing; 2013. pp. 15–46. [DOI]

37.

Katz S. Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc. 1983;31:721–7. [DOI] [PubMed]

38.

Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092–7. [DOI] [PubMed]

39.

Guarino A, Favieri F, Boncompagni I, Agostini F, Cantone M, Casagrande M. Executive Functions in Alzheimer Disease: A Systematic Review. Front Aging Neurosci. 2019;10:437. [DOI] [PubMed] [PMC]

40.

Sánchez-Valdeón L, Bello-Corral L, Mayo-Iscar A, Fernández-Lázaro D, Seco-Calvo J. Impact of discontinuing non-pharmacological interventions on cognitive impairment in dementia patients by COVID-19 lockdown. A pilot observational, longitudinal, retrospective study carried out in an adult day center in Spain during the COVID-19 pandemic. Front Med (Lausanne). 2023;10:1204151. [DOI] [PubMed] [PMC]

41.

Zhu G, Zhao J, Zhang H, Chen W, Wang G. Probiotics for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis. Foods. 2021;10:1672. [DOI] [PubMed] [PMC]

42.

Tripathi S, Kaushik M, Dwivedi R, Tiwari P, Tripathi M, Dada R. The effect of probiotics on select cognitive domains in mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis Rep. 2024;8:1422–33. [DOI] [PubMed] [PMC]

43.

Akyuz E, Arulsamy A, Aslan FS, Sarisözen B, Guney B, Hekimoglu A, et al. An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission. Mol Neurobiol. 2025;62:1631–74. [DOI] [PubMed] [PMC]

44.

Mombelli E, Lopizzo N, Marizzoni M, Mirabelli P, Luongo D, Salvatore M, et al. Effect of a Probiotic Administration on Inflammatory Profile and Clinical Features in Patients with Alzheimer’s Disease. Alzheimers Dement. 2020;16:e042737. [DOI]

45.

Kim H, Kim JS, Kim YG, Jeong Y, Kim JE, Paek NS, et al. Antioxidant and Probiotic Properties of Lactobacilli and Bifidobacteria of Human Origins. Biotechnol Bioproc E. 2020;25:421–30. [DOI]

46.

Ouanes S, Popp J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front Aging Neurosci. 2019;11:43. [DOI] [PubMed] [PMC]

47.

Dash UC, Bhol NK, Swain SK, Samal RR, Nayak PK, Raina V, et al. Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications. Acta Pharm Sin B. 2025;15:15–34. [DOI] [PubMed] [PMC]

48.

Wang Y, Wu Y, Wang Y, Xu H, Mei X, Yu D, et al. Antioxidant Properties of Probiotic Bacteria. Nutrients. 2017;9:521. [DOI] [PubMed] [PMC]

49.

Kleniewska P, Pawliczak R. The Link Between Dysbiosis, Inflammation, Oxidative Stress, and Asthma-The Role of Probiotics, Prebiotics, and Antioxidants. Nutrients. 2024;17:16. [DOI] [PubMed] [PMC]

50.

Martarelli D, Verdenelli MC, Scuri S, Cocchioni M, Silvi S, Cecchini C, et al. Effect of a probiotic intake on oxidant and antioxidant parameters in plasma of athletes during intense exercise training. Curr Microbiol. 2011;62:1689–96. [DOI] [PubMed]

51.

Shen Q, Shang N, Li P. In vitro and in vivo antioxidant activity of Bifidobacterium animalis 01 isolated from centenarians. Curr Microbiol. 2011;62:1097–103. [DOI] [PubMed]

52.

Bao Y, Wang Z, Zhang Y, Zhang J, Wang L, Dong X, et al. Effect of Lactobacillus Plantarum P-8 on Lipid Metabolism in Hyperlipidemic Rat Model. Eur J Lipid Sci Technol. 2012;114:1230–6. [DOI]

53.

Chandrasekaran P, Weiskirchen S, Weiskirchen R. Effects of Probiotics on Gut Microbiota: An Overview. Int J Mol Sci. 2024;25:6022. [DOI] [PubMed] [PMC]

54.

Xie J, Van Hoecke L, Vandenbroucke RE. The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology. Front Immunol. 2022;12:796867. [DOI] [PubMed] [PMC]

55.

Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87:10–20. [DOI] [PubMed] [PMC]

56.

Obianwuna UE, Agbai Kalu N, Wang J, Zhang H, Qi G, Qiu K, et al. Recent Trends on Mitigative Effect of Probiotics on Oxidative-Stress-Induced Gut Dysfunction in Broilers under Necrotic Enteritis Challenge: A Review. Antioxidants (Basel). 2023;12:911. [DOI] [PubMed] [PMC]

57.

Fernández-Lázaro D, Sánchez-Serrano N, Rabail R, Aadil RM, Mielgo-Ayuso J, Radesca Fabiano K, et al. Is Probiotics Supplementation an Appropriate Strategy to Modulate Inflammation in Physically Active Healthy Adults or Athletes? A Systematic Review. Appl Sci. 2023;13:3448. [DOI]

58.

De Marco S, Sichetti M, Muradyan D, Piccioni M, Traina G, Pagiotti R, et al. Probiotic Cell-Free Supernatants Exhibited Anti-Inflammatory and Antioxidant Activity on Human Gut Epithelial Cells and Macrophages Stimulated with LPS. Evid Based Complement Alternat Med. 2018;2018:1756308. [DOI] [PubMed] [PMC]

59.

Cristofori F, Dargenio VN, Dargenio C, Miniello VL, Barone M, Francavilla R. Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body. Front Immunol. 2021;12:578386. [DOI] [PubMed] [PMC]

60.

Aparicio-Pascual D, Clemente-Suárez VJ, Tornero-Aguilera JF, Rubio-Zarapuz A. The Effect of Probiotic Supplementation on Cytokine Modulation in Athletes After a Bout of Exercise: A Systematic Review and Meta-Analysis. Sports Med Open. 2025;11:58. [DOI] [PubMed] [PMC]

61.

Romero-Ferreiro V, García-Fernández L, Biscaia JM, Romero C, González-Soltero R, De la Fuente M, et al. Effect of probiotics on C-reactive protein levels in schizophrenia: Evidence from a systematic review and meta-analysis. Complement Ther Med. 2025;89:103126. [DOI] [PubMed]

62.

Bohlouli J, Namjoo I, Borzoo-Isfahani M, Hojjati Kermani MA, Balouch Zehi Z, Moravejolahkami AR. Effect of probiotics on oxidative stress and inflammatory status in diabetic nephropathy: A systematic review and meta-analysis of clinical trials. Heliyon. 2021;7:e05925. [DOI] [PubMed] [PMC]

63.

Lazou-Ahrén I, Björklund M, Molin G, Xu J, Önning G, Elmståhl S, et al. Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. Probiotics Antimicrob Proteins. 2025;17:3429–39. [DOI] [PubMed] [PMC]

64.

Wang Y, Ai Z, Xing X, Fan Y, Zhang Y, Nan B, et al. The ameliorative effect of probiotics on diet-induced lipid metabolism disorders: A review. Crit Rev Food Sci Nutr. 2024;64:3556–72. [DOI] [PubMed]

65.

Jones ML, Martoni CJ, Parent M, Prakash S. Cholesterol-lowering efficacy of a microencapsulated bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 yoghurt formulation in hypercholesterolaemic adults. Br J Nutr. 2012;107:1505–13. [DOI] [PubMed]

66.

Zarezadeh M, Musazadeh V, Faghfouri AH, Roshanravan N, Dehghan P. Probiotics act as a potent intervention in improving lipid profile: An umbrella systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2023;63:145–58. [DOI] [PubMed]

67.

Jia B, Zou Y, Han X, Bae JW, Jeon CO. Gut microbiome-mediated mechanisms for reducing cholesterol levels: implications for ameliorating cardiovascular disease. Trends Microbiol. 2023;31:76–91. [DOI] [PubMed]

68.

Wang G, Huang W, Xia Y, Xiong Z, Ai L. Cholesterol-lowering potentials of Lactobacillus strain overexpression of bile salt hydrolase on high cholesterol diet-induced hypercholesterolemic mice. Food Funct. 2019;10:1684–95. [DOI] [PubMed]

69.

Gao J, Mang Q, Sun Y, Xu G. Probiotic Supplementation Improves Lipid Metabolism Disorders and Immune Suppression Induced by High-Fat Diets in Coilia nasus Liver. Biology (Basel). 2025;14:381. [DOI] [PubMed] [PMC]

70.

Kumar M, Rakesh S, Nagpal R, Hemalatha R, Ramakrishna A, Sudarshan V, et al. Probiotic Lactobacillus rhamnosus GG and Aloe vera gel improve lipid profiles in hypercholesterolemic rats. Nutrition. 2013;29:574–9. [DOI] [PubMed]

71.

Park S, Kang J, Choi S, Park H, Hwang E, Kang YG, et al. Cholesterol-lowering effect of Lactobacillus rhamnosus BFE5264 and its influence on the gut microbiome and propionate level in a murine model. PLoS One. 2018;13:e0203150. [DOI] [PubMed] [PMC]

72.

Choi ID, Kim SH, Jeong JW, Lee DE, Huh CS, Hong SS, et al. Triglyceride-Lowering Effects of Two Probiotics, Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601, in a Rat Model of High-Fat Diet-Induced Hypertriglyceridemia. J Microbiol Biotechnol. 2016;26:483–7. [DOI] [PubMed]

73.

Ren T, Zhu J, Zhu L, Cheng M. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α. Nutrients. 2017;9:198. [DOI] [PubMed] [PMC]

74.

Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022;611:769–79. [DOI] [PubMed] [PMC]

75.

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease – is this type 3 diabetes? J Alzheimers Dis. 2005;7:63–80. [DOI] [PubMed]

76.

Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A. Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol. 2013;47:1045–65. [DOI] [PubMed]

77.

Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38. [DOI] [PubMed] [PMC]

78.

Kasińska MA, Drzewoski J. Effectiveness of probiotics in type 2 diabetes: a meta-analysis. Pol Arch Med Wewn. 2015;125:803–13. [DOI] [PubMed]

79.

Mazloom Z, Yousefinejad A, Dabbaghmanesh MH. Effect of probiotics on lipid profile, glycemic control, insulin action, oxidative stress, and inflammatory markers in patients with type 2 diabetes: a clinical trial. Iran J Med Sci. 2013;38:38–43. [PubMed] [PMC]

80.

Pegah A, Abbasi-Oshaghi E, Khodadadi I, Mirzaei F, Tayebinai H. Probiotic and resveratrol normalize GLP-1 levels and oxidative stress in the intestine of diabetic rats. Metabol Open. 2021;10:100093. [DOI] [PubMed] [PMC]

81.

Di Dio M, Calella P, Pelullo CP, Liguori F, Di Onofrio V, Gallè F, et al. Effects of Probiotic Supplementation on Sports Performance and Performance-Related Features in Athletes: A Systematic Review. Int J Environ Res Public Health. 2023;20:2226. [DOI] [PubMed] [PMC]

82.

Jarrett H, Medlin S, Morehen JC. The Role of the Gut Microbiome and Probiotics in Sports Performance: A Narrative Review Update. Nutrients. 2025;17:690. [DOI] [PubMed] [PMC]

83.

Aykut MN, Erdoğan EN, Çelik MN, Gürbüz M. An Updated View of the Effect of Probiotic Supplement on Sports Performance: A Detailed Review. Curr Nutr Rep. 2024;13:251–63. [DOI] [PubMed] [PMC]

84.

Khedr EM, Omeran N, Karam-Allah Ramadan H, Ahmed GK, Abdelwarith AM. Alteration of Gut Microbiota in Alzheimer’s Disease and Their Relation to the Cognitive Impairment. J Alzheimers Dis. 2022;88:1103–14. [DOI] [PubMed]

85.

Kumar A, Sivamaruthi BS, Dey S, Kumar Y, Malviya R, Prajapati BG, et al. Probiotics as modulators of gut-brain axis for cognitive development. Front Pharmacol. 2024;15:1348297. [DOI] [PubMed] [PMC]

86.

Su Y, Wang D, Liu N, Yang J, Sun R, Zhang Z. Clostridium butyricum improves cognitive dysfunction in ICV-STZ-induced Alzheimer’s disease mice via suppressing TLR4 signaling pathway through the gut-brain axis. PLoS One. 2023;18:e0286086. [DOI] [PubMed] [PMC]

87.

Zhu X, Shen J, Feng S, Huang C, Wang H, Huo F, et al. Akkermansia muciniphila, which is enriched in the gut microbiota by metformin, improves cognitive function in aged mice by reducing the proinflammatory cytokine interleukin-6. Microbiome. 2023;11:120. [DOI] [PubMed] [PMC]

88.

Zhou Y, Wang Y, Quan M, Zhao H, Jia J. Gut Microbiota Changes and Their Correlation with Cognitive and Neuropsychiatric Symptoms in Alzheimer’s Disease. J Alzheimers Dis. 2021;81:583–95. [DOI] [PubMed]

89.

Yang J, Wang L, Liu H, Xu H, Liu F, Song H, et al. Dysregulation of Ruminococcaceae and Megamonas could be predictive markers for rapid progression of mild cognitive impairment. Microb Pathog. 2023;183:106272. [DOI] [PubMed]

90.

Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, Anan Y, et al. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci. 2014;6:69. [DOI] [PubMed] [PMC]

91.

Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J. BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cell Mol Neurobiol. 2018;38:579–93. [DOI] [PubMed] [PMC]

92.

Ng TKS, Ho CSH, Tam WWS, Kua EH, Ho RC. Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer’s Disease (AD): A Systematic Review and Meta-Analysis. Int J Mol Sci. 2019;20:257. [DOI] [PubMed] [PMC]

93.

Dehghani F, Abdollahi S, Shidfar F, Clark CCT, Soltani S. Probiotics supplementation and brain-derived neurotrophic factor (BDNF): a systematic review and meta-analysis of randomized controlled trials. Nutr Neurosci. 2023;26:942–52. [DOI] [PubMed]

94.

Ngoc APT, Zahoor A, Kim DG, Yang SH. Using Synbiotics as a Therapy to Protect Mental Health in Alzheimer’s Disease. J Microbiol Biotechnol. 2024;34:1739–47. [DOI] [PubMed] [PMC]

95.

Molska M, Mruczyk K, Cisek-Woźniak A, Prokopowicz W, Szydełko P, et al. The Influence of Intestinal Microbiota on BDNF Levels. Nutrients. 2024;16:2891. [DOI] [PubMed] [PMC]

96.

Handajani YS, Hengky A, Schröder-Butterfill E, Hogervorst E, Turana Y. Probiotic supplementation improved cognitive function in cognitively impaired and healthy older adults: a systematic review of recent trials. Neurol Sci. 2023;44:1163–9. [DOI] [PubMed]

97.

Mendez MF. The Relationship Between Anxiety and Alzheimer’s Disease. J Alzheimers Dis Rep. 2021;5:171–7. [DOI] [PubMed] [PMC]

98.

Ferrari S, Mulè S, Parini F, Galla R, Ruga S, Rosso G, et al. The influence of the gut-brain axis on anxiety and depression: A review of the literature on the use of probiotics. J Tradit Complement Med. 2024;14:237–55. [DOI] [PubMed] [PMC]