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      Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer’s disease or mild cognitive impairment — a meta-analysis of randomized controlled trials

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          Abstract

          Probiotics are live microbes that confer health benefits to the host. Preliminary animal evidence supports the potential role of probiotics in ameliorating cognitive health, however, findings from clinical trials in Alzheimer’s disease (AD) or mild cognitive impairment (MCI) subjects are controversial. Thus, a meta-analysis is needed to clarify the efficacy of probiotics on cognition in AD or MCI patients. EMBASE, PubMed, Web of Science and Cochrane library were systematically searched and manually screened for relevant published randomized controlled trials (RCTs). Among the 890 citations identified, 5 studies involving 297 subjects met eligibility. There was a significant improvement in cognition (SMD = 0.37; 95% CI, 0.14, 0.61; P = 0.002; I 2 = 24%), while a significant reduction in malondialdehyde (SMD = −0.60; 95% CI, −0.91, −0.28; P = 0.000; I 2 = 0.0%) and high-sensitivity C-reactive protein (SMD = −0.57; 95% CI, −0.95, −0.20; P = 0.003; I 2 = 0.0%) post-intervention levels between the probiotics and control group. This meta-analysis indicated that probiotics improved cognitive performance in AD or MCI patients, possibly through decreasing levels of inflammatory and oxidative biomarkers. However, current evidence is insufficient, and more reliable evidence from large-scale, long-period, RCT is needed.

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          The gut microbiome in neurological disorders

          Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases. However, the field is nascent, and interpretation of such data is often difficult given that the composition of the microbiome is influenced by various factors such as diet and exercise. Longitudinal studies and randomised controlled trials in humans are needed to find out if targeting the microbiome can yield novel therapeutic strategies. Systems biology approaches will also be important in integrating such data with genomic and metabolomic datasets from clinical cohorts with neurological disease to help guide individual treatment selection.
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            Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

            Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.
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              Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment

              Background Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Herein, we examine how the gut microbiome differs in older adults with mild cognitive impairment compared to cognitively normal counterparts, and whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome signature in association with cerebrospinal fluid (CSF) AD biomarkers. Methods A randomized, double-blind, cross-over, single-center pilot study of MMKD versus American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 64.6 ± 6.4 yr), of which 11 have mild cognitive impairment, while 6 are cognitively normal. Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in CSF including amyloid β (Aβ)-40 and Aß-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. Findings At baseline, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures are detected in subjects with mild cognitive impairment. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in subjects with mild cognitive impairment. Several bacteria are differently affected by the two diets with distinct patterns between cognitively normal and impaired subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. Interpretation The data suggest that specific gut microbial signatures may depict the mild cognitive impairment and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in CSF.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                29 February 2020
                15 February 2020
                : 12
                : 4
                : 4010-4039
                Affiliations
                [1 ]State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing 400042, China
                [2 ]Department of Chemical Defense, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
                [3 ]Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
                Author notes
                Correspondence to: Mingliang Chen; email: chenmingliang1987@163.com
                Correspondence to: Zhongmin Zou; email: zouzhmin@yahoo.com
                Article
                102810 102810
                10.18632/aging.102810
                7066922
                32062613
                4c990384-c7a5-446d-81bf-19b2d0c49404
                Copyright © 2020 Den et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 July 2019
                : 24 January 2020
                Categories
                Review

                Cell biology
                probiotics,cognition,alzheimer’s disease,mild cognitive impairment,meta-analysis
                Cell biology
                probiotics, cognition, alzheimer’s disease, mild cognitive impairment, meta-analysis

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