Relationship Between the Gut Microbiota and Alzheimer’s Disease: A Systematic Review

Abstract

Background: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated. Objective: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer’s disease. Method: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish. Results: Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review. Conclusion: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

“…An improved understanding of LPS molecular genetic interactions along the GI tract–CNS axis involving GI-tract-derived microbial neurotoxins, AD and other related disorders should further support the hypothesis of altered LPS–miRNA–mRNA coupled signaling networks, and these concepts are currently supported by recently described experimental-findings in the scientific literature [ 29 , 30 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 ]. For example, targeting and/or modulating GI-tract-microbiome-LPS-mediated, miRNA-30b-regulated NF-L pathways and other miRNA-mediated gene expression circuitry could be valuable in the design of future therapeutic strategies that: (i) could support and maintain cytoarchitectural components essential for neuronal shape, axonal caliber, inter-neuronal signaling and synaptic plasticity; and (ii) may more effectively manage the many neurological diseases in which NF-L gene expression and abundance play a defining and/or determinant role [ 29 , 39 , 55 , 56 , 57 ]. Recent emerging evidence on dietary-based modifications of microbial dysbiosis may also be an attractive means to alter the abundance, speciation and complexity of enterotoxigenic forms of AD-relevant microbes such as B. fragilis and their potential for their long-term pathological discharge of highly neurotoxic microbial-derived glycolipid/lipoglycan secretions such as LPS [ 51 , 52 , 58 , 59 , 60 ] ( Figure 2 ).…”

“…Early studies suggested that the identification and characterization of unique microbial signatures in neuropsychiatric diseases could provide new possibilities in targeted anti- or pro-biotic treatments [ 31 , 32 ]. However, HMP and parallel GI-tract microbiome studies involving multiple human populations and animal models of AD provided evidence indicating that due to wide variation in the microbial and genetic composition of individual GI-tract microbiomes even during healthy aging, it would be difficult to associate the abundance, speciation and/or complexity of any single microbial genus, species or classification with any single human disease [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 45 , 47 , 55 , 59 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. This is especially relevant to highly complex and heterogeneous neurological syndromes, such as AD, prion disease and other age-related neurodegenerative disorders, against their complex background of familial genetics, patient age, gender, drug history, age of onset and duration, inter-current disease and other critical environmental and lifestyle risk factors [ 61 , 62 , 63 , 70 ].…”

“…MicroRNA miRNA-30b was previously implicated in targeting inflammasome function [ 36 , 39 ]. Importantly, the sensitivity of a small pro-inflammatory microRNA family consisting of miRNA-30b, miRNA-34a, miRNA-146a, miRNA-155 and others to NF-kB (p50/p65) signaling appears to be in part be due to the presence of one-to-several NF-kB-DNA-binding sites in the immediate promoters of the genes encoding these miRNAs [ 35 , 38 , 39 , 40 , 49 , 50 , 53 , 54 , 55 , 56 ]. An improved understanding of LPS molecular genetic interactions along the GI tract–CNS axis involving GI-tract-derived microbial neurotoxins, AD and other related disorders should further support the hypothesis of altered LPS–miRNA–mRNA coupled signaling networks, and these concepts are currently supported by recently described experimental-findings in the scientific literature [ 29 , 30 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 ].…”

“…Importantly, the sensitivity of a small pro-inflammatory microRNA family consisting of miRNA-30b, miRNA-34a, miRNA-146a, miRNA-155 and others to NF-kB (p50/p65) signaling appears to be in part be due to the presence of one-to-several NF-kB-DNA-binding sites in the immediate promoters of the genes encoding these miRNAs [ 35 , 38 , 39 , 40 , 49 , 50 , 53 , 54 , 55 , 56 ]. An improved understanding of LPS molecular genetic interactions along the GI tract–CNS axis involving GI-tract-derived microbial neurotoxins, AD and other related disorders should further support the hypothesis of altered LPS–miRNA–mRNA coupled signaling networks, and these concepts are currently supported by recently described experimental-findings in the scientific literature [ 29 , 30 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 ]. For example, targeting and/or modulating GI-tract-microbiome-LPS-mediated, miRNA-30b-regulated NF-L pathways and other miRNA-mediated gene expression circuitry could be valuable in the design of future therapeutic strategies that: (i) could support and maintain cytoarchitectural components essential for neuronal shape, axonal caliber, inter-neuronal signaling and synaptic plasticity; and (ii) may more effectively manage the many neurological diseases in which NF-L gene expression and abundance play a defining and/or determinant role [ 29 , 39 , 55 , 56 , 57 ].…”

Modulation of the intestinal microbiota impacts the efficacy of immunotherapy in cancer patients – A recent literature survey

“…Finally, recent research results suggest a deep impact of the gut microbiota on brain functions (“gut-brain axis”). For instance, associations of distinct gut microbiota signatures with autism spectrum disorders such as the ADNP syndrome, with Alzheimer's disease, and with other morbidities of the nervous system have been described [ 19–21 ].…”