Administration of pre/probiotics with conventional drug treatment in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease with long preclinical phase, typically followed by a slow decline in memory,thinking and reasoning abilities. The underlying pathological processes are not yet fully elucidated, although two main disease hallmarks have been associated with AD pathology: amyloid beta species and neurofibrillary tangles. The plaques are deposits of a protein fragment called beta-amyloid (Aβ), which accumulates in the spaces between neurons. Tangles are twisted fibers of the tau protein, which accumulates inside the cells.

AD is not curable, although some treatments to reduce symptoms are available. Currently, there are five AD drugs approved by the U.S.Food and Drug Administration that treat the symptoms of AD —temporarily helping memory and thinking problems. Four are cholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil)and the other (memantine) is an N-methyl-D-Aspartate (NMDA)receptor antagonist. However, these medications can only temporarily improve memory, quality of life of patients and decrease burden for caregivers.

Among the causes of the disease, the “inflammation hypothesis”of AD has emerged in the recent years and it is based on findings on cells of the immune response in central nervous system (CNS). It is known that microglia and astrocytes initiate the immune response in the brain after exposure to pathogens. However, when the activation of the immune system is permanent, a condition called neuroinflammation is established, causing damage to CNS neurons. In AD,a chronic neuroinflammatory state with release of proinflammatory cytokines has been observed, which appears to be correlated to the constant accumulation of Aβ within neurons. It is not clear whether the chronic neuroinflammation precedes the onset of the disease or is a consequence of Aβ accumulation. It has been hypothesized that the chronic neuroinflammation observed in AD is associated with an alteration of the balance of gut microbiota, a phenomenon known as dysbiosis, which can negatively affect neuronal activity (Jiang et al.,2017).

Gut microbiota are able to influence brain activity through either immune/humoral activity or the vagus nerve that connects intestinal neurons with those of the CNS. In this way, disturbance in gut microbiota can cause brain dysfunctions. The term Microbiota-Gut-Brain Axis has been introduced to describe this interaction, but the association between gut microbiota and AD is also related to the role of inflammation in the development and course of AD.

Some theories have been developed to explain the role of gut microbiota in inducing a chronic neuroinflammation in AD. The most important are: (1) a direct microbial infection inducing a neuroinflammatory state in the brain of AD patients; (2) an age-related dysbiosis”, which hypothesizes that AD arises during the process of aging of the immune system; (3) an antimicrobial protection hypothesis,which suggests that the accumulation of Aβ in the brain represents an immune response to the accumulation of harmful bacteria; and (4)the hygiene hypothesis of AD, which indicates in an excessive sanitation in early life the cause of late impaired function of the immune system.

In a recent publication, we examined in detail the scientific evidence for the role of gut microbiota in AD and the possible effects of compounds that alter its composition, such as pre- and probiotics and antibiotics (Angelucci et al., 2019).

The interactions among different factors in AD, such as individual's genetics, physical activity, lifestyle (including diet) and the use of medications, is very complex. The role of pre- and probiotics seems to be beneficial in restoring the balance of gut microbiota. Antibiotics can actually have a double action, positive or negative, depending on their specific microbiome target. Antibiotics that eradicate potentially harmful bacteria like Helicobacter pylori can have beneficial effects on the disease, while antibiotics that destroy so-called good bacteria can accelerate AD related pathology. In this scenario, we hypothesized that the use of agents that act on gut microbiota can have synergistic effect on AD treatments. However, because the role of gut microbiota in the disease has not been clearly identified, the use of pre or probiotics as AD therapy is still far from a practical application.

Nonetheless, interesting considerations can be made. First, we can try to understand if the current available treatments act positively or negatively on the composition of the gut microbiota. In this regard,the data present in the literature are very scarce but provide some interesting information. It has been shown that some pesticides with an inhibitory action on acetylcholinesterase resembling those of AD medications can affect the gut microbiota composition in laboratory animals, such as rodents (Liang et al., 2019) and zebrafish (Wang et al., 2019). Negative effects on gut microbiota were also found in rats treated with high doses of Tacrine (Yip et al., 2018).

From these data two conclusions can be drawn: (1) AD drugs that have negative effects on gut microbiota could lead to a worsening of the disease in the long term, although temporarily alleviating the symptoms; (2) it is possible that an adjuvant treatment with pre/probiotics can prevent and/or cure gut dysbiosis and, therefore, allow the therapeutic effects of AD drugs to be exploited more completely. In theory, if gut dysbiosis contributes to sustain the course of the disease and the current AD drugs may induce it, it is possible to hypothesize an explanation for the lack of permanent beneficial effects on disease progression and for the clinical observation that some patients are non-responders.

The concept of making the neurotransmitter acetylcholine available, or limiting the neuronal excitability with NMDA receptor antagonist, certainly has an important scientific rationale and it is supported by robust preclinical and clinical evidence. However, it must be considered that, if these beneficial effects are counteracted by a gut dysbiosis contributing to the progression of the disease, the curative potential of these treatments can be reduced.

Furthermore, the role of dysbiosis in AD drug development has been rather underestimated in the past. In in vitro pharmacological studies performed to characterize these and new therapeutic compounds, neuronal cell lines are normally used in absence of other cellular elements potentially influenced by gut microbiota, such as glial cells, cells of the immune response, and immune and endocrine molecules, such as cytokines and hormones. In in vivo studies using animal models of the disease, the role of gut microbiota in altering the activity of brain neurons is certainly less evident than in humans where cognitive brain functions are far more complex.

Much emphasis has been given to the failure of clinical trials with new compounds capable of reducing the accumulation of Aβ and tau proteins through various mechanisms. Among the possible side effects not properly investigated, an alteration of the intestinal flora composition cannot be excluded, especially for drugs taken orally.Not surprisingly, the search for new compounds is also shifting towards anti-inflammatory drugs that stimulate immune processes.These drugs could protect brain neurons from toxic proteins, including those produced by gut microbiota, such as pro-inflammatory cytokines and other innate immune activators.

It would therefore be interesting to study the effects of both novel and currently available drugs in association with treatments designed to restore and/or protect the composition of the gut microbiota. In this regard, some studies suggest that treatments based on substances regulating gut microbiota, i.e., tuna oil or algae oil, can lead to improved learning and cognition in mice exposed to aging-inducing agents (Zhang et al., 2018). Furthermore, these effects are comparable to those obtained with donezepil (Zhang et al., 2018).

Supporting this notion, it has been shown that healthy dietary patterns characterized by high intake of probiotics and prebiotics,in association to other nutrients, delay neurocognitive decline and reduce the risk of AD (Pistollato et al., 2018). In addition, it has been demonstrated that a diet rich in probiotics not only affect normal brain activity but also induces significant cognitive improvements in AD patients (Akbari et al., 2016). Also, in transgenic AD mice treated with pre and probiotics, increased cognitive performance and reduced number of Aβ plaques in the hippocampus have been observed(Abraham et al., 2019).

Figure 1 Putative synergistic action of pre/probiotics and AD drugs.

These data suggest that restoration of gut microbiota with pre and probiotics could be beneficial in AD and may affect the efficacy of the current medications, as we hypothesize in Figure 1. These adjuvant treatments could also interfere with the direct action of AD drugs on neurotransmitters, or target crucial molecules such as Aβ and tau proteins. It has been shown that the expression of hippocampal NMDA receptors (target of memantine) is dependent on the presence of gut microbiota, because it is significantly decreased in germ-free mice (Neufeld et al., 2011) and in rats treated with antibiotics (Wang et al., 2015). In addition, it has been recently demonstrated that pre/probiotics can reduce Aβ and tau proteins (targets of many AD drugs)and ameliorate cognition in rodent AD models. It was shown that rats injected with Aβ1-42and treated with probiotic substances display better memory and learning performance, reduced expression of intracellular Aβ and tau and oxidative stress biomarkers (Athari Nik Azm et al., 2018). In humans, avoidance to antibiotics, rich microbiota supplementation or variability in diet, like that of people who experience other eating habits while traveling, may be seen as beneficial.

In conclusion, the most recent data suggest that the association of pre/probiotic treatment with conventional drug treatments in Alzheimer is a field of investigation that may deserve some attention, given the repeated failures of new AD drugs in the clinic. It could be investigated whether the simultaneous administration of pre/probiotics and currently available medications (either separately or in one tablet)produces synergistic beneficial effects.

This work was supported by the Project No. LQ1605 from the National Program of Sustainability II (MEYS CR), the European Regional Development Fund-Project ENOCH (CZ.02.1.01/0.0/0.0/16_019/0000868), the Institutional Support of Excellence 2. LF UK (699012) and by the Grant Agency of Charles University (Project no. 176317); partially supported by the grants from the Ministry of Education, Youth and Sports of the Czech Republic (PROGRES Q40) and from the Ministry of Health of the Czech Republic (RVO-FN HK 00179906); supported by the project IT4Neuro(-degeneration), reg. nr. CZ.02.1.01/0.0/0.0/18_069/0010054.

Jakub Hort, Martin Valis, Francesco Angelucci＊Memory Clinic, Department of Neurology, 2ndFaculty of Medicine, Charles University and Motol University Hospital,Prague, Czech Republic (Hort J, Angelucci F)International Clinical Research Centre, St. Anne's University Hospital, Brno, Czech Republic (Hort J)Department of Neurology, University Hospital Hradec Králové,Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic (Valis M)

＊Correspondence to:Francesco Angelucci, PhD,francesco.angelucci@lfmotol.cuni.cz.

orcid:0000-0002-5956-5925 (Francesco Angelucci)

Received:July 3, 2019

Accepted:August 22, 2019

doi:10.4103/1673-5374.266057

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