Targeting Microbiota as a Novel Therapeutic Strategy: History
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Diana Filipa Silva
,
Nuno Empadinhas
,
Sandra Morais Cardoso
,
Ana Raquel Esteves
Gut microbiota are extremely dynamic and can be modified by genetic and environmental factors, such as exercise, diet, stress, and contaminants. On the other hand, gut microbiota influence human health by regulating metabolism, host immune response, inflammatory machinery, and detoxification mechanisms. Because alteration of the gut microbiota can induce changes in brain activity a new avenue for potential therapeutic manipulation of the microbiome in neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) has emerged. There are multiple gut microbiota interventions, including the administration of antibiotics, probiotics, prebiotics, or faecal microbiota transplantation (FMT).
  • Alzheimer’s disease
  • Parkinson’s disease
  • inflammation
  • oxidative stress

1. Antibiotics

Antibiotic treatment has been reported to change disease course in both PD and AD. For instance, minocycline was shown to have neuroprotective effects in the MPTP mouse model of PD by preventing nigrostriatal DA neurodegeneration and by blocking dopamine depletion in the striatum [1]. PD patients with Helicobacter pylori infection showed lower levodopa absorption, antibiotic treatment reduced gastritis, improved motor fluctuations, and levodopa pharmacokinetics [2]. On the other hand, a more recent trial reported that Helicobacter pylori eradication does not improve clinical outcomes in PD [3]. In AD patients, the elimination of Helicobacter pylori by a triple eradication regimen which included 2 antibiotics (clarithromycin, and amoxicillin) and omeprazole (used to treat gastric and duodenal ulcers) improved cognitive and functional parameters [4]. A study on healthy subjects pretreated with scopolamine to mimic AD showed a positive effect of D-cycloserine at low doses [5]. Moreover, the same antibiotic improved cognitive deficits in AD patients [6]. In APP/PS1 transgenic AD mouse model, the use of a long-term broad-spectrum combinatorial antibiotic treatment reduced Aβ plaque deposition [7]. Moreover, rifampicin administration in AD mice models and in humans was shown to reduce Aβ and pro-inflammatory cytokines brain levels [8]. Likewise, minocycline, which combines anti-inflammatory and antioxidant properties, showed similar effects, but also reduced microglia activation [9]. More recently, 5 × FAD mice treated with a mixture of antibiotics displayed attenuated hippocampal Aβ pathology and decreased neuronal loss, thereby delaying memory deficits [10].
However, all these antibiotics showed controversial results in clinical trials [11][12]. In line with this, antibiotics, besides their beneficial effect in some circumstances, are also potentially harmful agents, as their overuse has been linked to microbiota impairment and related disorders. In fact, streptozotocin have been used to induce sporadic AD in animal models [13]. Moreover, several studies reported a correlation between long-term use of antibiotics and increased risk for developing PD [14][15].

2. Probiotics and Prebiotics

Probiotics, called “good” microbes are specific microorganisms that produce beneficial effects on the host health by restoring microbiota and maintaining immune homeostasis, whereas prebiotics are soluble dietary fibres that beneficially affect the host by stimulating the growth and/or activity of specific bacteria in the gut.
The supplementation of a probiotic mix for 28 days improved the intestinal permeability of AD patients [16]. A randomized, double-blind, and controlled clinical trial was conducted in AD patients to assess the effects of probiotic supplementation and observed a positive effect on cognitive function and metabolic state [17]. Another clinical trial found that probiotic and selenium co-supplementation for 12 weeks improved cognitive function and some metabolic profiles in AD patients [18]. In an open-label, single-arm study oral supplementation of Bifidobacterium breve A1 in mild cognitive impairment participants improved cognitive function [19]. However, the supplementation in capsules containing another probiotic mix for 12 weeks did not improve memory scores, inflammatory and oxidative stress markers in AD patients [20]. In APP/PS1 transgenic mice subjected to exercise training and probiotic treatment AD progression slowed down [21]. In 3 × Tg-AD mice treated with a SLAB51 probiotic formulation showed reduction in cognitive decline due to a reduction in brain damage and reduced accumulation of Aβ aggregates [22]. In addition, D-Galactose-induced AD rats which were orally administered with Lactobacillus plantarum MTCC1325 not only ameliorated cognition deficits, but also decreased pathological hallmarks such as amyloid plaques and tau tangles [23]. Prebiotic administration in AD transgenic mice had similar effects alleviating AD-like symptoms by targeting the microbiota–gut–brain axis [24].
In the transgenic MitoPark PD mice daily administration with probiotics significantly reduced motor impairment and preserved tyrosine hydroxylase-positive cells in the SN [25]. Similarly, a probiotic cocktail containing a mixture consisting of Lactobacillus and Bifidobacterium protected DA neurons against MPTP and Rotenone neurotoxicity partially by increasing butyrate production [26]. Remarkably, PD patients that consumed preparations containing Lactobacillus acidophilus and Bifidobacterium infantis observed a significant reduction in abdominal pain and bloating [27]. PD patients with chronic constipation receiving milk fermented with the probiotic strain Lactobacillus casei Shirota significantly improve stool consistency and reduced bloating and abdominal pain [28]. In another trial in 2016 PD patients consumed fermented milk containing multiple probiotic strains and prebiotic fibre for 4 weeks, and showed an improvement in bowel movements [29]. More recently, in another study, investigators observed that probiotics (specifically belonging to the Lactobacillus and Bifidobacterium genus) significantly reduced proinflammatory cytokines and ROS production, whereas increased anti-inflammatory cytokines in peripheral blood mononuclear cells isolated from patients with PD compared to healthy controls [30]. Borzabadi and co-workers found that probiotics supplementation for 12 weeks in PD patients significantly down-regulated the gene expression of IL-1, IL-8, and TNF-α, all pro-inflammatory cytokines [31]. Probiotic supplementation improved movement and metabolic parameters in PD patients [32]. Interestingly, probiotics can promote the production of antioxidants, vitamins and bioactive molecules by microbiota which can exert beneficial effects in diseases associated with oxidative stress such as AD and PD. Interestingly, vitamin E, D3, riboflavin, and vitamin B6 have shown beneficial effects in PD patients [33]. Prebiotic fibres have been shown to modify the gut milieu improving bowel motility and reducing constipation that might be very relevant for inflammation and gastrointestinal-related symptoms in PD [34]. Hence, a few studies indicated that prebiotic fibres that generate butyrate show beneficial effects in PD animal models [35].

3. FMT

FMT consists in the introduction of a faecal suspension derived from a donor into the GI of a recipient individual. Moreover, it has been shown to be effective in the treatment of Clostridium difficile infection and its use was approved by the FDA [36]. Sampson and co-workers showed that faecal microbiota transplantation from PD patients to an ASYN transgenic mice model displayed worse ASYN pathology and motor deficits [37]. Another study showed that FMT from healthy mice improved motor function, increased striatal DA, and decreased neuroinflammation in a MPTP mouse model [38]. Colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels [39]. Accordingly, FMT treatment improved cognitive deficits and reduced Aβ deposition in the brain of APP/PS1 transgenic mice [40]. Additionally, germ-free C57BL/6N mice transplanted with faecal samples from an AD patient show significantly reduced performance on Object Location Test and Object Recognition Test when compared to mice transplanted with faecal samples from a healthy volunteer [41].
FMT in PD patients was shown to temporary improve motor symptoms and gastrointestinal function [42]. In another study, FMT via colonoscopy reduced the motor and non-motor symptoms with acceptable safety in PD patients [43]. As for AD, the only report is a case-study in which an 82-year-old AD patient showed remission of Clostridium difficile infection symptoms after receiving a single FMT from his 85-year-old wife and a negative stool test 2 months later. Interestingly, the cognitive score and memory retention of the patient increased 2 months after FMT [44]. An AD mouse model transplanted with healthy microbiota was reported to reduce the formation of Aβ plaques and tau pathology [45]. On the other hand, a germ-free wild-type mouse transplanted with gut microbiota from a patient with AD presented less abundant metabolites related to the nervous system and reduced cognitive function [41]. FMT may be a promising prodromal therapeutic strategy; however, it shows several challenges including risk of infection transmission and maintaining the viability and diversity of bacterial population.

4. Anti-Microbial Peptides (AMPs)

A recent opportunity with therapeutic potential for prevention and treatment of AD and PD has been highlighted with AMPs. AMPs are natural bioactive small proteins produced by all living organisms as important and indispensable components of innate immune response and are part of host defence with broad-spectrum activities from antibacterial to antifungal [46]. As opposed to antibiotics AMPs are less susceptible to antibiotic resistance [47] and can discriminate between bacteria and host cell through the differences in the cell membrane structure [48]. Interestingly, the AMP Lumbricusin (NH2-RNRRWCIDQQA) showed neuroprotective effects in a 6-OHDA induced mouse PD model, ameliorating the motor dysfunction [49]. Moreover, 2 host-defence antimicrobial peptides of α-defensins (HNP-1 and NP-3A), have been shown to prevent the aggregation and misfolding of different amyloid proteins like Aβ [50].
On the other hand, as previously discussed, in vitro and in vivo studies demonstrated that Aβ oligomers have antimicrobial activity by forming fibrils that entrap pathogens and disrupt cell membranes [51]. In addition, ASYN also exhibits antibacterial activity [52]. This is interesting and poses the possibility that in these diseases the increase in either Aβ and ASYN oligomers can be an initial protective response against these pathogens.

This entry is adapted from the peer-reviewed paper 10.3390/antiox11112141

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