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Connection between GUT Metabolome and Neurological Disorders: History
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Contributor: Małgorzata Anna Marć , Rafał Jastrząb , Jennifer Mytych

Scientific evidence indicates that the administration of probiotic bacteria exerts beneficial and protective effects as reduced systemic inflammation, neuroinflammation, and inhibited neurodegeneration. The experimental results performed on animals, but also human clinical trials, show the importance of designing a novel microbiota-based probiotic dietary supplementation with the aim to prevent or ease the symptoms of Alzheimer’s and Parkinson’s diseases or other forms of dementia or neurodegeneration. The alterations of the gut microbiota, which are called dysbiosis, have been connected with the pathophysiology of numerous common diseases such as type 2 diabetes, obesity, gastrointestinal diseases, and cardiovascular events. Dysbiosis state is also implicated in neurological and neurodegenerative disorders such as autism, and Alzheimer’s (AD) or Parkinson’s (PD) diseases.

  • microbiome
  • metabolome
  • probiotics
  • neurodegeneration
  • Parkinson’s disease
  • Alzheimer’s disease
  • gut microbiota

1. Introduction

The gut microbial community is the largest micro-ecosystem in the human body, formed by more than 1000 different species, with high density per mL and encoding approximately 4 × 106 genes, 150 times more unique than the human genome [1]. It is predicted that the total weight of human gut microbiota deposit circulates around 1–2 kg, approximately reaching the human brain weight [2]. Ninety-five percent of symbiotic microorganisms are located in the gut [3][4]. These multi-species ecological arrangements mostly comprise anaerobic bacteria, with at least 500–1000 different species and more than 7000 strains, mainly from the Firmicutes and Bacteroidetes families (accounting for approx. 90% of bacterial species). In addition, the gut microbiome is co-inhabited by bacteria belonging to Proteobacteria, Actinobacteria, and Verrucomicrobia phyla, as well as archaea, viruses, fungi, bacteriophages, and protozoa (especially during pathologic conditions), which reside in the gastrointestinal (GI) tract, maintaining symbiosis with the host [5][6][7].
The gut microbiome is crucially engaged in the regulation and maintenance of human health and homeostasis, i.e., proper intestine motion, fibre digestion, regulating the development of host immunity, and exerting a protective effect against pathogenic factors (such as Campylobacter jejuni, Helicobacter pylori, and Clostridium difficile) [8][9][10]. The Irish ELDERMET study (Elderly to benefit from Research Project) demonstrated the correlation between intestinal microbiota diversity and health outcomes such as overall health, frailty, and proper immune functions, underlying the gut microbiota composition as a possible indicator of healthy ageing [11]. Multiple studies showed the interplay between the intestinal microbiota and modulation of central nervous system (CNS) functions and neurodegeneration processes [11], pointing to the microbiome-gut–brain axis as one of the factors modulating host homeostasis in health and disease. In the past decade, the alterations of the gut microbiota, which are called dysbiosis, have been connected with the pathophysiology of numerous common diseases such as type 2 diabetes, obesity, gastrointestinal diseases, and cardiovascular events. Dysbiosis state is also implicated in neurological and neurodegenerative disorders such as autism, and Alzheimer’s (AD) or Parkinson’s (PD) diseases [9][12]. During dysbiosis, disrupted homeostasis allows the pathobionts to expand, which can further amend the bowel’s mucosal barrier, exerting neurogenic inflammatory processes [9][13][14].
However host–microbiota interplay is not exclusively restricted to cell–cell interactions. Intestinal microbes are capable of producing a plethora of different types of compounds, i.e., small molecules (amino acids, neurotransmitters, short-chain fatty acids (SCFAs) and other fatty acid derivatives, indoles, vitamins, and cofactors), polysaccharides, and proteins (i.e., bacteriocins), which have been reported as important factors in shaping the bacterial community and modulation of the immune system [15]. It has been demonstrated that intestinal bacterial strains such as Escherichia coli or Lactobacillus spp. interact directly with the host’s CNS (central nervous system), as they can release neurotransmitters such as dopamine, noradrenaline, histamine, acetylcholine, GABA (gamma-aminobutyric acid), or serotonin [16]. This metabolic status of the microbiome is also vulnerable to dysbiosis and compositional changes and often leads to metabolic disturbances. For example, dysbiosis can induce elevated reactive oxygen species (ROS) levels, intensifying oxidative stress and neuronal inflammatory processes [10][17]. It has been estimated that 40% of the metabolites detected in humans are the products of bacterial metabolism [18], which plays a fundamental role in the modulation of the host’s physiological processes, including immune-mediated neurodegeneration or affecting neural cell metabolism [19].

2. Microbiota–Brain–Gut Axis and Neurodegenerative Diseases/Brain Disorders

Some research reports underline the crucial role of the microbiome in the normal development, regulation of behavior, cognition, and brain functions, but also in the etiology, the pathogenesis, and the progression of debilitating neurological disorders, e.g., Alzheimer’s and Parkinson’s diseases, autism spectrum disorder, multiple sclerosis, or even bipolar disorder, depression, schizophrenia, Huntington’s, stroke, and brain ageing [18][20]. Animal studies have demonstrated the participation of microbiota in neural-related processes such as neurodevelopment, neuroinflammation, interactions with neurons and glia, and behavior [11]. It has been postulated that microbiome influences neurological homeostasis via the microbiome–gut–brain axis.
The gut microbiota and brain crosstalk is a complex process including the vagus nerve, the immune system, gut hormone signaling pathways, tryptophan amino acid metabolism, hypothalamic–pituitary–adrenal axis, and the products of bacterial metabolism such as short-chain fatty acids [21] or gut-derived neurotransmitters [22] (Figure 1). Experimental studies demonstrated that even minor modifications in gut microbiota composition can lead to serious modification of brain functions, subsequently affecting intestinal activity through the secretion of specific hormones, neuropeptides, and neurotransmitters [23]. For example, butyrate, acetate, or propionate can induce the release of leptin and glucagon-like peptide-1, which are the gut hormones interacting with the vagus nerve and brain receptors [24][25][26]. In a mice model, the reduction of the variety of microbiota significantly diminished the blood–brain barrier (BBB) expression of tight junction proteins, occludin and claudin-5, disrupting the barrier function of endothelial cells. Therefore, rodent neural cells become more susceptible to stimuli produced by bacteria, among them lipopolysaccharide (LPS) and factors such as oxidative stress mediators [27]. Moreover, defects in mucosal barrier tight junction proteins increase intestinal permeability, causing the “leaky gut” effect followed by systemic inflammation and pathogenic agents translocation into the bloodstream (e.g., LPS) with elicit pro-inflammatory cytokine release [28][29]. Aoyama et al. provided evidence of the spontaneous neutrophil apoptosis triggered by butyrate and propionate through a histone deacetylase (HDAC) inhibition, the expression of caspase-3, caspase-8, and caspase-9 pathways, and proteins belonging to the Bcl-2 family, affecting the intestines and different organs. Butyrate and propionate activated neutrophil apoptosis both in the absence and presence of LPS or tumor necrosis factor α (TNF-α), and therefore in normal and pro-inflammatory conditions. Moreover, the expression of the proapoptotic bax mRNA was significantly elevated and, just the opposite, the expression level of antiapoptotic mcl-1 and a1 mRNA was importantly decreased by the abovementioned SCFAs in non-activated neutrophils. LPS induction highly increased the expression of mcl-1 and a1 mRNA; interestingly, this effect was neutralized by SCFAs [30]. Moreover, clinical trials suggest an altered gut microbial composition of patients with neurodegenerative disorders, together with significant differences in microbial and serum metabolomic profiles [31]. These data indicate that both microbiome composition and microbiome metabolome affect neurological diseases. It is worth mentioning that gut peripheral tissues are a residue for 70% of the human immune system, which is a well-known mediator of changes in gut ecosystem, inflammatory response, and also regulates multiple processes in CNS [32]. A good example of the interplay between gut-located immune cells and brain cells is the influence of regulatory T cells, which exert a neuroprotective effect by stimulating oligodendrocyte differentiation and triggering neuronal remyelination by interleukin IL-10 [19]. At the molecular level, there is evidence that mammalian Toll-Like Receptors (TLRs) play an important role in neurodegeneration. TLRs receptors are one of the main receptor families engaged in transducing and shaping innate immune responses. They are expressed both in immune and non-immune cells, especially increasing after contact with microbial pathogens or bacterial elements, i.e., cell walls, peptidoglycans, or DNA [33]. TLR activation (mainly TLR2 and TLR4) induces an inflammatory response cascade, preceding the neuronal loss characteristic for Parkinson’s disease [34], which could be a result of a “cascade reaction”: disrupted microbial composition and metabolome, increased permeability of the gut cell wall, and increased exposure to TLR ligands. Moreover, the microbiome and its metabolites are associated with immune-mediated neuroinflammation processes, brain injury, and neurogenesis [35]. Microglia cells are brain glial-resident immune cells responsible for maintaining proper immune functions including phagocytosis, antigen presentation, the production of cytokines, and the subsequent inflammatory reactions [36][37]. Research reports indicate the influence of microbiota on microglial maturation and function; however, this mechanism is still unclear [38]. It has been confirmed that gut dysbiosis can augment intestinal permeability and bacterial translocation, causing an over-response of the immune system and the subsequent systemic/central nervous system inflammation [39][40]. The adaptive immune system also participates in the regulation of healthy microbiota. The crucial players in intestinal homeostasis maintenance are B cells, which produce secretory IgA antibodies targeted toward specific bacteria [41]. Additionally, gut microbiota can stably influence the host’s gene expression through epigenetic mechanisms, including histone modifications, methylation of DNA, and non-coding RNA expression [42]. Overall, the microbiome plays a big role in moderating the maturation of immune cells residing in the CNS tissues via an interplay and crosstalk with the peripheral immune system. Gut microbiota act as a multifunctional hub modulating the immune system via the production of immunomodulatory and anti-inflammatory signaling molecules, reaching immune cells. Commensal microbes fabricate various metabolites from digested food, SCFAs among them, which participate in the maintenance of intestinal homeostasis, exerting anti-inflammatory activity on the intestinal mucosa [43]. The gut microbiota participates in signal transduction pathways as it can communicate between the host’s innate immune system cells, which are located at the interface between the host and the microbiome [44].
Figure 1. The interplay between the microbiome, microbial metabolites, and neuropathological processes present during neurodegenerative diseases such as AD and PD. The microbiome and microbial metabolites could regulate brain homeostasis via four different ways: 1. direct absorption of specific metabolites which have the ability to cross the BBB; 2. interaction between peripheral immune systems, which interact with brain glia cells and astrocytes; 3. influence on gut hormones and the enteroendocrine system; 4. communication via the vagus nerve. These four routes may have an influence on pathological symptoms such as increased BBB leakage and neural inflammation, enhanced beta-amyloid and alpha-synuclein formation, and finally neuron loss and motor/cognitive deficits.

3. Microbiota Metabolites and the Severity of Neurodegenerative Diseases

Scientific evidence indicates that the metabolic status of microbiota exerts a more important role than the equilibrium between bacterial species. Microbial metabolites can act as positive modulators of the gut–brain-axis constituents, boosting the immune cells and exerting a positive/protective effect on neurodegenerative disease progression [45]. On the other hand, disrupted equilibrium between microbial species often leads to specific switches in the microbial metabolome, which may be harmful and associated with neurodegenerative disease progression. For example, dysregulation of Gram-negative bacteria in the gastrointestinal area leads to the production of harmful metabolites (i.e., endo- and exotoxins, saccharides, and amyloids) [46]. Exotoxins, such as LPS, which have the ability to activate the production of pro-inflammatory cytokines, exert negative effects. LPS belongs to glycolipid molecules, mostly produced by Gram-negative bacterial strains. These molecules participate in the integrity maintenance of the bacterial outer-membrane permeability barrier, playing an important role in host-pathogen interplay [47]. The overproduction of bacterial LPS can cause the activation of the macrophage–monocyte nod-like receptor P3 inflammasome, therefore stimulating the production of cytokines with pro-inflammatory activity, such as IL-18 or IL-1β. LPS can be translocated and intensify neuroinflammatory diseases such as AD [48]. Additionally, it was demonstrated that IL-1β can decrease the phagocytic function of microglial cells, stimulating the hyperphosphorylation of tau protein, and causing reduced synaptic plasticity and cognitive deterioration [48][49][50]. These cytokines can induce microbiota dysregulation, increasing gut permeability and influencing gut bacteria diversity [51][52].
On the other hand, the gut microbiome is able to produce a broad spectrum of metabolites, which have beneficial effects on human health (Figure 2).
Figure 2. A healthy, abundant, and diverse microbiome (left side) is able to produce proper amounts of SCFAs, amino acids, and neurotransmitters. This type of microbiome and its metabolites positively influence gut barrier integrity and leads to the healthy maturation of the peripheral immune system, which is able to counteract external immune stimuli properly. A dysbiotic microbiome (right side) could be characterized by reduced diversity and an abundance of species able to produce positive metabolites and an increased abundance of species producing harmful metabolites such as LPS, beta-amyloids, small toxic metabolites, or other toxins. These switches may lead to disruption in the intestinal barrier, increased absorption of toxic metabolites, over-activation of the immune system, and, finally, pro-inflammatory responses which influence other organs, including the brain.
Recently, bacterial strains producing SCFAs have gained extreme popularity. SCFAs are small organic monocarboxylic acids, released after the fermentation of indigestible alimentary fiber (mainly galacto- or fructooligosaccharides), plant-derived polysaccharides, or the metabolism of amino acids, and are considered a key gut-derived metabolites with beneficial health effects and as essential in gut-brain crosstalk [53][54]. The type of formed SCFAs is correlated with the kind of fiber ingested and the overall gut microbiota population. For example, microbes belonging to Firmicutes phyla (e.g., Lachnospiraceae, Eubacterium, or Roseburia belonging to the Clostridia class) are responsible for the main production of butyrate, whereas Bifidobacteria spp. produce lactate and acetate [55]. SCFAs are significantly reduced during dysbiosis, where disrupted gut epithelial integrity, inflammation, and altered microbiome metabolic processes occur [56][57][58]. In a healthy colon, levels of SCFAs can vary depending on a diet; however, in multiple diseases, these levels are altered. SCFAs may also act in an indirect or direct way through G-protein-coupled receptors or as histone deacetylase epigenetic modulators [59]. They participate in various physiological processes, such as cell energetics and colonocyte metabolism and skeletal, adipose, and liver tissue modulation [60]. Their major functions comprise the activation of trophic factors, energy management, and the manufacturing of regulatory T-cells [61]. Short-chain fatty acids can be considered as key intermediaries in numerous neurological diseases such as Parkinson’s and Alzheimer’s diseases, stroke, and neuropsychiatric conditions.

4. Nutritional Intervention as a Promising Solution to Prevent the Progression of Neurodegenerative Diseases

Currently, researchers have defined multiple factors which have an influence on the microbiome’s composition and its metabolome, i.e., environmental (such as exposure to pesticides or heavy metals), biological (infections), and sociodemographic factors such as inadequate diet, stress, mode of delivery at birth, lack of breastfeeding during the neonatal period, or antibiotic therapy [62][63][64]. All of these factors could negatively modulate the microbiome and finally lead to dysbiosis. However, if researchers try to indicate the most powerful factor, then diet is one of the strongest lifetime modulators of microbiome composition [65][66].
For example, the Western diet is a well-known negative modifier of microbiome composition and a promoting factor of multiple common diseases [67]. It is characterized by high fat and sugar ingestion and low fiber content, which are positively linked to Bacteroidetes and Actinobacteria abundance, but negatively correlated with fiber-rich nourishment. A contradictory connotation could be observed for Proteobacteria and Firmicutes [68].
Contrarily, as a positive example, balanced diets (i.e., Mediterranean diet and Dietary Approaches to Stop Hypertension) can be mentioned. Diets abundant in natural compounds with anti-inflammatory activity, antioxidants, polyunsaturated fatty acids, and plant-origin nutrients (proteins, polyphenols, vitamins, and fibers), together with reduced caloric intake, such as the Mediterranean diet, are correlated with a lower risk of dementia, decrease age-related cognitive deterioration, and the risk of neurodegeneration occurrence [69][70][71]. Moreover, the Mediterranean diet increases the amount of gut Bifidobacterium and Lactobacillus and reduces malignant bacteria belonging to Clostridium and Bacteroides, thereby improving memory and cognitive processes in healthy females after menopause and disorder patients. Additionally, following such a diet significantly reduces amyloid aggregation and therefore the frequency of amyloid-related diseases in the aging population [14][72][73]. There are scientific reports that he gut dysfunction is related to the inflammation of the CNS, which can especially be observed in Parkinson’s disease patients, where dysregulation of the gut–brain axis was observed in 80% of patients [74].
In the past decade, single dietary factors which can positively manipulate the gut microbiota–brain axis through microbiome modulation have gained significant attention [75][76]. One of these factors is probiotic bacteria and/or prebiotics. Probiotics are defined as microbial organisms with a beneficial role in the host’s health and homeostasis, which help to preserve digestive, metabolic, immune, and neuroendocrine functions [77]. Naturally probiotic bacteria can be found in fermented food [78][79]. Experimental results revealed that the administration of probiotics alone or in combination with prebiotics (fructooligosaccharides or galactooligosaccharides) improved the gastrointestinal barrier [80][81], which is the first line of “defence” from harmful factors occurring in food, and the microbiome. Probiotics and prebiotics are well-documented “problem-solution” for gastrointestinal diseases [82][83]. Moreover, probiotics can reduce CNS inflammatory processes and activation of microglia, demonstrating promising potential for use in neurodegenerative diseases as ingestible “psychobiotics”. Many studies indicate that the ingestion of probiotics can serve as a microbiological strategy against neurodegenerative diseases such as AD [84][85][86]; however, the exact mechanism is under investigation [87]. Experiments performed on mice underline the hypothesis that mechanisms related to neuroprotective effects of Bifidobacterium breve administration may be connected with neuroinflammation and cognition pathways, probably through the production of the brain-derived neurotrophic factor (BDNF) neurotransmitter and the regulation of the gut microbial composition [88]. Clinical results of a randomized double-blind controlled trial revealed that 3-month exposure to Lactobacillus spp. And a Bifidobacterium bifidum “cocktail” enhanced cognitive functions and memory, as examined in a mini-mental state test [89]. It was demonstrated that Bifidobacterium breve exerts positive and unique activity in AD patients, improving cognitive functions and reducing neuroinflammation. Controlled, double-blind, randomized clinical trials with a 12-week multispecies probiotic treatment (comprised of Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum) caused a significant decrease in malondialdehyde in the probiotic-treated group [89].

This entry is adapted from the peer-reviewed paper 10.3390/nu14193967

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