Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a progressively debilitating neurodegenerative disease characterized by α-synucleinopathy, which involves all districts of the brain-gut axis, including the central, autonomic and enteric nervous systems. The highly bidirectional communication between the brain and the gut is markedly influenced by the microbiome through integrated immunological, neuroendocrine and neurological processes. The gut microbiota and its relevant metabolites interact with the host via a series of biochemical and functional inputs, thereby affecting host homeostasis and health. Indeed, a dysregulated microbiota-gut-brain axis in PD might lie at the basis of gastrointestinal dysfunctions which predominantly emerge many years prior to the diagnosis, corroborating the theory that the pathological process is spread from the gut to the brain. Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing conserved motifs primarily found in microorganisms and a dysregulation in their signaling may be implicated in α-synucleinopathy, such as PD. An overstimulation of the innate immune system due to gut dysbiosis and/or small intestinal bacterial overgrowth, together with higher intestinal barrier permeability, may provoke local and systemic inflammation as well as enteric neuroglial activation, ultimately triggering the development of alpha-synuclein pathology. In this review, we provide the current knowledge regarding the relationship between the microbiota-gut–brain axis and TLRs in PD. A better understanding of the dialogue sustained by the microbiota-gut-brain axis and innate immunity via TLR signaling should bring interesting insights in the pathophysiology of PD and provide novel dietary and/or therapeutic measures aimed at shaping the gut microbiota composition, improving the intestinal epithelial barrier function and balancing the innate immune response in PD patients, in order to influence the early phases of the following neurodegenerative cascade.

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

“…The possible pieces of evidence supporting the efficacy of probiotics in PD could be related to the alternation of PD-associated microbiota composition, improvement of GI function, reduction of harmful gut bacteria, gut leakiness, bacterial translocation, proinflammatory cytokines, oxidative stress, potentially pathogenic bacterial overgrowth, and the associated neural inflammation in the ENS [24][25][26][27]30,55]. In addition, to enhance the effects of anti-inflammation and anti-oxidative stress in the GI system, combining the probiotics and other drug treatments (e.g., anandamide or calcitonin gene-related peptide) may have better effects to inhibit the inflammatory process and preserve the integrity of gastric mucosa, by improving the endogenous release of nitric oxide (NO) and increasing the blood flow [13,21,[56][57][58][59].…”

“…Another possible mechanism is the anti-inflammation effects of probiotics. It has been found that PD patients have greater intestinal permeability (gut leakiness), which might upregulate the local/systemic inflammatory response and oxidative stress induced by lipopolysaccharides (LPSs, also termed endotoxin), leading to α-synucleinopathy in the enteric nervous system [13]. Furthermore, the higher levels of gut-derived LPSs could promote the neuroinflammation and damage in substantial nigra via the disruption of blood-brain barrier (BBB) integrity [70].…”

“…It has been hypothesized that GI dysfunctions could reflect the disruptions of the microbiome-gut-brain axis, leading to serious GI inflammatory diseases (e.g., acute pancreatitis or inflammatory bowel disease), endothelial dysfunction, altered immune functioning and regulation of appetite control, neural inflammation, subsequent neurodegeneration, cognitive or psychoneurological disorders (e.g., depression, anxiety, autism, dementia), and disease progression of PD [8][9][10][11][12][13][14][15][16][17][18][19]. In addition to the use of peptides for the improvement of gastrointestinal or digestive dysfunctions [13,[20][21][22], and in order to improve GI function and the balance of microbiota, probiotics could be one of the powerful tools to be used for altering the PD-associated microbiota composition and mitigating the related inflammatory process [12,23]. It could, therefore, inhibit the harmful gut bacteria and decrease the bacterial translocation, gut leakiness, and the associated neural inflammation in the enteric nervous system (ENS) [24][25][26][27].…”

Gastrointestinal Immunity and Alpha-Synuclein

“…Induction of ␣S in the setting of an infectious insult would initially attract protective immune cells, followed by the engagement of the adaptive immune system. As yet we do not know the mechanisms that are involved in the induction of neuronal ␣S by infection, such as the role of TLRs (which are present on neurons) [29,30], or the release of pro-inflammatory mediators, such as IL-17 and IL-22 (which potently stimulate induction of epithelial AMPs) [31].…”

Anti-hypertensive peptides released from milk proteins by probiotics

“…The efficacy of some probiotics against diarrhoea has been reported [33], as well as providing intestinal microbial balance [34], reduces the risk of colon and breast cancer [35], reduces blood pressure [17,[22][23][24]36], reduces lipid profiles [37], reduces allergies and food intolerances [38], inhibits the growth of pathogenic bacteria and is immunomodulatory [12,[39][40][41][42] (Figure 1). More recently, dysbiosis has been implicated to be involved in the pathogenesis of a number of disorders such as, Sjogren's syndrome [43], Parkinson's disease [44] and multiple sclerosis [45]. The use of probiotics and prebiotics could be used as therapeutic approaches against diseases.…”