## 4 Alteration of Gut-Brain Axis and Neurodegeneration
### Gut Microbiota in Parkinson's Disease: The Non-Motor Symptoms  
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms (NMSs). NMSs include neuropsychiatric manifestation such as anxiety, depression, sleep disorders, cognitive impairment, and autonomic dysfunctions involving the whole GI tract, which represent one of the most common NMSs in patients with PD. The precise mechanisms underlying the gut microbiota and PD are still poorly understood, and it is still unclear whether the alteration of microbial composition is the cause or the consequence of PD. Evidence supports the hypothesis that PD may initiate in the gut since GI dysfunctions appear many years before motor impairments. The reciprocal influence between neural function and the gut microbiota can contribute to the pathogenesis of PD, and the ENS is a gateway for the bidirectional interaction between the brain and the gut [61].  
The pathological hallmark of PD is represented by the toxic accumulation of \(\alpha\)-synuclein (\(\alpha\)-syn) in both the CNS and the ENS of PD patients [62]. This \(\alpha\)-syn accumulation was detected in gastric, duodenal, and colonic biopsies several years prior to the onset of the motor symptoms of PD [63]. Using mice that overexpress \(\alpha\)-syn, it was demonstrated that gut dysbiosis is required for motor deficits, microglia activation, and \(\alpha\)-syn pathology, and enteric \(\alpha\)-syn correlates with higher intestinal permeability and inflammation [64; 65]. These findings suggest a centripetal spread of \(\alpha\)-syn pathology from the ENS to the CNS.  
Figure 2: Schematic representation of the role of the gut microbiota in the pathogenesis of neurodegenerative and mental disorders and vice versa. A growing body of evidence suggests the bidirectional signaling between the gut microbiota and the brain in mediating brain diseases. Alterations in gut microbiota composition or microbial-derived products play an important role in modulating the gut-brain axis. Prolonged activation of Toll-like receptors (TLRs) by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), SCFAs, \(\alpha\)-synuclein, etc. represents an important contributory factor to the development of neurodegenerative diseases through mechanisms which involve the immune response and inflammation. The disruption of tight junctions leads to the leakage of microbial products, including neurotransmitters, SCFAs, and neuroactive molecules into the system circulation. Endotoxemia associated with the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, alteration of the HPA, and hyperpermeability of BBB further contributes to neuroinflammation and brain disorders. Gut dysbiosis alters the levels of neurotransmitters and neurotrophins, thereby exacerbating the pathological state. In turn, neurodegenerative disorders could affect gastrointestinal functions by creating a vicious circle. NT, neurotransmitters; IM, intestinal membrane; SCFAs, short-chain fatty acids.  
In addition, Gram-negative bacteria are abundant in PD patients and produce lipopolysaccharide-saccharide (LPS), the main endotoxin that, through inflammatory pathways, contributes to \(\alpha\)-syn aggregation, dopaminergic neuronal death, reduction of dopamine levels, and, therefore, motor impairments [66].  
Mast cells are reported to surround neuronal cells, including astrocytes and microglia, and they may play a role in PD pathogenesis [67]. The ENS alteration could \"prime\" these cells to respond to different stimuli and become activated, releasing neuromodulators, cytokines, and other inflammatory mediators that trigger a bidirectional communication able to damage the dopaminergic neurons. The intake of probiotics could modify the composition of the gut microbiota and modulate the mast-cell activation, leading to an improvement in levodopa adsorption, thereby inducing neuroprotection.