New Pieces for an Old Puzzle: Approaching Parkinson's Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics

Abstract

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.

Keywords: Parkinson’s disease; animal models; constipation; dopamine; gastrointestinal; gut-brain axis; lipidome; microbiota; non-motor symptoms; probiotics.

Figure 1

Phases of the development of Parkinson’s disease. Abbreviations: w, with; wo, without.

Figure 2

Schematic representation of the main pathophysiological mechanisms linking intestinal microbiota and PD. Dysbiosis is associated with altered patterns of microbial metabolism, including, as relevant for PD, altered ratios in the production of short-chain fatty acids (SCFA), changes in dopamine and propanoate production, and generation of different abnormal metabolic byproducts (for instance, increased levels of bacterial-derived lipopolysaccharides or toxins). All these factors lead to the alteration of gut permeability, generating a pathophysiological state known as “leaky gut.” The increase in permeability facilitates the entrance of immunogenic products from the intestinal lumen, including bacteria (bacterial translocation), bacterial components, and their metabolic byproducts. These factors interact among them in a positive manner, inducing metabolic changes within the intestinal cells (such as alterations in oxidative stress processes) and a state of immune activation. Altogether, these factors facilitate the altered deposition of α-synuclein in the enteric nervous system (ENS). Enteric α-synuclein can be retrogradely transported via the vagus nerve (brain–gut axis), in a prion-like manner, to the central nervous system (CNS). Within the CNS, α-synuclein will initiate the cascade of events that leads to glial and neuronal dysfunction, as a base for the neurological symptoms that characterize PD. Additionally, immune mediators and bacterial metabolic byproducts can also reach the CNS through alterations of blood–brain barrier (BBB) permeability, thus contributing to the glial and neuronal dysfunction. Moreover, the pathophysiological alterations present within the GI tract contribute to the development of gut pathology, which, in PD patients, is characterized by the presence of dysmotility resulting in constipation. Additionally, altered bacterial metabolism due to the dysbiotic state might produce alterations in the synthesis of neurotransmitters, such as GABA, contributing to the neural dysfunction.