Gut microenvironmental changes as a potential trigger in Parkinson’s disease through the gut–brain axis

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut–brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.

Comprehensive Review on Potential Signaling Pathways Involving the Transfer of α-Synuclein from the Gut to the Brain That Leads to Parkinson’s Disease

“…EECs, ECCs, and the mucosal immune system interact with several microbial metabolites, including as SCFAs, LPS, secondary bile acids, and tryptophan metabolites, to mediate communication between the gut and the brain. Some of these metabolites, however, may also cross the BBB and make their way into the brain via the BBB after passing through the intestinal barrier. ,, Blood is the medium through which neuroactive substances produced by microbes can be distributed throughout the body and trigger a signaling response. As host signaling molecules, SCFAs regulate the production of tight junction proteins including zonula occludens (ZO)-1 and claudin-1 to keep intestinal epithelial cells functional.…”

“…27,28 Abnormal neurotransmitters are released as a result of altered microtubule function and dysfunction of the presynaptic terminal of neurons. 29 2.2. Alteration in the Digestive System.…”

“…Thus, this toxic fibrillar form of α-syn can cause neurodegeneration through a variety of mechanisms, including mitochondrial dysfunction, which is responsible for oxidative stress in cells (Figure ). , Stress in the ER leads to its disruption and the trafficking of the Golgi bodies, , disturbances in the proteosomal mechanisms such as UPS and ALP, and an increase in the production of pathological proteins such as amyloid beta and tau. , Neuroinflammation is caused by the activation of microglia. , Abnormal neurotransmitters are released as a result of altered microtubule function and dysfunction of the presynaptic terminal of neurons …”

Pathogen infection in Alzheimer’s disease: pathophysiology and therapeutic strategies

“…Gut microbiota is involved in the metabolism of polyunsaturated fatty acids (PUFAs). Metabolites of PUFAs are increased in the gut of AD patients and modulate microglial activation in the brain [46] . R13 exerts its therapeutic efficacy on AD both by directly activating TrkB and restoring normal constituents of the gut microbiota.…”

Gut microbiota, pathogenic proteins and neurodegenerative diseases

“…Pathogenic α-syn was found in both enteroendocrine cells and intestinal neurons. It could reach the brain from the intestine through the vagus nerve and cause pathological changes in the central nervous system (Holmqvist et al, 2014;Chen and Lin, 2022). The study found that pathogenic α-syn was injected into the duodenum and pylorus muscle layer in mice produced symptoms similar to those of PD and successively in the vagus nerve dorsal motor nucleus, after brain tail, the basolateral amygdala, dorsal raphe nucleus and substantia nigra compacta found pathogenic α-syn, and cut off the vagus nerve can inhibit the occurrence of this phenomenon (Kim et al, 2019).…”