Microbial Dysbiosis and α-Syn

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This entry is adapted from the peer-reviewed paper 10.3390/ijms24087137

Alpha-synuclein (α-Syn) is a short presynaptic protein with an active role on synaptic vesicle traffic and the neurotransmitter release and reuptake cycle. The α-Syn pathology intertwines with the formation of Lewy Bodies (multiprotein intraneuronal aggregations), which, combined with inflammatory events, define various α-synucleinopathies, such as Parkinson’s Disease (PD). The microbiota—which consists of thousands of bacterial, viral, and fungal species that inhabit different parts of the human body—plays a critical role in human health, not only through its barrier function against pathogens, but also through its regulatory role of the immune system as well as its impact on other important functions, such as the regulation of movement. The human gut microbiota in particular has been the focus of intense research. This microbiota is shaped by lifetime determinants (such as diet, disease history, age, or genetic heritance) and produces a variety of molecules, some of which can enter the bloodstream and affect overall systemic health.

alpha-synuclein inflammation neuroinflammation synucleinopathies

1. Gut Microbiota and α-Syn

Recent lines of research have been exploring the potential mechanisms by which changes in the gut microbiota and their products (such as LPS and intestinal-mucosa-derived inflammatory factors) might contribute to the misfolding and abnormal aggregation of α-Syn in the enteric nervous system (ENS), and upon transportation via projections of the vagus nerve and autonomic enteric fibers, in the CNS ^[1]^[2]^[3]. The transport of toxic α-Syn species through the microbiota–gut–brain axis ultimately results in the loss of dopaminergic neurons and causes a microglial inflammatory response that is in the pathogenesis of α-synucleinopathies ^[4]. In fact, PD patients appear to present differences regarding the level of certain species of gut bacteria when compared to healthy counterparts ^[5]^[6]^[7]^[8]. Therefore, it is crucial to highlight the microbiota–gut–brain axis, as it represents a complex and interdependent network between the ENS, the gut microbiota, the immune system, and the brain and provides key insights into how intestinal alterations might affect distant organs, such as the brain ^[9]. In fact, the gastrointestinal tract’s communication network with the CNS includes pathways such as the systemic circulation of hormones, inflammatory cytokines, and microbial products, as well as the autonomic nervous system through the vagus nerve ^[10]. Interestingly enough, of the non-motor features that comprise the prodromal phase of PD—which include gastrointestinal, olfactory dysfunction, autonomic dysregulation, fatigue, sleep disorders, and mood disturbances—the early constipation and gastrointestinal inflammation support the involvement of the microbiota–gut–brain axis ^[8]^[9]^[11]^[12]^[13]. However, even though the gut microbiota’s role in neurodegeneration has started to be explored, research on the involvement of oral microbiota on such mechanisms is still due ^[8]^[14].

In a recently conducted study, Shi et al. ^[12] explored whether mucosal microbiota in PD patients would correlate with changes in intestinal mucosal a-Syn. To this end, nineteen PD patients were compared to healthy counterparts for duodenal and sigmoid mucosal samples with next-generation metagenomic sequencing. Overall, the results showed that oligomer a-Syn in the sigmoid mucosa is transferred from the epithelial intestinal wall to the cytoplasm, acinar lumen, and stroma. Furthermore, the intestinal mucosal microbiota composition changed with the increase in the relative abundance of pro-inflammation inducing bacteria in the duodenal mucosa ^[12]. Beyond the unequivocal potential for diagnosis of PD using such samples, these results show that intestinal microbiota may have a role in the levels of a-Syn at the intestinal mucosa.

2. Oral Microbiota and α-Syn

There is a clear clinical association between periodontitis and PD that has been centered on both the progressive installment of motor disturbances and cognitive decline, which implicate on the patient’s self-care ability and compromises oral hygiene, as well as fewer dental attendances ^[15], which ultimately precipitate oral diseases ^[13]^[14]^[16]. However, the extent of the existing evidence regarding a concrete α-Syn or other crosstalk biomarkers linking periodontitis and PD is sparce and still relies on a bioinformatic genomic analysis ^[17]^[18].

Periodontitis knowingly disturbs systemic health, either through its inflammatory burden or bacterial blood dissemination ^[19]^[20]^[21]^[22]. In particular, an association between periodontal inflammation and neurodegenerative conditions has been reported in studies regarding cognitive function ^[23]^[24], dementia ^[25], and very recently PD ^[26]. The hypothesis in which an active periodontal infection promotes the secretion of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, TNF-α, and reactive oxygen species (ROS) and might increase the risk of PD has been proposed ^[27], alongside the fact that periodontal infection constitutes a new entryway for bacterial translocation in PD ^[15]. In addition, not only were Porphyromonas gingivalis and its toxic proteases (gingipains) identified in the brain of Alzheimer’s disease (AD) patients ^[28], but an increase in the deposition of beta amyloid has also been reported in the brain of periodontitis-induced mice models for AD ^[29]. The presence of these key periodontal pathogens in distant tissues, and their association with inflammation, may suggest that the migration of these microorganisms might cause local inflammatory reactions, and are often related to pathological mechanisms of major neurological diseases.

The researchers have recently demonstrated a higher prevalence of periodontitis in PD patients ^[26] and possible systemic repercussions with the elevation of circulating white blood cell counts ^[30] and c-reactive protein ^[31]. In fact, systemic inflammation caused by periodontitis has been hypothesized to develop chronic neuroinflammation and ultimately interfere with PD pathogenesis ^[27]. The chronic pattern of periodontitis may be responsible for sustained local and systemic inflammatory states with unknown consequences in PD, perhaps suggesting the involvement of a microbiota–mouth–brain axis, and these results may pinpoint mechanistic clues for future research on the biological mechanisms and paths. In addition, immunologically different traits and patterns mediated by oral microbiota might interfere with the pro-inflammatory state in PD, with the individual as well as horizontal and vertical inheritance having a conceivable role.

The first study to investigate the oral microbiota in PD was based on the hypothesis that this disease is often characterized by neuropathological changes in olfactory and gastrointestinal tissues. Therefore, Pereira et al. compared oral and nasal samples from PD patients with controls ^[32]. Gene sequencing data revealed a different oral and nasal microbiota in the abundance of individual bacterial taxa, but without significant differences in PD patients. Despite the lack of apparent differences, the authors outlined the potential importance of tracking gut microbiota for potential clinical purposes. Later, Rozas et al. ^[33] conducted a similar cross-sectional case–control study, examining the oral microbiota from hard and soft tissues of PD patients (and matched healthy controls). The bacterial identification results showed significant differences in soft tissue diversity with a higher abundance of opportunistic oral pathogens in PD. When potential confounders were examined, the presence of dysphagia, drooling, and salivary pH emerged as the most influential. Taken together, these findings revealed novel microbiota differences and clinical signs that could explain them.

Years later, and with new data pointing to the importance of diet in the pathophysiology of PD, Zapała et al. ^[34] compared the dietary preferences and oral microbiota profile of PD patients with healthy matched controls. Gene sequencing showed that the oral microbiota in PD differed from the controls, with a lower abundance of Proteobacteria, Pastescibacteria, and Tenercutes. On the other hand, a high relative abundance of Prevotella, Streptococcus, and Lactobaccillus was found. In addition, dietary patterns showed correlations with microbial taxa, suggesting a possible role of diet in the oral bacterial profile of PD patients.

In addition, a recent exploratory study examined the composition of oral microbiota (saliva and subgingival samples) and the level of oral inflammation (by periodontal and dental examination and quantification of gingival crevicular fluid levels of IL-1β, IL-6, IL-1 receptor antagonist, interferon-γ, and TNF-α) ^[35]. Both in saliva and subgingival plaque, the composition of plaque showed different patterns between PD and control subjects ^[35]. There was a higher abundance of Streptococcus mutans, Kingella oralis, Actinomyces AFQC_s, Veillonella AFUJ_s, Scardovia, Lactobacillaceae, Negativicutes, and Firmicutes. On the contrary, there was less abundance of Treponema KE332528_s, Lachnospiraceae AM420052_s, and phylum SR1 ^[35]. Even though there were no differences between dental and periodontal statuses among PD and control patients, there was a higher level of IL-1β and IL-1 receptor antagonists in the gingival crevicular fluid of people with PD, showing a different inflammatory pattern on the periodontal apparatus.

The apparent specific oral microbiota profiling in PD raised other questions of major importance regarding the pathophysiological features of this movement disorder. Particularly, Zheng et al. ^[36] collected oral mucosa samples using a cytological brush from people with PD and age-matched controls. Immunofluorescence analysis revealed increased α-Syn, pS129, and oligomeric α-Syn levels in oral mucosa cells of PD patients. While α-Syn species were distributed intracellularly, pS129 was mainly located in the cytoplasm, and oligomeric α-Syn in the nucleus and perinuclear cytoplasm. In addition, the oral mucosa α-Syn and oligomeric α-Syn levels of participants with PD significantly correlated with the clinical staging of PD, assessed with the Hoehn–Yahr scales.

At that point, several studies were able to identify a distinct gut microbial composition in PD. Jo et al. ^[37] furthered the research on the microbiome by studying the functional alteration of the microbiome in PD. The taxonomic oral and gut microbiome profile significantly differed between PD patients and healthy controls, with a higher abundance of Lactobacillus and opportunistic pathogens ^[37]. Functional analysis revealed a down-regulation of microbial glutamate and arginine biosynthesis gene markers and an up-regulation of antibiotic resistance gene markers in PD patients compared to healthy controls ^[37].

At this stage, research has identified changes in the oral microbiota of PD patients, with reductions in some bacterial species and increases in others, but without consistent patterns that may be explained by multiple factors. To this date, the researchers expect the number of studies investigating this particular issue to increase. This body of knowledge may contribute to new frontiers in the understanding of how the oral microbiota, which is an integral part of the gut microbiota, plays a role in PD. On the one hand, these microbial changes can potentially serve as a non-invasive diagnostic tool for PD. By analyzing the genetic material of the oral microbiota, researchers can identify specific bacterial species or gene pathways associated with PD. This information could be used to develop diagnostic tests that can detect the disease earlier and more accurately than current methods. On the other hand, gene sequencing of the oral microbiota could also lead to the development of new treatments for PD. Researchers could identify specific bacterial species or gene pathways that contribute to the disease and target them with probiotics or other therapies. These treatments could potentially slow or even halt the progression of PD. While this is still highly speculative, several lines of evidence point to the key role of the gut microbiota in the CNS, the so-called gut–brain axis, and this should be a central focus of research in the coming years.

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1. Gut Microbiota and α-Syn

2. Oral Microbiota and α-Syn

References