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The Gut-Brain Connection in Parkinson (PD)
Lake Forest College
Lake Forest, Illinois 60045
Abstract: Gut Microbiota has been shown to promote motor dysfunction, microglia activation, and alpha synuclein pathology in genetically engineered mice that over express alpha synuclein. Depletion of gut bacteria from mice model displayed unreactive microglia, which lead to limited pathophysiology. Microbial metabolites (SCFAs) are crucial to change microglia morphology and physiology, which in turn enhance PD pathophysiology. Non-sterile mice’ microbiota is susceptible to produce SCFAs, which lead to activation of disease competent microglia, thus displaying motor dysfunction and disease pathology. Human gut microbiota from PD patients increased motor dysfunction in mice. Overall, these findings indicate combined impact of genetics (alpha synuclein over expression) and environment (dysbiosis) in the development of PD, and reveals that gut microbiota possibly lead to etiology of PD.
There are trillions of microorganisms that reside in our gut and impact our physical and mental health. The Gut is also known as our body’s second brain, which may be the root cause of our mental health. Gut bacteria regulate the physiology of immune cells in the intestine, periphery, and brain (Erny et al., 2015). Growing evidence has shown biaxial communication between the gut and the brain in anxiety, depression, and autism spectrum disorder (Mayer, Padua, & Tillisch, 2014). Previous studies showed that hippocampal neurogenesis is impacted in sterile and non-sterile mice, which impaired mice spatial and object recognition ability (Mohle et al., 2016). Furthermore, compromised cortical myelination and altered blood brain barrier function has been reported in sterile mice (Braniste el al., 2014). Several neurological diseases have been linked to changes in human microbial composition (Schroeder and Backhed, 2016). However, the contribution of altered human microbial composition in PD remains a mystery as PD patients have been long known to complain about constipation and GI dysfunction.
Indeed, Timothy R. Sampson and the team suggested a connection between PD and the Gut microbiome. PD is a progressive hypokinetic neurodegenerative disorder that has been linked to loss of Dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in dysregulation of basal ganglia circuits (Bartels & Leenders, 2009). A key pathological hallmark of PD is the presence of Lewy bodies, which are mainly composed of misfolded, aggregated alpha synuclein protein. Previously, it had been hypothesized that alpha synuclein accumulates initially in the gut and spreads through vagus nerve to the brain (Del Tredici and Braak, 2008). However, retrograde transmission of alpha synuclein aggregation from enteric nervous system to central nervous system is not supported by a strong evidence. Previously, PD patients reported constipation and altered microbiome many years before onset of PD (Braak et al., 2003). Based on previous findings, Timothy R. Sampson team decided to uncover the etiology of PD by hypothesizing that gut bacteria promote motor dysfunction, and pathophysiology of synucleinopathies such as PD.
In the latest study, Timothy’s team analyzed genetically programmed mice that overexpress alpha synuclein, as a result they became vulnerable to develop PD. These mice were assessed in sterile (Germ Free) and non-sterile (Specific pathogen free) environment. Non-sterile mice showed a significant decline in gross motor skills and altered Gastrointestinal function (GI); however, sterile mice were similar to wild type mice. This finding suggests that presence of gut microbes impairs coordinated motor and intestinal functions. Additionally, non-sterile mice expressed increased activation of microglia in caudate, putamen, inferior midbrain and Frontal cortex compared to sterile mice, which indicates gut bacteria promote alpha synuclein dependent activation of microglia in specific brain regions.
In order to establish that postnatal microbial signals modulate alpha synuclein dependent pathophysiology in adulthood, Timothy’s team treated non-sterile mice with antibiotics to completely diminish microbiota and sterile mice with microbiota of previously non-sterile mice. Antibiotic treated mice displayed little alpha synuclein dependent motor dysfunction, improved GI function which was clear from increased fecal output, and their microglia length resemble sterile mice. Conversely, sterile mice with complex microbiome displayed significant alpha synuclein dependent motor dysfunction, decreased fecal output, and long microglia. These results indicate active gut-brain signaling by the microbiota during postnatal development.
To demonstrate that short chain fatty acids (microbial metabolites) are enough to promote alpha synuclein dependent neuroinflammation, Timothy’s team fed short chain fatty acids (SCFAs) to both non-sterile and sterile mice. Thus, non-sterile mice produced disease competent microglia and displayed motor dysfunction and PD pathology compared to sterile mice which indicates that SCFAs promote in vivo alpha synuclein aggregation independent of direct molecular mechanism.
Additionally, oral treatment of sterile mice with heat killed bacteria did not promote motor dysfunction, which indicates bacteria needed to be metabolically active to initiate a response. Similarly, oral treatment of SCFAs-fed animals with anti-inflammatory compound reduced alpha synuclein aggregation, and improve motor function, which suggest that microbiota actively produce SCFAs, that are required for alpha synuclein aggregation.
To uncover microbiota function, Timothy’s team treated mice with gut microbiome of PD patients and healthy individuals. Mice treated with PD patients’ microbiota displayed significant increase in motor dysfunction compared to healthy individuals. This observation supports the hypothesis that microbiota plays a functional role in synuclienopathies.
To sum up, this study shows that alpha synuclein overexpression and dysbiosis both play an important role in the development of PD in mice which indicates the combined role of both genetics and epigenetics in the onset of PD. This study supports that gene-microbiome interactions signify a newly discovered PD etiology. This study is significant because it uncovers that microbiota are needed for hallmark motor and GI dysfunction in PD mice model. Furthermore, it shows a new trend that neurological disorders that have been long known as brain disorders may also have unrecognized etiologies in the gut.
Figure 1. Non-sterile mice contain specific pathogen free microbiota that produces short chain fatty acids, and leads to the activation of microglia, which results in motor dysfunction and PD pathophysiology. Conversely, germ free mice did not show activation of microglia and displayed limited pathophysiology.
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