GUTS AGAIN..THIS TIME ITS PARKINSONS DISEASE !!!
JUST PUBLISHED IN Cell...
News regarding a Gut micro biome link to Parkinsons Disease..
This is fascinating research and again confirms the importance of the micro biome...
Discussion
Parkinson’s disease represents a growing health concern for an ever-aging population. While genetic risks have been identified, environmental factors and gene-environment interactions probably account for most PD cases (Nalls et al., 2014, Ritz et al., 2016). We provide evidence that the gut microbiota are required for postnatal events that promote hallmark motor deficits in an animal model. Under GF conditions, or when bacteria are depleted with antibiotics, transgenic animals overexpressing human αSyn display reduced microglia activation, αSyn inclusions, and motor deficits compared to animals with a complex microbiota. Treatment with microbially produced SCFAs restores all major features of disease in GF mice, identifying potential molecular mediators involved in gut-brain signaling. Exacerbated motor symptoms in humanized mice transplanted with a PD microbiota compared to healthy controls suggest that αSyn overexpression (genetics) and dysbiosis (environment) combine to influence disease outcomes in mice. Extrapolation of these preclinical findings to humans may embolden the concept that gene-microbiome interactions represent a previously unrecognized etiology for PD.
Mechanisms by which gut bacteria promote αSyn-mediated pathophysiology are likely complex; herein, we have identified one potential pathway requiring microbiota-dependent effects on microglia. Recent studies have demonstrated an active role for the gut microbiota in promoting full maturation and inflammatory capabilities of microglia through the production of SCFAs (Erny et al., 2015). Despite a requirement for the SCFA receptor FFAR2 for microglia maturation, these cells are not known to express FFAR2, but do express other SCFA-responsive genes such as the histone deactylases that modulate gene expression (Erny et al., 2015). SCFAs may cross the BBB and impact the physiology of cells in the CNS (Mitchell et al., 2011), or they may have peripheral effects, which indirectly activate and mature microglia by currently unknown mechanisms (Erny et al., 2015). Further, insoluble aggregates and oligomeric forms of αSyn activate microglia (Kim et al., 2013, Sanchez-Guajardo et al., 2013). Increases in the activation state of microglia and the production of pro-inflammatory cytokines alter neuronal function and increase cell death in models of PD and other neurodegenerative diseases (Kannarkat et al., 2013, Sanchez-Guajardo et al., 2013). Intriguingly, an inflammatory environment is known to enhance αSyn aggregation, which may further activate microglia upon contact and promote a feed-forward cascade that leads to additional αSyn aggregation and propagation and progression of disease (Gao et al., 2011). If true, possible future treatment options may include targeting immune activation by the microbiota, a notion consistent with research into anti-inflammatory therapeutic modalities for PD (Valera and Masliah, 2016).
While the microbiota promote microglia maturation, there are likely other disease-modifying processes that remain undiscovered. These include effects by the microbiota on autophagy (Lin et al., 2014), a cellular recycling process that is genetically linked to PD risk and when impaired may lead to reduced clearance of αSyn aggregates (Beilina and Cookson, 2015, Nalls et al., 2014). Additionally, intestinal bacteria have been shown to modulate proteasome function (Cleynen et al., 2014), which may also aid in the clearance of αSyn inclusions. The protective effects of autophagy and the proteasome are not specific to synuclienopathies, and the ability of the microbiota to modulate these critical cellular functions suggests that other amyloid disorders, such as Alzheimer’s and Huntington’s diseases, may be impacted by gut bacteria. In fact, recent studies have implicated the gut microbiota in promoting amyloid beta pathology in a model of Alzheimer’s disease (Minter et al., 2016). Though we have explored postnatal effects of the microbiota in a model of neurodegenerative disease, our findings do not address the likely important role of microbial signals during prenatal neurodevelopment. Whether gut microbes alter the development of the dopaminergic system, perhaps by modulating neurogenesis or neural differentiation in utero or early life, remains unexplored. Furthermore, gut microbes can produce dopamine and its precursors from dietary substrates, with almost half of the body’s dopamine generated in the GI tract (Eisenhofer et al., 1997, Wall et al., 2014). Deciphering microbiota effects on microglia activation, cellular protein clearance pathways, neurotransmitter production, and/or other mechanisms may offer an integrated approach to understand the pathogenesis of a complex and enigmatic disorder such as PD.
We reveal that gut bacteria from PD patients promote enhanced motor impairment compared to microbiota from healthy controls when transplanted into genetically susceptible ASO mice. This surprising finding suggests that distinct microbes associated with PD, rather than general microbial stimulation, manifest disease symptoms. Several bacterial taxa are altered in mice receiving fecal transplants from PD patients compared to healthy controls. Additionally, a number of bacterial genera are changed specifically in ASO animals, but not WT mice, receiving microbes from the same donor. These include depletions in members of family Lachnospiraceae and Ruminococceae in recipient mice, a notable finding as these same genera are significantly reduced in fecal samples directly from PD patients (Keshavarzian et al., 2015). Conversely, the gut microbiomes in human subjects with PD contain an increased abundance of Proteobacteria (Hasegawa et al., 2015, Keshavarzian et al., 2015, Scheperjans et al., 2015, Unger et al., 2016), remarkably similar to our results in mice. Whether these specific microbes play a role in disease processes remains unknown. Intriguingly, a recent study demonstrated alterations in fecal SCFA ratios between patients and healthy controls, including an elevated relative concentration of butyrate, possibly implicating a role for SCFAs in PD (Unger et al., 2016). Accordingly, we observe altered SCFA abundances in animals colonized with PD donor-derived microbiota, and the discovery that SCFAs are sufficient to generate αSyn-reactive microglia in the brain is consistent with expansive literature showing that altered microbial communities impact immune responses in the gut and periphery (Hooper et al., 2012).
What causes dysbiosis in PD? Physiological functions in affected individuals, such as altered intestinal absorption, reduced gastric motility, or dietary habits, represent factors that may change the microbiome. Epidemiological evidence has linked specific pesticide exposure to the incidence of PD (Ritz et al., 2016), with some pesticides known to impact microbiome configuration (Gao et al., 2016). Given the structure of αSyn and its ability to associate with membranes (Jo et al., 2000), it is tempting to speculate that extracellular αSyn may act as an antimicrobial, similar to recent observations with amyloid beta (Kumar et al., 2016), and shape the PD microbiome. Whether microbial community alterations are caused by extrinsic or intrinsic factors, the PD microbiota may be missing or reduced in protective microbes, harbor increased pathogenic resident microbes, or both. In turn, dysbiosis will result in differential production of microbial molecules in the gut. Metabolites produced by a deranged microbiota may enter the circulation (or even the brain) and impact neurological function. Identification of bacterial taxa or microbial metabolites that are altered in PD may serve as disease biomarkers or even drug targets, and interventions that correct dysbiosis may provide safe and effective treatments to slow or halt the progression of often debilitating motor symptoms.
Our findings establish that the microbiota are required for the hallmark motor and GI dysfunction in a mouse model of PD, via postnatal gut-brain signaling by microbial molecules that impact neuroinflammation and αSyn aggregation. Coupled with emerging research that has linked gut bacteria to disorders such as anxiety, depression, and autism, we propose the provocative hypothesis that certain neurologic conditions that have classically been studied as disorders of the brain may also have etiologies in the gut.