• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Evidence for the Gut Microbiome to Contribute to Parkinson's Disease


  • Please log in to reply
No replies to this topic

#1 reason

  • Guardian Reason
  • 1,101 posts
  • 241
  • Location:US

Posted 05 December 2016 - 01:20 PM


In this open access paper, researchers provide evidence in support of the hypothesis that the development of Parkinson's disease starts in the gut, with changes in the microbiome that promote dysfunction:

Neurological dysfunction is the basis of numerous human diseases. Affected tissues often contain insoluble aggregates of proteins that display altered conformations, a feature believed to contribute to an estimated 50 distinct human diseases. Neurodegenerative amyloid disorders, including Alzheimer's, Huntington's, and Parkinson's diseases (PD), are each associated with a distinct amyloid protein. PD is a multifactorial disorder that has a strong environmental component, as less than 10% of cases are hereditary. Aggregation of α-synuclein (αSyn) is thought to be pathogenic in a family of diseases termed synucleinopathies, which includes PD, multiple system atrophy, and Lewy body disease. αSyn aggregation is a stepwise process, leading to oligomeric species and intransient fibrils that accumulate within neurons. Dopaminergic neurons of the substantia nigra pars compacta (SNpc) appear particularly vulnerable to effects of αSyn aggregates.

Although neurological diseases have been historically studied within the central nervous system (CNS), peripheral influences have been implicated in the onset and/or progression of diseases that impact the brain. Indeed, emerging data suggest bidirectional communication between the gut and the brain. Gastrointestinal (GI) physiology and motility are influenced by signals arising both locally within the gut and from the CNS. Neurotransmitters, immune signaling, hormones, and neuropeptides produced within the gut may, in turn, impact the brain. The human body is permanently colonized by microbes on virtually all environmentally exposed surfaces, the majority of which reside within the GI tract. Increasingly, research is beginning to uncover the profound impacts that the microbiota can have on neurodevelopment and the CNS. Dysbiosis (alterations to the microbial composition) of the human microbiome has been reported in subjects diagnosed with several neurological diseases. For example, fecal and mucosa-associated gut microbes are different between individuals with PD and healthy controls. Yet, how dysbiosis arises and whether this feature contributes to PD pathogenesis remains unknown.

Gut bacteria control the differentiation and function of immune cells in the intestine, periphery, and brain. Intriguingly, subjects with PD exhibit intestinal inflammation, and GI abnormalities such as constipation often precede motor defects by many years. It is posited that aberrant αSyn accumulation initiates in the gut and propagates via the vagus nerve to the brain in a prion-like fashion. This notion is supported by pathophysiologic evidence: αSyn inclusions appear early in the enteric nervous system (ENS) and the glossopharyngeal and vagal nerves. Further, injection of αSyn fibrils into the gut tissue of healthy rodents is sufficient to induce pathology within the vagus nerve and brainstem. However, the notion that αSyn aggregation initiates in the ENS and spreads to the CNS via retrograde transmission remains controversial, and experimental support for a gut microbial connection to PD is lacking.

Based on the common occurrence of GI symptoms in PD, dysbiosis among PD patients, and evidence that the microbiota impacts CNS function, we tested the hypothesis that gut bacteria regulate the hallmark motor deficits and pathophysiology of synucleinopathies. Herein, we report that the microbiota is necessary to promote αSyn pathology, neuroinflammation, and characteristic motor features in a validated mouse model. We identify specific microbial metabolites, short-chain fatty acids, that are sufficient to promote disease symptoms. Remarkably, fecal microbes from PD patients impair motor function significantly more than microbiota from healthy controls when transplanted into mice. Together, these results suggest that gut microbes may play a critical and functional role in the pathogenesis of synucleinopathies such as PD.

Link: http://dx.doi.org/10...ell.2016.11.018


View the full article at FightAging




0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users