Linking the brain, gut and bacteria in neurological disease.

The lifetime risk of developing neurological disease is influenced by variety of factors: genetics, cardiovascular health, and of course, age and neuroscience research continues to uncover more subtle links. 

Recent work elaborates on a long-suspected connection between that occasionally troublesome leftover, the appendix, and Parkinson’s disease risk, while other researchers have raised the possibility of the brain having its own microbiome, with implications for a bacterial influence on the risk and course of neurological disease.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterised by the accumulation of mis-folded proteins in the brain: amyloid β and tau proteins in the case of AD, and α-synuclein in PD, where it is the main constituent of “Lewy bodies”- clumps of aggregated protein found within neurons and a hallmark of PD and other dementias. Mutations within the α-synuclein gene are found in familial PD and efforts are ongoing to determine the normal function of α-synuclein and whether preventing its aggregation or accumulation in the brain might be of benefit.

PD causes both motor and non-motor symptoms and gut-associated problems such as constipation and impaired emptying of the stomach are common years before the onset of motor symptoms. That the aberrant form of α-synuclein can be found throughout the gastrointestinal tract in individuals with PD has been known for several years, although this also the case in those who don’t develop PD.

   

The highest levels of aberrant α-synuclein are found the appendix, raising the possibility that it serves as reservoir for dysfunctional protein which makes its way to the brain via the vagus nerve and potentiates the transformation of normal α-synuclein into the aggregated form. Circumstantial evidence for a link between the appendix and PD risk has been found in a large epidemiological study, with individuals who had undergone surgical severing of the vagus nerve (usually to manage hard to treat chronic duodenal ulcers) being at  lower risk of developing PD.

  

Defining the role of the appendix in PD has proved elusive, and three recent epidemiological studies failed to find any obvious link. By analysing medical records from over 1.6m Swedes from 1964, a research group at the Van Andel Institute has established that appendectomy reduces the risk of developing PD by around 20%, although this protective effect was only apparent in individuals living in rural areas. Pesticide and herbicide exposure are linked with a higher risk of PD and appendectomy may in some way mitigate environment-related PD risk.  Further analysis indicated that appendectomy delayed the onset of PD by an average of more than three and a half years in those who had undergone appendix removal 30 years or more before.

Biochemical analysis of appendix samples from healthy individuals and those with PD identified aberrant forms of α-synuclein. These were present in 46 of 48 normal individuals.  Mixing normal appendix tissue with normal α-synuclein resulted in the protein being broken down into forms resembling those found in PD brain samples.

 

Although far from being a recommendation for elective appendectomy, the finding that aberrant α-synuclein is common in healthy people suggests that PD risk requires its migration to the brain. Finding ways of confining, or even eliminating, the protein from the appendix could conceivably reduce PD risk.

It’s postulated that appendix might play a role in monitoring and restoring the gut microbiome and that inflammation results in changes which favour bacteria which generate “pro-PD” metabolites. That the gut flora might directly influence the neurological environment is not as far-fetched as it once would have seemed although a poster presentation given at the Society for Neuroscience annual meeting suggests the possibility that a local, rather than distant, microbiome might potentially influence conditions in the brain.

University of Alabama researchers have found that rod-shaped structures first observed on electron microscopic examination of brain samples from schizophrenics are, in fact, bacteria. These were most abundant in the substantia nigra, hippocampus and prefrontal cortex but rarer in the striatum. Bacteria were also found within brain cells, particularly in the ends of astrocytes closest to the blood-brain barrier locations, in dendrites, glial cells and in and around myelinated axons.

To rule out sample contamination, the group compared fresh brain samples from mice raised in a normal environment and those born and maintained in a germ-free environment: bacteria were only found in the former. Nucleic acid sequencing indicated that most of the bacteria belonged to groups commonly found in the gut, although their means of passage to the brain- whether from blood, the nose or through the nervous system.

Since bacteria were found in the brains of both normal individuals and those with schizophrenia, there’s no obvious causal relationship, but, as the study of gut, oral and skin microbiomes has shown, bacterial nutrients and metabolites can cause subtle but important changes in cell and organ function. Whether the presence of bacteria in the brain truly indicates a permanent ecosystem and not merely a post-mortem artefact remains to be established. But, as with the appendix and PD, confirmation that the brain is indeed influenced by local (or distant) bacteria may help better define neurological disease risk and uncover new means of treatment and prevention.

Updated 30th June 2019:

Animal studies conducted by John Hopkins researchers provide further support for the gut-brain connection in Parkinson's disease. 

New research shows Parkinson's disease origins in the gut. Experiments in mice show transmission of nerve-killing protein from the gut into the brain. John Hopkins Medicine, online 26th June 2019. http://tinyurl.com/y655mr2m 

The news items that prompted my blog piece appeared in Science Translational Medicine and were reported by Kelly Servick:

Do gut bacteria make a second home in our brains?  Science Magazine News, online 9^th November Nov. 9, 2018. http://tinyurl.com/y7qabpdv

Seeds of Parkinson’s disease may hide in the appendix. Science Magazine News, online 31^st October 2018. http://tinyurl.com/yagm7sx8.

The vermiform appendix impacts the risk of developing Parkinson’s disease. Killinger, BA, et al. Science Translational Medicine 31st October 2018:Vol. 10, Issue 465, eaar5280. DOI: 10.1126/scitranslmed.aar5280 (paid access: abstract available).

The human brain microbiome; there are bacteria in our brains! Robert, RC et al. Poster presentation Poster #: 594.08/YY23, 6th November 2018. (Abstract only, but can be found in the downloadable full session abstract collection: Society for Neuroscience, Neuroscience 2018, 3rd-7th November 2018, San Diego http://tinyurl.com/yc3b52hl