A growing number of preclinical studies suggest that the microbiome is a key regulator that may predispose to various diseases, including neurodegenerative disorders.
The relationship between gut flora and brain is increasingly becoming the focus of research. Through autonomic, neuroendocrinological, gastrointestinal and immunological pathways, communication between the gut microbiome and the central nervous system (CNS) occurs bidirectionally.1 Pathological complications alter the balance of neurotransmitters, which increases the activity of the hypothalamic-pituitary-adrenal (HPA) axis and results in chronic inflammation. Intestinal secretions, gut permeability and gut motility are strongly influenced by the CNS. Conversely, the gut microbiota is also known to influence brain function through the release of certain metabolites. Even anxiety, stress and social problems can affect bile secretion by altering the genes responsible for bile production.2
Studies in animal models and initial work in humans provide evidence that microbes - or changes in their composition - may trigger or influence the course of diseases, including Parkinson's disease, autism spectrum disorders, depression, Alzheimer's disease and multiple sclerosis.
A recent feature in the journal Nature uses the example of several neurodegenerative diseases to show how research findings in recent years have revolutionised our understanding of gut-brain interactions.3 We know that misfolded α-synuclein is important in Parkinson's disease. The first misfolded protein causes others to misfold until the damaging clumps known as Lewy bodies form in the brain. Prof. Robert P. Friedland, a senior neurologist at the University of Louisville, Kentucky, proposed a new hypothesis in 2015 about what initiates this cascade.
After reading that gut bacteria can make proteins whose structure resembles that of the faulty α-synuclein, he suspected that bacteria-derived proteins might be a template for the misfolding.3,4
His research group fed rats a particular strain of Escherichia coli that produces one of these clumping proteins (more precisely, a type of amyloid fibre known as curli protein) in the gut. In the brains of these animals, they observed an increased accumulation of α-synuclein. A paper published last year by another team confirmed Friedland's hypothesis.
Incidentally, doctors had the idea that Parkinson's could start in the gut much earlier, without being able to prove this experimentally, but from the observation that some patients suffer from constipation long before they develop motor symptoms. There is even an anecdote about one of the first author's patients: he complained of numbness and tingling in his arms and James Parkinson, noticing considerable constipation in the man's bowels, administered a laxative. Ten days later, not only was the bowel fine, but the symptoms had disappeared.3
One likely pathway is the vagus nerve, which connects the brainstem to many organs, including the colon, like a highway. Studies on animals and humans suggest that it plays a central role in transmitting at least some messages between the gut and the brain. This fits with the following observation: a common treatment for gastric ulcers in the 1970s was the complete or partial removal of the nerve to inhibit acid formation in the stomach. Later, a peculiar side effect was reported: Patients after complete vagotomy had a significantly lower risk of developing Parkinson's disease.5
A recent study in mice investigated this further.6 Injection of misfolded α-synuclein into the intestine gave rise to just that in the brain. However, if the vagus nerve was removed beforehand, no α-synuclein appeared in the brain. In this case, the administered α-synuclein itself seems to remain in the intestine and from there trigger a domino effect: misfolded proteins transmit the error upwards via the vagus nerve (also known as the pneumogastric nerve) until finally proteins misfold in the brain. Another team of researchers is in the process of verifying the same for the curli protein.
Bacterial amyloids are certainly not the only factor involved in pathologies as complex as Parkinson's, but they may be an important linchpin. Misfolded proteins also characterise other diseases, such as Alzheimer's disease and motor neurone disease. Evidence is growing that bacterial proteins may be involved here too.3
References:
1. Editor's Pick: Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disorders. European Medical Journal https://www.emjreviews.com/neurology/article/current-paradigms-to-explore-the-gut-microbiota-linkage-to-neurological-disorders/ (2020).
2. Bruce-Keller, A., Salbaum, J. M. & Berthoud, H.-R. Harnessing Gut Microbes for Mental Health: Getting from Here to There. Biol Psychiatry 83, 214-223 (2018).
3. Willyard, C. How gut microbes could drive brain disorders. Nature 590, 22-25 (2021).
4. Friedland, R. P. Mechanisms of Molecular Mimicry Involving the Microbiota in Neurodegeneration. Journal of Alzheimer's Disease 45, 349-362 (2015).
5. Svensson, E. et al. Vagotomy and subsequent risk of Parkinson's disease. Ann Neurol 78, 522-529 (2015).
6. Kim, S. et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson's disease. Neuron 103, 627-641.e7 (2019).