A Novel Hypothesis: The Microbiota–Gut–Brain Axis

The two most common neurodegenerative disorders have a very long history. The first reported case of Alzheimer’s disease (AD) was in 1906, while Parkinson’s disease (PD) was described in 1817. Since then, intensive research has provided plenty of clinical, genetic, and molecular evidence of AD and PD signs, mechanisms, and druggable targets, leading to the discovery of pharmacological therapies, unfortunately only symptomatic. AD and PD are prevalent disorders with heavy societal costs. In the USA alone, 5.8 million Americans are currently affected by AD and ~1 million are living with PD. The sum of global healthcare costs of AD, other dementias, and PD is estimated to be more than US$300 billion per year. The scientific community has seen many failures in large clinical trials addressing neurodegenerative disorders, and novel drug discovery strategies are mandatory. Based on this scenario, many researchers began to think that most accepted current hypotheses for AD and/or PD pathogenesis are probably only part of the answer, and that we need fresh viewpoints.A promising novel hypothesis for AD and/or PD etiology looks at the pathogenic role of intestinal microbiota in brain neurodegeneration. The microbiota comprises a complex community of microorganisms: it is dynamic and tunable according to age, diet, and medication. It is composed of metabolically active bacteria, viruses, and fungi, and can also be found in the mouth and nose, from which there are multiple ways to reach the central nervous system (CNS), for instance through cranial nerves (particularly the olfactory nerve), promoting subacute and long-lasting inflammatory responses potentially relevant for AD and/or PD pathogenesis. This functional relation between the intestinal microbiota and the brain, referred to as the ‘microbiota–gut–brain axis’, shifts the trigger of AD and/or PD from the CNS to the body periphery, and this different perspective has an impact on therapeutic strategies. Human studies are accumulating fast: they support an imbalance of microbiota bacterial strains towards a proinflammatory profile in patients with AD and/or PD and suggest selected strains involved in AD and/or PD pathology or drug response. For instance, Porphyromonas gingivalis, a strain commonly present in the oral cavity, was suggested to have a role in AD through a well-described mechanism that involves toxic proteases called gingipains, while the gut strains Enterococcus faecalis and Eggerthella lenta have been associated with the decreased bioavailability of the PD medication levodopa. The importance of the gut microbiota for AD and/or PD pathology is still not fully clear, but our understanding is rapidly expanding to other CNS disorders.

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