In this month of Alzheimer's & Brain Awareness, we wanted to provide some scientific facts for how our gut microbiota might play a significant role in Alzheimer’s disease (AD). For more details on this exciting subject, and about microbiota and neurology in general, please check our annual review MICROBIOTA #6 this Fall.
According to the World Health Organization (WHO), “dementia is a syndrome in which there is deterioration in memory, thinking, behaviour and the ability to perform everyday activities”. It is estimated to affect around 50 million people worldly, with almost 10 million new cases every year. As there is currently no available treatment for dementia it represents a significant decrease in quality of life for both the patient and his/her relatives, and a significant practical and financial burden on society. In 2015, the overal cost of dementia was estimated at over US$800 billion in the US alone. Unsurprisingly, WHO has therefore recognized dementia as a public health priority.
AD represents approximately 60-70% of all dementia cases. It is a chronic disease that is characterized by a progressive decline in cognitive capacities, and is eventually associated with other neuronal symptoms. Aging and some genetic predispositions are thought to play a central role, but the AD etiology remains poorly characterized, which probably explains the failures and shortcomings of clinical trials to date. The neurodegeneration itself is due to the aggregation of misfolded proteins in the brain (mainly amyloid-beta and tau) that acquire some prion-like properties. Other possible pathological factors in the brain include inflammation, vascular damage, calcium imbalance, and energy metabolic disruptions.
The bidirectional interactions between the gut and the brain have been demonstrated for several decades, leading to the concept of “gut-brain axis” that involves both neural and humoral pathways. Central to this gut-brain axis is the gut microbiota, which represents trillions of microganisms, including 103-104 bacteria. Gut dysbiosis represents a change in gut microbiota that is associated with a disease state. A growing body of evidence in both animal models and human cohorts shows that gut dysbiosis is observed in neurodegenerative diseases and might even be part of their pathogenesis.
One mechanism by which gut bacteria could lead to AD is via the secretion of curli amyloidogenic proteins that are thought to reach the brain using similar pathways to prions. In 2017, Friedman & Chapman proposed the concept of “MAPRONOSIS”, that stands for Microbiota-Associated PRoteopathy And Neuroinflammation process (“OSIS”). However, other bacterial molecules (e.g. endotoxins) or bacteria-induced signals (e.g. mucosal cytokines) might also play a role after reaching the brain via the established gut-brain axis pathways. Interestingly, most studies on gut microbiota in animal models of AD or AD patients have found a decrease in anti-inflammatory bacteria and an increase in pro-inflammatory ones, despite some differences in microbiota profiles between studies. These studies also highlight a decrease in bacterial diversity in AD. Interestingly, in the “hygiene hypothesis”, such reduced microbiota diversity is associated with abnormal immune markers and AD is considered to be a neuro-inflammatory disease with a Th1:Th2 imbalance.
All these findings have led to imagining that, one day, modulating the microbiota could become a tool to treat neurodegenerative diseases, such as AD. However, it is important to keep in mind that despite its plasticity, the brain might not be able to recover. Therefore, microbiota modulation might be better used prophylactically, like a healthy diet and exercise. In addition, there is presently no robust approach that permanently modifies the gut microbiota and modulators have to be administered long-term.
Frieland & Chapman, PLOS Pathogens 2017
Hu X et al, Sci China Life Sci 2016