Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria

Abstract

ObjectiveIdiopathic Parkinson’s disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.DesignTo test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation.ResultsBMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits.ConclusionTaken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with ‘gut-first’ PD.

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

“…Although this field is vast, one area of interest involves the naturally occurring bacterial toxin ß-N-methylamino-L-alanine (BMAA). Occasionally found in dangerously toxic concentrations within certain seafood, BMAA consumption has been shown to cause a significant shift in the microbial environment of the gut [ 122 , 123 ], demonstrating to have profound effects on the propagation of αSyn from the gut to the brain and the subsequent development of PD [ 122 , 124 ]. Interestingly, BMAA has causal links to both ALS and PD, being the key contributor to the rare incidence of the ALS-PD complex in the western Pacific islands of Guam and Japan [ 125 , 126 ].…”

Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation

“…Most importantly, a recent report from our group demonstrated that BMAA oral administration in WT mice increased intestinal inflammation, loss of intestinal barrier integrity and caudo-rostral progression of ASYN. Furthermore, we observed that BMAA induced mitochondrial dysfunction leading to neuroinflammation, dopaminergic neuronal loss, and motor deficits [ 176 ]. Considering the above, accumulating evidence suggests that some members of the gut microbiota may produce toxins targeting the mitochondria of the ENS and CNS that could result in subsequent neurodegeneration [ 139 ].…”

Toxic trail from the gut to the brain

“…In GUT, Esteves et al 9 used the bacterial toxin β-N-methylamino-L-alanine (BMAA), which is naturally produced by dinoflagellates and cyanobacteria and can accumulate to dangerous levels in seafood like mussels and oysters 10. BMAA was supplemented in the drinking water of mice to investigate whether a body or gut first type of PD could be elicited.…”

“…Esteves et al 9 also touch on the vulnerability of different brain regions in their model. In line with what is known, they find mesencephalic neurons to be much more sensitive to the insult than neurons in other regions of the brain.…”

“…The paper by Esteves et al 9 is an important contribution to the field as it uses a realistic trigger (ingested foodborne toxin12) to set off a cascade of events, with local gut and midbrain damage, which culminates in parkinsonian symptoms in mice. Given that this toxin can enter the food chain via contaminated seafood also begs the question for possible regulation of BMAA levels in popular seafood like mussels, clams and oysters.…”