Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria, 2021, Esteves et al

In mice.

Abstract

Objective
Idiopathic 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.

Design
To 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.

Results
BMAA 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.

Conclusion
Taken 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.

Open access, https://gut.bmj.com/content/early/2021/11/29/gutjnl-2021-326023

 

Thought this looked interesting.

"BMAA targets mesencephalic mitochondria

Our findings support the notion that BMAA, a non-proteinogenic amino acid of microbial origin, may target their ancient relatives, the mitochondria. After BMAA treatment we isolated mice mesencephalic mitochondria and observed a reduction in mitochondrial function, namely a decrease in basal and maximal respiration and a decrease in ATP synthesis (figure 4A–D), which reduced mitochondrial pool calcium-buffering capacity (figure 4E–F). However, cortical mitochondria isolated from BMAA-treated mice were not affected (figure 4G–L). To investigate if BMAA contributes to neurodegeneration by specifically targeting neuronal mitochondria, we performed in vitro experiments using pure isolated mitochondria, to find that acute BMAA administration decreased oxidative phosphorylation both in isolated mesencephalic mitochondria (online supplemental figure S4A–G) and in cortical mitochondria of WT mice.21 "