Propionic Acid and Autism: A Mechanistic Study

Many times now, I have written about propionic acid (PPA) and its likely role in causing autism (here and here, to give you just a couple of many examples).  In fact, one of the earliest posts on this blog was an introduction to you of the work of Dr. Derrick MacFabe, one of my favorite researchers, and the “father” of propionic acid research.  If you remember, PPA is a short chain fatty acid (SCFA), a metabolite of gut bacterial fermentation, that at “…appropriate level…improves immune function, facilitates, cell signaling, and reduces food intake.” [i]  Too much, however, is almost definitely proven to be a key player in the current autism epidemic:  “High levels of PPA, but not other SCFAs, have been reported in the stools of autistic spectrum disorder (ASD individuals.  Studies have demonstrated that intraventicular infusions of PPA caused abnormal behavioral patterns, such as abnormal social interaction and anxiety-like behavior in rats similar to those seen in humans with ASD.”  (Here is another post about “too much of a good thing” re: PPA and other SCFAs.)

As you know, it is well-established that those on the autism spectrum have abnormal gut bacteria.  We know that these individuals appear to have high levels of propionic acid producers, like Clostridia and Desulfovibrio.  The work of Dr. MacFabe has been instrumental in establishing the autism-PPA connection.

However, the exact mechanism of how PPA might induce such neurodevelopmental issues is still unknown.  The paper I am discussing today provides new insight into the possible mechanism.  Previous research has already shown that SCFAs may modulate levels of neurotransmittors, including BDNF (brain derived neurotrophic factor) which is responsible for neurogenesis (i.e. growth of neurons).

First a little explanation.  Dendrites are the part of a neuron through which signals from other cells are transmitted, to reach the actual neuronal cell body.  These  dendrites may have more than a thousand “spines” which “…participate in the establishment of excitatory synapses.”  That is, the spines are crucial in the normal transmission of cellular signaling.  During brain development, spines are “highly dynamic” and “…defective synapse formation or development has been implicated in many neurological diseases.”

Another important definition in understanding this research:  autography is a process in which damaged organelles (small structures within the cell which allow it to operate properly) are degraded to be recycled to produce energy and to regenerate the cell.  In the initial step of autography, the organelles are “…engulfed inside a double-membraned vesicle called an autophagosome” which, in turn fuses with an autolysosome and degrades the faulty organelles using lysosomal enzymes.  The take away:  “…disruption of autography has been associated with several cellular pathologies, including tumors and neurological diseases.”  Makes sense:  leaving faulty components in cells will disrupt the working of the cell.   Now think about impaired autography during the development of nerve cells.

In studies on fruit flies, impaired autography greatly affects the size and construction of neuronal synapses.  With this in mind, these researchers isolated cells from the hippocampus of embryonic rats.  They then treated them with PPA.  Sure enough, these cells had “…visibly decreased dendritic spine density” – in fact, 39.13% less than controls:  “These findings indicate that PPA induces dendritic spine loss in hippocampal neurons.”  What happened?  PPA actually caused an increase in the initiation of autography but impaired autolysosome fusion.  Thus, the engulfed faulty organelles are not degraded, and the cell is left without that energy and building blocks to synthesize whatever it may need…like normal dendritic spines:  “Our findings suggest that PPA induces spine loss by disrupting the maturation of …autolysosomes…”  Mature autolysosomes means functioning autography which in turn “…helps to maintain cellular homeostasis and remodel synapses.”

Essentially, PPA disrupts the normal creation and development of neurons by interrupting the ability of the cells of the neuron to function properly.

The paper concludes by pointing out that, “A growing number of studies have implicated gut microbiota dysbiosis in behavioral and neurologic pathologies, such as in Alzheimer’s, Parkinson’s disease and ASD….Dendritic spines may serve as a common substrate for many neuropsychiatric disorders, particularly those that involve cognitive deficits, and dysregulation in spine morphology has been implicated in ASD.”

According to the press release by the Korea Brain Research Institute which is where this research was conducted, “This study is significant in that it identified the effect of a human gut bacterial metabolites on neurons by discovering that an excessive use of PPA, which is one of the most frequently used food additives, may induce autism.”[ii]

And…there you go.  Another log on the fire.


[i] Choi H, Kim IS, Mun JY. Propionic acid induces dendritic spine loss by MAPK/ERK signaling and dysregulation of autophagic flux. Mol Brain. 2020 Jun 2;13(1):86. doi: 10.1186/s13041-020-00626-0. PMID: 32487196; PMCID: PMC7268420.


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