As you know, I’ve been following the research of Dr. Derrick MacFabe for a good 20 years now. I’ve described it before on this blog, several times, including this first post 2 ½ years ago – to which, if you remember, Dr. MacFabe was kind enough to respond.
A short refresher: the Clostridial family of bacteria have both probiotic and pathogenic members, including C.difficile, which you likely have heard of as a serious, potentially lethal, species which causes severe diarrhea. The bacteria that causes botulism are also in this family. Various kinds of Clostridia are normal members of our bacterial microbiome, and are known to be major producers of the short-chain fatty acid, proprionic acid (PPA), which can easily cross the blood-brain barrier. Because it’s a normal, and usually beneficial, metabolite of gut bacteria, and has potent anti-fungal properties, PPA is frequently used as a preservative in food. So while short-chain fatty acids, like PPA, are usually great for us, to old adage still holds true: you can have too much of a good thing.
In light of the differences in the gut bacteria of those with autism, including very high levels of Clostridia, Dr. MacFabe and colleagues injected PPA directly into the ventricle of the heart (so into the blood stream) in rats to see what would happen and found that it induced, “…abnormal motor movements, repetitive interests, electrographic [EEG] changes , cognitive deficits, perseveration [repetitive behaviors], and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation…” The animals also went on to “…display brain electrical changes resembling some types of human epilepsy, which often co-exists with autism.” Repeated administration of PPA over time, increases the severity and effects, which suggests “…that PPA can exert permanent effects on brain and behavior.”[i]
For those of you who want to learn more, definitely take a little time to watch Dr. MacFabe talk – for example, here. Pay particular attention to the slides starting around minute 33, where you can actually footage of these “autistic” rats. It’s mind blowing.
The mechanism of action though, as to how and why PPA exerts a toxic influence was still not entirely known but yesterday, I read a paper that moves this research forward to a whole new level.[ii] Noting Dr. MacFabe’s work, and his finding that PPA led to increased glial cells (I’ll define this in a moment) in rats’ brains – and that previous research also shows abnormalities in the autistic gut biome (including elevated levels of the species Clostridia, Bacteroidetes and Desulfovibria (which I have also written about in the past)), researchers from the University of Central Florida introduced PPA to human neural stem cells to see what would happen. In people, these stem cells develop into the different kinds of cells in the brain, including neurons…and glial cells, which are a part of the brain’s immune system, pump out inflammatory cytokines when the brain is damaged or under attack, and also “…play a role in neurons development, connectivity, and protection.”
These researchers hypothesized that exposure to excessive levels of PPA, starting in utero, may cause these stem cells to excessively product glial cells which, in turn, increases inflammation in the brain and disturbs neural connectivity. Their theory was based on 20 years of mounting evidence of PPA’s role in autism, and also, the incredible parallels between autism and a condition called neonatal Proprionic Acidemia, in which a genetic mutation leads to PPA accumulation in the blood. This causes “…severe seizures, movement disorders, gastrointestinal issues, aloofness, and overall developmental delays.” In fact, growing evidence “…suggests that ASD may stem from a disorder in glial cells.”
In this in vitro experiment, these researchers indeed found that PPA induced excessive differentiation of the neural stem cells into glial cells and raise brain inflammation levels. This led them to propose that exposure to PPA during fetal gestation, in the early stages of brain development, leads to gliosis (excessive glial cell formation), inflammation and thus, abnormal brain connections: “Overall, the data in this study suggest that microbiome shift in maternal gut leads to formation of by-product such as PPA which then interferes with neural patterning during the early stages of the fetus’ neural development.”
They suggest that it is the mother’s diet that leads to excessive PPA in her gut, potentially harming the fetus: “During the early stages of pregnancy, increased consumption of PPA-rich processed foods combined with pre-existent dysbiosis may lead to accumulation of PPA in the maternal GI, travel through general circulation, cross the placental barrier, and interfere with neural differentiation…” Certainly, this may well be a factor. As this article points out, the numbers of children with autism in the United States has gone from 1 in 150, in 2000, to 1 in 59, in 2018. Several decades ago, it was 1 in 10,000. And yes, PPA has become a more and more common food additive. However, this does not explain why children on the spectrum have altered gut microbiota, and are themselves producing excessively high levels of PPA from their earliest days, even while not eating processed foods…nor does this explain why children from mothers who eat healthy, unprocessed food diets are also having children with autism. That dysbiosis is a multi-generational problem in the industrialized world is a given at this point. (You can read more about this on The Biome Buzz as well.)
So, while it certainly takes us a step closer to an answer, it’s not the whole answer. It certainly seems likely that the maternal biome may play a role in some cases of autism. We still need though to take into account the early introduction and overuse of leading to alterations in the infant biome. After all, we know that people who have been on antibiotics tend to be very prone to Clostridia infections. Perhaps this explains some of the enormous variability found in the autism population: perhaps it’s all a matter of timing? And the number and severity of the pro-Clostridia events in the baby’s life?
[i] Parracho, HMRT, Bingham, MO, Gibson, GR, McCartney, AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology: 2005, 54, 987-991.
[ii] Abdelli, LS, Samsam, A, Naser, SA. Proprionic acid induces gliosis and neuro-inflammation through modulation of PTEN/AKT pathway in autism spectrum disorders. Scientific Reports. 2019. 9(8824). doi.org/10.1038/s41598-019-45348-z