New Research into the Negative Side of Short-Chain Fatty Acids: Too Much of a Good Thing

I have spent a fair bit of virtual ink over the years talking about both the positives and the negatives of short chain fatty acids (SCFAs), mentioning that indeed, you really can have too much of a good thing.  For example, as healthy as it is to stay well hydrated, you can actually kill yourself by drinking too much water.  (This is called water intoxication, and by diluting the blood too much, you can dilute the levels of electrolytes (like sodium), which leads to swelling of cells and disruption of brain function.)  When it comes to health, just-the-right-amount is key.

Gut bacteria produce SCFAs upon their consumption of polysaccharides (fibers) and in turn, SCFAs feed other good bacteria, on top of having many direct positive effects upon the human body.  Science has shown  that some diseases (Parkinson’s, for example), are associated with low levels of SCFAs.

SCFAs are really complicated:  it turns out that not only do you need just the right amount, but you also need just the right amount at just the right time, especially when it comes to brain development. I’ll come back to this in a moment.

As I mentioned above, I have actually talked on this blog about the dangers of excessive levels of SCFAs, especially propionic acid (PPA or propionate), excess levels of which are now generally accepted as one of the likely causes of autism in our current epidemic. (Read about that here. )  I first mentioned this concept several years ago, not long after I started this blog, in a post about Dr. Derrick MacFabe, a Canadian neuroscientist, whom I first saw speak at a conference many years ago – and whose research I believed from that first moment to be among the most critical ever done in the field of autism.    Dr. MacFabe has spent nearly 2 decades now looking at the neurotoxic effects of excess levels of propionic and his findings have been continually ground-breaking.

In that first post, I described a paper he published back in 2012:  “According to Dr. MacFabe, PPA can readily enter the blood stream from the gut.  In his rat models, in the short term, small amounts immediately produce hyperactivity, repetitive behaviors and social impairment.  Repeated administration of PPA over time, increases the severity and effects, which suggests ‘…that PPA can exert permanent effects on brain and behavior.’”[i]

My regular readers may remember that Dr. MacFabe actually contacted me not long after that, and I had a conversation with him just this past week about some of his more recent research.  Over the next few months, I am going to delve in depth into both his work and other research into PPA as it is a topic of major concern for all of us, in regards to our health and the health of our children.

While excess PPA is now implicated in the development of autism (so all you prospective parents, new parents, and parents of children already on the spectrum should pay particular attention to these posts), PPA also looks like a likely suspect in many other chronic illnesses of our modern era, including potentially obesity.  This past September (during what I dubbed the Buzz’s first official Propionic Acid Week), I discussed research out of Harvard which showed that PPA  adversely affects metabolism by raising blood sugar levels.[ii]  From that post:  “The scientists looked at both animal and humans, and the latter were involved in a double-blind trial with 14 healthy volunteers. The researchers discovered that PPA stimulates the liver to produce more glucose by increasing levels of the hormones, glucagon and fatty acid-binding protein 4, which signal the liver to release sugar into the blood…In the humans in the study, this continued release of unneeded blood sugar led to insulin resistance:  their bodies no longer responded optimally to insulin, which lowers blood sugar levels.”

Remember:  PPA is not just produced by gut bacteria but is ubiquitous in foods commonly eaten in industrialized societies, including cheeses, baked goods and artificial flavors. So between those exogenous sources and what is produced in the gut from potentially altered bacterial composition, raised levels of PPA may be becoming one of the big health dangers of modern times. Fetuses, who are exposed to maternally derived PPA through the placenta are especially at risk during this critical period of brain development.  PPA easily passes through the placenta and the blood-brain barrier.

A very recent paper of Dr. MacFabe and colleagues demonstrates that even physiological levels (normal amounts found in humans) of SCFAs, including PPA, may affect brain development.[iii]  In vitro experimentation done on human neural progenitor cells (hNPCs, which are stem cells that develop into either neuron cells or glial cells (support cells for the neurons)) shows that exposure to normal, physiologic doses of SCFAs (acetate, propionate, butyrate), “…increased the growth rate of hNPCs significantly…,” while “…high levels…of SCFAs had toxic effects on hNPCs.”  As the authors write, “The SCFAs present in the human body fluid derive mainly from bacterial carbohydrate fermentation in the gut.  However, they are also present naturally in dairy, fermented foods, maternal milk and are added as antifungal agents in refined carbohydrates and dairy.  The amounts and composition of gut short-chain fatty acids are dependent not only on bacterial species but also on type of substrate (increased propionate with wheat and dairy, increased butyrate with inulin-containing diets).  Their effects are remarkably tissue and dose dependent.”  And timing dependent, too.  If babies are exposed to high levels in utero, brain development is potentially affected.

On the topic of altering the brain: Dr. MacFabe and other scientists published another 2019 study that showed that in rats, “…the data indicate that even low dose of propionic acid produces in adolescent rodents immediate changes in social behavior, and structural/ultrastructural alterations in amygdala.”[iv]  The amygdala is the area of the brain responsible for the perception of emotion (anger, fear, pleasure, etc.) and for controlling aggression.

The take-away message:  in the right amounts at the right times, SCFAs, including propionic acid, are crucially important for good health.  On the other hand, excessive amounts, from altered gut flora and dietary intake (and in fetuses, maternal exposure) appear to have profoundly negative effects on brain development and human health.

In one of those coincidences you all know I love, I happen to notice a market research report just released over this past weekend:  Sodium Propionate Market Will Generate Massive Revenue in Coming  Years.[v]  I’ll end this post then on an extremely disturbing note: “Rising demand for food preservatives in the food industry is the major driving factor for the global sodium propionate market. Sodium propionate prevents the growth of mold and some bacteria, thereby prolonging the shelf life of packaged baked goods. According to the Code of Federal Regulations, sodium propionate is generally recognized as safe when used as a food additive. It is also used to prevent mold growth in packaged and processed cheese products.”

(For more information on Dr. MacFabe’s work, check out his website, The Kilee Patchell-Evans Autism Research Group (KPEARG))


[i] MACFABE, Derrick F.. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microbial Ecology in Health and Disease, [S.l.], v. 23, aug. 2012. ISSN 1651-2235.

[ii] Tirosh, A, et. al.  The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans.  Science Translational Medicine. 2019:11(489).  DOI: 10.1126/scitranslmed.aav0120

[iii] Yang, LL, Millischer, V, Rodin, S, MacFabe, D, Villaescusa, JC, Lavebratt, C. Enteric short-chain fatty acids promote proliferation of human neural progenitor cells.  Journal of Neurochemistry. 2019.  doi: 10.1111/jnc.14928

[iv] Lobzhanidze, G, Lordkipanidze, T, Zhvania, M, Japaridze, N, MacFabe, DF, Pochkidze, N, Gasimov, E, Rzaev, F. Effect of propionic acid on the morphology of the amygdala in adolescent male rats and their behavior. Micron. 2019.  doi: 10.1016/j.micron


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