Ameliorating the Adverse Effects of Excess Propionic Acid

I am officially declaring this Biome Buzz’ first annual Propionic Acid Week! (Unfortunately, this is not a cause for celebration.)

If you remember, propionic acid (PPA) is a short-chain fatty acid produced by gut bacteria.  Ordinarily, PPA , like the other SCFAs, is great for you:  it is highly anti-inflammatory, beneficial for the gut flora, and so forth.  However, to disprove the old adage, “you can’t have enough of a good thing,” excess amounts are linked to severe neurological issues, including autism.

As a follow up to last week’s post about PPA and autism – really out of sheer curiosity – I took a look to see if there were any known treatments to alleviate the effects of excess PPA in autism and was absolutely floored. Just published, in July of this year, there was an article about using a medication called pioglitazone (brand name, Actos) to do just this.[i]

Why was a floored? Well, therein lies a tale:

Back in the early-ish 2000’s, back when my son, Alex, was really, really sick, we were working with a whole team of doctors.  Our immunologist was Dr. Marvin Boris, a wonderful man who – completely coincidentally – had been my pediatrician when I was a child, and who I adored even back then.  Also in that practice was my friend, his physician assistant, Alan Goldblatt.  Brilliant men, both of them. They were looking at immune issues in the autism population and hypothesized that using pioglitazone would be highly beneficial to deal with the major inflammatory problems in this population that were already accepted by the scientific community, even back then.  I’m going to make a long story short here: they did a clinical study on 25 children for a few months, which was published in 2007, measuring behavioral symptoms (hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy), and found “…apparent clinical improvement without adverse events…behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity).”[ii]

(We were among the first to try it and yes, Alex responded very favorably to pioglitazone. In fact, it was one of the few things that helped him, prior to me finding the Specific Carbohydrate Diet, when he was at his sickest.)

These findings have now been replicated several times.  Just a couple of examples:

  1. In 2015, a study assessed the efficacy of adding pioglitazone to a treatment regime of children with autism already on the atypical antipsychotic, Risperdal.  The study was 10 weeks long, double-blind, placebo- controlled, on 44 patients.  They found that adding the pioglitazone led to a marked decrease in irritability, lethargy/social withdrawal and hyperactivity/non-compliance.[iii]
  2. In 2018, a 16 week long single blind study with 25 children found, again, no serious adverse effects and  “…statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors…”[iv]

The point is, we’ve known for over 12 years now that pioglitazone  has a very beneficial effect on those with autism and we’ve also known, for at least that long, that excess PPA is common in the population has has extremely adverse effects, both on the immune system and neurologically.

Back now to the findings of this propionic acid/ pioglitazone study:

As I mentioned last week, PPA can easily cross the blood-brain barrier and get into the central nervous system causing brain inflammation.  In fact, patients with elevated PPA levels in stool and blood show similar symptoms to those with autism.

These scientists took rats that would be equivalent of 3-4 years old humans and gave them PPA for 3 consecutive days. They then broke them up into a total of 8 groups, testing the potential effects of different substances.  Yet again, PPA caused marked decreases in sociability, exploratory behaviors, hyperactivity, and worsening anxiety, etc. The rats also had much lower levels of the antioxidant, glutathione (which is also one of the major detoxification molecules in our bodies), and “significant elevation” in inflammatory cytokines as well as a dramatic decrease in the regulatory cytokine, IL-10, which modulates inflammation:  “This indicates the neuroinflammation in PPA treated rats as compared with control rats.”  However, those treated with pioglitazone showed significantly lowered levels of those inflammatory cytokines and increased IL-10 in the brain.

However (and this is upsetting but not unexpected):   “…pioglitazone significantly ameliorated PPA induced changes but this is only partial and not complete as results of pioglitazone treatments in rats are still significantly different from control rats.”

In other words – in rats at least – the changes induced by abnormally high levels of PPA were not entirely reversible.  The damage had been done.

They conclude that their results are in line with everything we already know.  PPA is a significant factor in causing autism; pioglitazone appears to be way to reduce the subsequent neuroinflammation.

On the bright side then, perhaps pioglitazone is a way to at least ameliorate the effects of excess PPA at an early point in life, when perhaps we can make the most difference in the future of children.  On the not so bright side, none of this explains the reasons for the excess PPA issue in the first place.  Antibiotics?  C-sections?  Formula feeding?  Maternal diet?  We just don’t know yet.

In my next post, to continue not-celebrating PPA week, I will describe to you other new study into adverse effects of PPA on humans.

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[i] Mirza, R, Sharma, B. A selective peroxisome proliferator-activated receptor- γ agonist benefited propionic acid induced autism-like behavioral phenotypes in rats by attenuation of neuroinflammation and oxidative stress.  Chemico-Biological Interactions. 2019; 311:108758. doi: 10.1016/j.cbi.2019.108758.

[ii] Boris, M, Kaiser, CC, Goldblatt, A, Elice, MW, Edelson, SM, Adams, JB, Feinstein, DL.  Effect of pioglitazone treatment on behavioral symptoms in autistic children.  Journal of Neuroinflammation. 2007;4(3). doi: 10.1186/1742-2094-4-3

[iii] Ghaleiha, A, Rasa, SM, Nikoo, M, Farokhnia, M, Mohammadi, MR, Akhondzadeh, S. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: effects on aberrant behavior in children with autism.  Psychiatry Research. 2015;229(1-2):181-7. doi: 10.1016/j.psychres.2015.07.043.

[iv] Capano, L, Dupuis, A, Brian, J, Mankad, D, Genore, L, Hastie Adams, R, Smile, S, Lui, T, Odrobina, D, Foster, JA, Anagnostou, E. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018;9(59). doi: 10.1186/s13229-018-0241-5

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