A Bacterial-Derived Metabolite and Anxiety in Autism and Schizophrenia

Readers with (or who have family members with) anxiety issues, autism, or schizophrenia, please pay special attention to today’s post.  I have feeling that this is a really significant finding.

Researchers at Cal Tech (along with colleagues at Stanford and other major California Universities) have discovered that a small gut-bacterial-derived metabolite seems to be very much an activator of anxiety behaviors.[i]  They started, of course, looking at a rodent model.  Several years back, researchers in their lab had noted that a metabolite of the bacterial microbiome called 4-ethylphenyl sulfate, or 4EPS, which is readily absorbed into the blood stream in both humans and mice, was at much higher levels in mice with altered neurological development – especially in mice that presented with rodent models of autism and schizophrenia.  While other metabolites also differed in the animal guts, 4EPS was by far the most altered.  And when they looked at humans, in a study of 231 people, 4EPS was found to bey 7X higher in children with autism than non-autistic controls!

In this most recent work, published last week in the eminent journal, Nature, the scientists compared two groups of mice, one of which was colonized with 2 kinds of bacteria that were engineered to produce 4EPS.  The control mice were also colonized with the same 2 bacterial species, but normal ones, not engineered to produce 4EPS.  The mice were then introduced to a novel environment to see what would happen. The former set, the 4EPS ones, did not normally explore their new environments and spent much of their time  hiding, as compared to the controls.  Brain scans of the 4EPS mice showed that the regions of the brain associated with fear and anxiety were more activated, and to boot, there were changes in brain activity and functional connectivity.  Cells in the altered regions, called oligodendrocytes, which produce myelin (the protective coating – like insulation – around neurons and nerve fibers) were different.  The oligodendrocytes were less mature and produced less myelin, leading to thinner myelin sheathes around nerves: “Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS.”

Now for the good news, which you may have just spotted:  when the 4EPS mic were treated with a drug known to increase myelin production in oligodendrocytes, the mice regained normal production of myelin and returned to normal behavior![iii]  I do not as yet have the name of that medication – I’m waiting for the full text of the paper to arrive and will fill you in on that when it does.

But Jude, you’re thinking, this was in mice!  How does this apply to us humans?!  Wait for it….

A second study, also performed by one of the lead authors of the above paper (this one published last week as well, in Nature Medicine) showed that giving mice an oral medication called Kremezin, which is an FDA approved drug for the treatment of chronic renal failure, is highly effective in treating this issue as well.[ii]  It was so effective on rodents, and is so safe, that the scientists were immediately permitted to try it in a small pilot study on humans – 30 individuals with autism. I did a lot of snooping around, and found that Kremezin  seems to be basically a high-powered form of activated charcoal:  it is capable of absorbing even small molecules, including bacterial-derived metabolites, including 4EPS, in the gut before they have a chance to make their way into the blood.

In both mice and humans, 8 weeks of Kremezin (given 3x per day) led to reduced levels of 4EPS in both the blood and urine, and decreased both anxiety and irritability:  ”AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints [in mice], most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment [in both mice and humans].”

Kremezin is available from Japanese pharmacies, if anyone is interested in trying it.

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[i] Needham, B.D., Funabashi, M., Adame, M.D. et al. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature (2022). https://doi.org/10.1038/s41586-022-04396-8

[ii] Stewart Campbell, A., Needham, B.D., Meyer, C.R. et al. Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial. Nat Med (2022). https://doi.org/10.1038/s41591-022-01683-9

[iii] https://www.sciencedaily.com/releases/2022/02/220214121254.htm

 

 

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