Preprint Frataxin Deficiency Drives Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering Inflammatory Phenotype in Microglia,2023,Sciarretta+

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia
Francesca Sciarretta; Fabio Zaccaria; Andrea Ninni; Veronica Ceci; Riccardo Turchi; Savina Apolloni; Valerio Chiurchiu; Marta Tiberi; Nadia D'Ambrosi; Silvia Pedretti; Nico Mitro; KATIA AQUILANO; Daniele Lettieri Barbato; Ilaria Della Valle; Martina Milani

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreich’s ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies.

Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance.

In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.


Link | PDF (Preprint: BioRxiv)

 

... unless you have a strong negative response to a metabolic product of fibre fermentation. I developed that earlier this year, and had to avoid fermentable fibre. Oral acetate had no effect; probably absorbed/used before reaching the colon. I seem to have a stronger response to pectin, which produces 80% acetate, and the weakest response to oats, which produce 43/31/26 acetate/propionate/butyrate.

FWIW, after months of minimal butyrate-producing fibre, I haven't noticed any significant worsening of any symptoms. Eating a significant amount of butter doesn't have noticeable effects either.

 

Perhaps expanded more clearly as:

"itaconate improved the immunometabolic profile in microglia [that were] downregulating FXN[,] through Nrf2-mediated mechanism"

 

i eat a low fiber diet because when i tried taking capsules of fiber they caused gastroparesis attacks.

 

What is Oral acetate?

I googled but got an avalanche that I couldn’t understand.

 

Orally taken acetate. In my case, I added some baking soda to vinegar, which results in sodium acetate. Fizzy drink; needs flavouring. Pectin, which generates lots of acetate in the colon, is really nasty for me (or was, not really eager to retest that).

Update: I tried probiotics (14 strains), and it's increased my tolerance for oats. I'm testing 4 tsps of oats this morning, and will try 5 tonight, trying to find my new limit, since the old one was just 1. I also tried wheat flour and chocolate, but one or both of those resulted in the same symptoms, so the probiotics weren't a complete fix.

 

Ahh thanks, I was imagining you could buy acetate tablets of some kind.

Pretty sure I am not brave enough to try the vinegar baking soda drink. What symptoms does it help with, or is supposed to help with in theory?

 

It doesn't have the unpleasantness of either ingredient. It's just a fizzy drink. If you wait for the fizz to stop, it's probably not worse tasting than some mineral waters. I expect acetate tablets are available, but I had these ingredients, so that's cheap and convenient.

For acetate? I took it to see whether that was the metabolite that was causing my worsening of symptoms (brainfog, aches, lethargy). Butyrate is supposed to be helpful for some things. Propionate is harmful if you take too much. I didn't come across anything about effects of acetate supplementation. I couldn't find a cheap source for propionate (just a $70 sack), so I couldn't test that on its own. I would have needed slow-dissolving capsules too, or apply it as an enema. However, since I couldn't think of any way to apply the knowledge of which metabolite was responsible, I wasn't willing to go to extremes (or mess/discomfort) to test it.

 

You took acetate to see if it would make your symptoms worse?

 

Yes, quite a few of my ME experiments are done expecting to make my symptoms worse. I like the black box approach: poke the box and see if anything changes. If it makes me feel worse, I know to avoid that factor in the future. I've had a number of surprises, where the factors I expected to make me feel worse failed to do so. Then there were experiments like the sodium acetate, which was a failure as an experiment because I didn't take into account the likelihood of it reaching my colon. Still valuable, since I now know that acetate at the start of the digestive tract (and I assume in the blood) does not cause the symptoms, but acetate in the colon seems to. That changes how I set up future experiments.