Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich’s ataxia mouse model

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

“…Metabolomic analysis of butyrate-treated macrophages revealed a substantial reduction in glycolysis (Flemming, 2019; Schulthess et al, 2019) as well as limited inflammatory response in microglia (Caetano-Silva et al ., 2023). By virtue of the recently demonstrated anti-inflammatory effects of BUT on white adipocytes and BMDM of KIKO mice (Turchi et al ., 2023), we asked if butyrate treatment was also effective in counteracting the changes of the immunometabolic profile in activated BV2 FXN- . As reported in Fig.…”

“…Remarkably, the transcriptional profile of PBMC isolated from FRDA patients, revealed a strong enrichment for an inflammatory innate immune response (Nachun et al, 2018). Although high inflammatory susceptibility was described in FRDA mice and human (Khan et al ., 2022; Shen et al ., 2016; Turchi et al ., 2023), the mechanisms underlying this condition remain unexplored. Herein we demonstrated that the loss of FXN forces glycolytic catabolism promoting inflammatory phenotype in microglial cells.…”

“…The supplementation of butyrate in male mice was performed as previously reported (Turchi et al ., 2023). Sodium butyrate was incorporated into their food pellets (at a rate of 5 g per kg per day, consistent with their regular daily caloric intake) starting at 4 months of age.…”

“…Butyrate has been identified as a high-affinity ligand for the Gi-linked heterotrimeric guanine nucleotide-binding protein–coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCAR2) (Carretta et al, 2021), which is expressed in the brain and has been shown to modulate microglial actions in several neuroinflammatory diseases such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease (Moutinho et al, 2022; Offermanns, 2014). Recently, diminished abundance of butyrate-producing bacteria has been demonstrated in a mouse model of FRDA (Turchi et al, 2023). Dietary butyrate supplementation in FRDA mice limited macrophage activation in white adipose tissue and in bone marrow-derived macrophages, suggesting that this molecule could be also efficient in mitigating neuroinflammation and neurobehavior disability.…”

Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism

“…Butyrate has been identified as a high-affinity ligand for the Gi-linked heterotrimeric guanine nucleotide-binding protein–coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCAR2) ( Carretta et al, 2021 ), which is expressed in the brain and has been shown to modulate microglial actions in several neuroinflammatory diseases such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease ( Offermanns, 2014 ; Moutinho et al, 2022 ). Recently, diminished abundance of butyrate-producing bacteria has been demonstrated in a mouse model of FRDA ( Turchi et al, 2023 ). Dietary butyrate supplementation in FRDA mice limited macrophage activation in white adipose tissue and in BMDM, suggesting that this molecule could be also efficient in mitigating neuroinflammation and neurobehavior disability.…”