(1051) Butyrate Mitigates Kidney and Liver Mitochondrial Dysfunction in a Lipopolysaccharide Mouse Model

Introduction: Commensal butyrate-producing bacteria are lost from the intestinal microbiome during sepsis, while fecal transplant to restore these organisms reduces inflammation in animal models. Because sepsis-induced mitochondrial dysfunction is linked to inflammation, we hypothesized that exogenous butyrate could offer precision therapy to prevent or reverse mitochondrial dysfunction in sepsis.

Methods: We studied juvenile male C57BL/6 mice injected with saline (controls, n=9), intraperitoneal (IP) LPS 5 mg/kg (n=8), pre-treatment with IP butyrate 1200 mg/kg followed 2 hours later by LPS (n=8), post-treatment with IP butyrate 1 hour after LPS (n=7), or butyrate only (n=8). Mice were euthanized at 24 hours to harvest kidney and liver to measure mitochondrial respirometry, electron transport complex (ETC) enzyme activity (spectrophotometry), and mitochondrial content (mtDNA/nDNA using ND5, β-actin genes via PCR). Data (mean ±SD) were compared using ANOVA with Dunnett tests for pair-wise comparisons.

Results: Kidney mitochondrial respiration through ETC I+II decreased after LPS compared to controls (275 ±23 vs 439 ±129 pmol/sec/mg tissue; p=0.02) while butyrate alone did not alter respiration (433 ±183; p=0.94). Butyrate pre-treatment increased respiration (367 ±61; p=0.02) compared to LPS; butyrate post-treatment was higher than LPS but not significantly (313 ±51; p=0.43). Liver mitochondrial respiration exhibited a similar pattern as in kidney, but differences were not significant. Mitochondrial ETC IV respiration and ETC enzyme activity did not differ between groups in kidney or liver. Butyrate pre-treatment blunted the decrease in mtDNA/nDNA caused by LPS slightly in kidney (control 1.0±0.2, LPS 0.9±0.2, butyrate 1.0±0.3; p=0.71) and more profoundly in liver (1.2±0.7, 0.7±0.2, 1.2±0.8; p=0.14) but differences were not significant.

Conclusions: In an endotoxemia mouse model, butyrate was able to prevent, but not significantly reverse, an LPS-induced decrease in mitochondrial respiration in kidney, with a similar, though non-significant, pattern in liver. Mitochondrial protection was not attributable to changes in ETC activity, but butyrate’s effect on mitochondrial content was not conclusive. These data support further studies of butyrate to protect against sepsis-induced mitochondrial dysfunction.