Protection of Testis against Lipopolysaccharide-Induced Toxicity: Mildronate-Induced L-Carnitine Depletion as a Modulator of Gut Microbiome Composition and Gastrointestinal Inflammation

Abstract

L-carnitine plays a critical role in sperm functioning and maintaining male fertility. Mildronate is a widely used drug for treating cardiovascular diseases. Mildronate inhibits L-carnitine biosynthesis and transport into cells while increasing glucose supply. Therefore, it is speculated that mildronate may impair male fertility by depleting L-carnitine. On the other hand, mildronate is known to have anti-inflammatory effects, which can positively influence the male reproductive system in certain physiological conditions. In this study, we induced inflammation in mice through lipopolysaccharide (LPS) injections and examined some inflammation markers in the testes and intestine, which contribute significantly to the development of systemic inflammation. We demonstrated that mildronate reduces inflammation in mouse testes and preserves mitochondrial DNA integrity. Importantly, mildronate-induced L-carnitine depletion did not have a negative impact on testicular properties or sperm count. We propose that the anti-inflammatory effect of mildronate may be linked to its action on the bacterial composition of the gut microbiome. Mildronate increases the Firmicutes/Bacteroidetes ratio, which is reduced after LPS injections. In contrast to L-carnitine supplementation, mildronate does not decrease the level of Alloprevotella, a bacterial genus that is necessary for reducing inflammation. Additionally, mildronate decreased the expression of pro-inflammatory cytokines and inflammation markers in the intestine, which aligns with our hypothesis regarding its anti-inflammatory effect.

Keywords

• mildronate
• L-carnitine
• lipopolysaccharide
• mitochondrial DNA
• male fertility
• gut microbiome