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

Date Published: 2023-12-05

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.

Introduction:
Inflammation significantly affects the male reproductive system, and it can arise from various sources, such as bacterial and viral pathogens, as well as autoimmune processes [1]. The gastrointestinal tract, and primarily the microorganisms associated with it, known as the gut microbiome, play a crucial role in the regulation of inflammatory processes [2]. Disturbance in the bacterial composition of the gut microbiome can lead to thinning of the mucosal barrier layer, making it more susceptible to pathogen…

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