Abstract
BackgroundMinocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug’s direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline’s antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression.MethodsHere, we sought to determine minocycline’s effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter.ResultsWe found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery.ConclusionWe show that minocycline’s microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.
Highlights
Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties
It is well characterized that Spinal cord injury (SCI) results in the activation of microglia [60], which was confirmed by the increased area of IBA1 staining in all SCI rats relative to uninjured groups
Minocycline treatment following SCI resulted in an increased area of IBA1 immunoreactivity rostral to the injury at C4 and caudal to the injury at C6 compared to untreated SCI rats (Fig. 2e–g)
Summary
Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. Additional effects of SCI include autonomic dysreflexia, immune suppression, intestinal dysbiosis, and an increased risk of mental health disorders [1,2,3,4,5,6,7,8,9,10] Such system-wide consequences of SCI are detrimental to the quality of life but can lead to increased mortality rate [11,12,13,14]. Minocycline is a synthetic tetracycline derivative that has been shown to have anti-inflammatory, antioxidative, and direct neuroprotective effects after SCI [15,16,17,18,19,20,21] These positive preclinical results, coupled with minocycline’s long safety record in humans [22], resulted in a phase II placebo-controlled randomized clinical trial to test the therapeutic effects of minocycline treatment for acute SCI [23]. Another study reported no significant functional improvement between the minocycline and placebo groups in individuals with acute traumatic brain injury [33], further highlighting the contradicting findings on the efficacy of minocycline treatment
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