Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota

Abstract

Background Minocycline 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. Methods Here, 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. Results We 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. Conclusion We 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.

Gut Microbiota and Acute Central Nervous System Injury: A New Target for Therapeutic Intervention

“…FMT could increase the amount of fecal SCFAs and downregulate IL-1b/NF-kB signaling in the spinal cord and NF-kB signaling in the gut following SCI (118). A recent study also reported that minocycline treatment attenuated SCI-induced anxiety-like behavior and systemic inflammatory response via altering the Firmicutes/Bacteroidetes ratio (119). Engineered liposomes targeting the MGBA may also be a potential treatment (126).…”

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors

“…Pooled data for two RCTs recently showed that minocycline, a specific microglial inhibitor, improved depressive symptoms and reduced the severity of anxiety in a total of 112 participants with major depressive disorders ( Zazula et al, 2021 ). However, there is concern about other risks of using minocycline to treat anxiety and depression because it is also an antibiotic ( Schmidt et al, 2021 ).…”

Decreased PPARgamma in the trigeminal spinal subnucleus caudalis due to neonatal injury contributes to incision-induced mechanical allodynia in female rats

“…Vc microglia in female rats might not be an inflammatory phenotype after re-incision. Minocycline is widely used in glial research to inhibit the transformation of microglia toward an inflammatory phenotype 8 , 16 and does not affect microglial ramification or IBA1 expression under normal conditions 25 , 26 . Therefore, it is possible that minocycline unaffected Vc microglia in female rats even after re-incision.…”

“…All rats were acclimated to the testing environment for 5 days. The von Frey filaments (4,6,8,10,15,26,30,40,50,60, and 80 g) were applied to the left whisker pad skin according to the method described previously 47 . Each filament was used ascending manner.…”