Gut dysbiosis impairs recovery after spinal cord injury

The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology. Disruption of this gut microbiome, a process known as dysbiosis, causes or exacerbates various diseases, but whether gut dysbiosis affects recovery of neurological function or lesion pathology after traumatic spinal cord injury (SCI) is unknown. Data in this study show that SCI increases intestinal permeability and bacterial translocation from the gut. These changes are associated with immune cell activation in gut-associated lymphoid tissues (GALTs) and significant changes in the composition of both major and minor gut bacterial taxa. Postinjury changes in gut microbiota persist for at least one month and predict the magnitude of locomotor impairment. Experimental induction of gut dysbiosis in naive mice before SCI (e.g., via oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment and spinal cord pathology after SCI. Conversely, feeding SCI mice commercial probiotics (VSL#3) enriched with lactic acid–producing bacteria triggers a protective immune response in GALTs and confers neuroprotection with improved locomotor recovery. Our data reveal a previously unknown role for the gut microbiota in influencing recovery of neurological function and neuropathology after SCI.

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Gut Dysbiosis and Recovery of Function After Spinal Cord Injury

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.242 ◽

2019 ◽

Author(s):

Kristina A. Kigerl ◽

Phillip G. Popovich

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Immune System ◽

Gut Microbiota ◽

The Body ◽

Gut Dysbiosis ◽

Organ Systems ◽

Immune System Development ◽

Probiotic Treatment ◽

Cord Injury

Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve. After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.

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Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury

Cells ◽

10.3390/cells10010073 ◽

2021 ◽

Vol 10 (1) ◽

pp. 73

Author(s):

Bilal El Waly ◽

Vincent Escarrat ◽

Jimena Perez-Sanchez ◽

Jaspreet Kaur ◽

Florence Pelletier ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Immune Cell ◽

Two Photon ◽

Sensory Axons ◽

Promising Therapeutic Approach ◽

Cord Injury ◽

Biochemical Signals ◽

Coated Carbon ◽

Striking Effect

The extension of the lesion following spinal cord injury (SCI) poses a major challenge for regenerating axons, which must grow across several centimetres of damaged tissue in the absence of ordered guidance cues. Biofunctionalized electroconducting microfibres (MFs) that provide biochemical signals, as well as electrical and mechanical cues, offer a promising therapeutic approach to help axons overcome this blind journey. We used poly(3,4-ethylenedioxythiophene)-coated carbon MFs functionalized with cell adhesion molecules and growth factors to bridge the spinal cord after a partial unilateral dorsal quadrant lesion (PUDQL) in mice and followed cellular responses by intravital two-photon (2P) imaging through a spinal glass window. Thy1-CFP//LysM-EGFP//CD11c-EYFP triple transgenic reporter animals allowed real time simultaneous monitoring of axons, myeloid cells and microglial cells in the vicinity of the implanted MFs. MF biocompatibility was confirmed by the absence of inflammatory storm after implantation. We found that the sprouting of sensory axons was significantly accelerated by the implantation of functionalized MFs after PUDQL. Their implantation produced better axon alignment compared to random and misrouted axon regeneration that occurred in the absence of MF, with a most striking effect occurring two months after injury. Importantly, we observed differences in the intensity and composition of the innate immune response in comparison to PUDQL-only animals. A significant decrease of immune cell density was found in MF-implanted mice one month after lesion along with a higher ratio of monocyte-derived dendritic cells whose differentiation was accelerated. Therefore, functionalized carbon MFs promote the beneficial immune responses required for neural tissue repair, providing an encouraging strategy for SCI management.

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

Journal of Neuroinflammation ◽

10.1186/s12974-021-02123-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Emma K. A. Schmidt ◽

Pamela J. F. Raposo ◽

Abel Torres-Espin ◽

Keith K. Fenrich ◽

Karim Fouad

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Spinal Cord Injury ◽

Nervous System ◽

Gut Microbiota ◽

Microglial Activation ◽

Motor Recovery ◽

Long Term Effects ◽

Cord Injury ◽

Anti Inflammatory

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.

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