Approximately 1.4 million Americans are suffering from traumatic spinal cord injury (SCI) (1). The most noticeable effects of SCI are damage to both motor and sensory function. However, SCI manifests several “hidden” pathologies including changes in our gut microbiota (1). The gut microbiota not only regulates nutrient metabolism and immune responses, but also provides protection against pathogens. The nervous system in our gastrointestinal tract, also known as the “mini brain”, interacts bidirectionally with the brainstem and spinal cord. SCI can damage this bidirectional connection, causing intestinal dysfunction (1,2). The impaired gastrointestinal tract can trigger gut dysbiosis, gut microbiome imbalance, and microbial translocation to the bloodstream. All of these events can elicit several pathological responses including systemic inflammation and chronic pain. Therefore, besides treating motor and sensory dysfunction, it is important to understand the systemic changes associated with chronic SCI. This will help in development of novel therapeutic interventions to improve the health of people suffering from SCI (1,2). 

Trillions of microorganisms reside on the mucosal surface of the gut, which far exceeds the number of human cells present in the body (1). Although microorganisms are 1000 times smaller than human cells, they comprise approximately 2% of total body mass (3). The gut microbiota influence the functioning of all the organ systems, and therefore plays an important role in maintaining the homeostasis of the human body (1). The microorganisms break down complex molecules in food and release metabolites in the process. These metabolites not only influence cellular function in the gut, but can travel via the circulatory system and affect the functioning of other tissues including the liver, peripheral immune organs and central nervous system (1).  Several pathological conditions such as chronic stress or trauma can increase the gut mucosal permeability, which allows the gut microorganisms themselves to enter the bloodstream and elicit inflammatory responses throughout the body (1). 

Animal models of SCI have shown the increased permeability of intestinal epithelial cells and bacterial translocation to several organs including the lungs following SCI (1). It would be interesting to know whether the gut microbes can translocate to the injured spinal cord and elicit local inflammatory responses at the injury site. Studies indicate that both the blood-spinal cord barrier and the intestinal barrier are disrupted at similar times following SCI, therefore there is a high possibility that gut microbiota can circulate to the spinal cord (1). 

Both clinical and pre-clinical studies suggest a connection between SCI, gut microbiome imbalance, and systemic inflammation. A study done using the rat model of SCI suggested the microbiome changes 8 weeks after SCI and these changes are correlated with increased levels of proinflammatory cytokines (proteins that modulate immune responses) including IL-1β, IL-12, TNF-α, and MIP-2 (2,4). Another pre-clinical study also suggested the increase in expression of IL-1β, IL-10, and TNF-α in the mesentery, as well as gut dysbiosis after SCI (2,5). The gut microbial imbalance is also observed in patients with chronic traumatic SCI (6).

 The majority of SCI patients suffer from chronic pain and anxiety-like symptoms, both of which are shown to correlate with gut microbial imbalance (7,8). Further, gut dysbiosis can delay the recovery post SCI injury. The experimental introduction of microbial imbalance, prior to SCI induction in mice, resulted in exaggerated neurological impairment and spinal cord pathology. On the contrary, mice fed with commercial probiotics before SCI induction, showed reduced neuronal injury, and rapid locomotor recovery (5). Additionally, the fecal transplant following the SCI injury prevented gut dysbiosis and behavioral changes, including anxiety, in the rats (8). 

SCI can seriously impact the physical and mental health and social life of an individual. The above evidence indicates that there is a feed-forward loop between SCI and gut microbiome. SCI causes gut microbial imbalance, which can further ignite pathological events including inflammation, pain, and delayed recovery. Therefore, remodeling of gut microbiota following SCI, possibly by fecal transplant or use of probiotics, can help improve the quality of life of SCI patients. However, there is a paucity of research in this area, thus further investigation is required to establish mechanistic links between the gut microbiome and spinal cord injury. Additionally, clinical studies are required to prove if gut microbiota can be a therapeutic target for SCI. 

1.         Kigerl KA, Zane K, Adams K, Sullivan MB, Popovich PG. The spinal cord-gut-immune axis as a master regulator of health and neurological function after spinal cord injury. Exp Neurol. 01 2020;323:113085. doi:10.1016/j.expneurol.2019.113085

2.    Wallace DJ, Sayre NL, Patterson TT, Nicholson SE, Hilton D, Grandhi R. Spinal cord injury and the human microbiome: beyond the brain-gut axis. Neurosurg Focus. 03 2019;46(3):E11. doi:10.3171/2018.12.FOCUS18206

3.     Castillo DJ, Rifkin RF, Cowan DA, Potgieter M. The Healthy Human Blood Microbiome: Fact or Fiction? Front Cell Infect Microbiol. 2019;9:148. doi:10.3389/fcimb.2019.00148

4.         O’Connor G, Jeffrey E, Madorma D, et al. Investigation of Microbiota Alterations and Intestinal Inflammation Post-Spinal Cord Injury in Rat Model. J Neurotrauma. 09 2018;35(18):2159-2166. doi:10.1089/neu.2017.5349

5.         Kigerl KA, Hall JC, Wang L, Mo X, Yu Z, Popovich PG. Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med. 11 2016;213(12):2603-2620. doi:10.1084/jem.20151345

6.         Zhang C, Zhang W, Zhang J, et al. Gut microbiota dysbiosis in male patients with chronic traumatic complete spinal cord injury. J Transl Med. 12 2018;16(1):353. doi:10.1186/s12967-018-1735-9

7.         Bannerman CA, Douchant K, Sheth PM, Ghasemlou N. The gut-brain axis and beyond: Microbiome control of spinal cord injury pain in humans and rodents. Neurobiol Pain. 2021 Jan-Jul 2021;9:100059. doi:10.1016/j.ynpai.2020.100059

8.         Schmidt EKA, Torres-Espin A, Raposo PJF, et al. Fecal transplant prevents gut dysbiosis and anxiety-like behaviour after spinal cord injury in rats. PLoS One. 2020;15(1):e0226128. doi:10.1371/journal.pone.0226128