Spinal Cord Injury Changes the Structure and Functional Potential of Gut Bacterial and Viral Communities

Abstract

Emerging data indicate that gut dysbiosis contributes to many human diseases, including several comorbidities that develop after traumatic spinal cord injury (SCI). To date, all analyses of SCI-induced gut dysbiosis have used 16S rRNA amplicon sequencing. This technique has several limitations, including being susceptible to taxonomic “blind spots,” primer bias, and an inability to profile microbiota functions or identify viruses. Here, SCI-induced gut dysbiosis was assessed by applying genome- and gene-resolved metagenomic analysis of murine stool samples collected 21 days after an experimental SCI at the 4th thoracic spine (T4) or 10th thoracic spine (T10) spinal level. These distinct injuries partially (T10) or completely (T4) abolish sympathetic tone in the gut. Among bacteria, 105 medium- to high-quality metagenome-assembled genomes (MAGs) were recovered, with most (n = 96) representing new bacterial species. Read mapping revealed that after SCI, the relative abundance of beneficial commensals (Lactobacillus johnsonii and CAG-1031 spp.) decreased, while potentially pathogenic bacteria (Weissella cibaria, Lactococcus lactis_A, Bacteroides thetaiotaomicron) increased. Functionally, microbial genes encoding proteins for tryptophan, vitamin B6, and folate biosynthesis, essential pathways for central nervous system function, were reduced after SCI. Among viruses, 1,028 mostly novel viral populations were recovered, expanding known murine gut viral species sequence space ∼3-fold compared to that of public databases. Phages of beneficial commensal hosts (CAG-1031, Lactobacillus, and Turicibacter) decreased, while phages of pathogenic hosts (Weissella, Lactococcus, and class Clostridia) increased after SCI. Although the microbiomes and viromes were changed in all SCI mice, some of these changes varied as a function of spinal injury level, implicating loss of sympathetic tone as a mechanism underlying gut dysbiosis. IMPORTANCE To our knowledge, this is the first article to apply metagenomics to characterize changes in gut microbial population dynamics caused by a clinically relevant model of central nervous system (CNS) trauma. It also utilizes the most current approaches in genome-resolved metagenomics and viromics to maximize the biological inferences that can be made from these data. Overall, this article highlights the importance of autonomic nervous system regulation of a distal organ (gut) and its microbiome inhabitants after traumatic spinal cord injury (SCI). By providing information on taxonomy, function, and viruses, metagenomic data may better predict how SCI-induced gut dysbiosis influences systemic and neurological outcomes after SCI.

Effect of Acute Physical Interventions on Pathophysiology and Recovery After Spinal Cord Injury: A Comprehensive Review of the Literature

“…The effects of SCI extend beyond somatic functions to include numerous autonomic and systemic changes. [98][99][100] Early rehabilitation has the potential to enhance protective effects on cardiac indices at early time points following SCI in rats, but only if rehabilitation is continued over time. 101 Rehabilitation initiated at later time points can still elicit positive effects, but subsequently increases time to recovery.…”

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

“…Additionally, the above analyses of SCI-induced gut microbiota dysbiosis were assessed by 16S rRNA amplicon sequencing, which cannot profile microbiota function or identify viruses (123). Du et al studied gut microbiota dysbiosis after experimental SCI at T4 or T10 using genome-and gene-resolved metagenomic analysis (122). The results suggested that the abundance of beneficial commensals (Lactobacillus johnsonii and CAG-1031 spp.)…”

“…The results suggested that the abundance of beneficial commensals (Lactobacillus johnsonii and CAG-1031 spp.) (122). In a Yucatan minipig model with a contusioncompression SCI at T2 or T10, Doelman et al presented a dynamic view of the microbiome changes following SCI and identified acute stage, 0-14 post-SCI, as a special time-frame that many of the bacterial fluctuations occur before returning to "baseline" levels (120).…”

The Association of Altered Gut Microbiota and Intestinal Mucosal Barrier Integrity in Mice With Heroin Dependence

“…The microbiota-gut-brain axis were considered as the bidirectional system of communication between central nervous system (CNS) and the gastrointestinal tract ( 27 ). Many CNS diseases such as autism spectrum disorder, Parkinson's disease, and major depressive disorder are more susceptible to gastrointestinal symptoms disorder ( 28 , 29 ), even more, gastrointestinal symptoms of individuals seems to strongly correlate with the severity of CNS diseases ( 28 ).…”