Degenerative Cervical Myelopathy induces sex-specific dysbiosis in mice

Abstract

Degenerative Cervical Myelopathy (DCM) is the most common cause of spinal cord impairment in elderly populations. It describes a spectrum of disorders that cause progressive spinal cord compression, neurological impairment, loss of bladder and bowel functions, and gastrointestinal dysfunction. The gut microbiota has been recognized as an environmental factor that can modulate both the function of the central nervous system and the immune response through the microbiota-gut-brain axis. Changes in gut microbiota composition or microbiota-producing factors have been linked to the progression and development of several pathologies. However, little is known about the potential role of the gut microbiota in the pathobiology of DCM. Here, DCM was induced in C57BL/6 mice by implanting an aromatic polyether material underneath the C5-6 laminae. The extent of DCM-induced changes in microbiota composition was assessed by 16S rRNA sequencing of the fecal samples. The immune cell composition was assessed using flow cytometry. To date, several bacterial members have been identified using BLAST against the largest collection of metagenome-derived genomes from the mouse gut. In both, female and males DCM caused gut dysbiosis compared to the sham group. However, dysbiosis was more pronounced in males than in females, and several bacterial members of the families Lachnospiraceae and Muribaculaceae were significantly altered in the DCM group. These changes were also associated with altered microbe-derived metabolic changes in propionate-, butyrate-, and lactate-producing bacterial members. Our results demonstrate that DCM causes dynamic changes over time in the gut microbiota, reducing the abundance of butyrate-producing bacteria, and lactate-producing bacteria to a lesser extent. Genome-scale metabolic modeling using gapseq successfully identified pyruvate-to-butanoate and pyruvate-to-propionate reactions involving genes such as Buk and ACH1, respectively. These results provide a better understanding of the sex-specific molecular effects of changes in the gut microbiota on DCM pathobiology.

Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy

“…Currently, several studies link motor disorders with the homeostasis of gut microbiota and nutrient metabolism ( Gungor et al, 2016 ; Zhang et al, 2018 ; Lin et al, 2020 ; Farini et al, 2023 ). From this standpoint, we explored the possibility that DCM mice could experience intestinal dysfunction as a neurogenic consequence, considering prior reports showing changes in gut microbiota composition after DCM ( Farkas et al, 2023 ). In a mouse model of traumatic SCI, gut dysbiosis exacerbated the lesion size and neuroinflammation within the SC, inducing changes in gut-associated lymphoid cells and impairing neurological function.…”

“…For instance, without the intention of perpetuating a historical gender bias, we use only male mice to evaluate all the parameters presented here. Future studies should compare females and males given the contribution of sex-related biological factors and the compensatory phenotypes observed in some neuromuscular diseases, especially energy metabolism and contractile properties of muscles ( Glenmark et al, 2004 ; Deenen et al, 2015 ; Deschenes et al, 2018 ; Farkas et al, 2023 ; Landen et al, 2023 ; Levy et al, 2023 ; Vinciguerra et al, 2023 ). On the other hand, human and murine gut microbiota share over 80–90% similarities in phyla and genera, suggesting a high gut microbiota resembling.…”

“…This study was conducted in 8-weeks-old male C57BL/6 mice. We have focused our study on this sex because the incidence of DCM is greater in men versus women and because the male DCM mouse model has shown the highest dysbiosis compared with the female DCM mouse model ( Nouri et al, 2022 ; Farkas et al, 2023 ). The DCM mouse model was generated using an aromatic polyether polymer as previously described ( Karadimas et al, 2013 ; Ulndreaj et al, 2022 ).…”

“…Complementing these results, a DCM mouse model has shown changes in the gut microbiota composition during DCM progression. Specifically, there is a reduction of butyrate-producing bacteria and butyrate production ( Nouri et al, 2020 ; Davies et al, 2022 ; Farkas et al, 2023 ), suggesting a link between the gut–brain axis and the neuromotor axis.…”