Degenerative Cervical Myelopathy (DCM) induces sex-specific dysbiosis in the mouse gut bacterial microbiome, altering abundance and function

<strong>Background:</strong> Degenerative cervical myelopathy (DCM) represents the commonest cause of spinal cord impairment induced by non-traumatic events in the elderly population. It describes a spectrum of disorders that cause progressive spinal cord compression, neurological impairment, loss of bladder and bowel functions, as well as gastrointestinal dysfunction. The gut microbiota has been increasingly recognized as an environmental factor that can modulate both the central nervous system and immune response through the microbiota-gut-brain axis. Changes in gut microbiota composition or in the microbiota producing factors have been linked in the progression and development of several different pathologies such as traumatic spinal cord injury (SCI). Little is known about the molecular mechanisms that trigger DCM manifestation, and the potential role of the gut microbiota. <strong>Results: </strong>Herein DCM was induced in female and male C57BL/6 mice by implanting an aromatic polyether material underneath the C5-6 laminae. The extent of DCM-induced changes in microbiota composition, also known as dysbiosis, was assessed by 16S rRNA sequencing from fecal samples at 3 different time points (6, 9 and 12 weeks after DCM induction). Several bacterial members were identified based on BLAST against the largest collection of metagenome-derived genomes from the mouse gut up to date. In both, female and males DCM caused gut dysbiosis compared with the sham group. However, dysbiosis was more pronounced in males than females, where several bacterial members of the families <em>Lachnospiraceae</em> and <em>Muribaculaceae</em> were significantly altered in the DCM group. These changes were also associated with altered immune cell composition in gut-associated lymphoid tissue, blood, and microbe-derived metabolic changes in propionate, butyrate, and lactate-producing bacterial members. <strong>Conclusions: </strong>Our results demonstrate for the first time that DCM causes dynamic changes over time in the gut microbiota. Furthermore, we identify specie-specific abundance changes during DCM progression. DCM strongly reduces the abundance of butyrate-producing bacteria, and lactate-producing bacteria in much less extent. Sequence-based pangenomics cores were not resolved between the latter bacteria, but the gap-filling reactions and metabolic modelling successfully identified pyruvate-to-butanoate and pyruvate-to-propionate genes such as Buk and ACH1, respectively. These results aid to better understand markers and the molecular mechanisms that over time trigger DCM manifestation in females and males.**背景：** 退行性颈脊髓病（Degenerative Cervical Myelopathy, DCM）是老年人群中非创伤性事件引发脊髓功能受损的最常见病因。该疾病涵盖一系列可导致进行性脊髓受压、神经功能缺损、膀胱与直肠功能丧失，乃至胃肠道功能紊乱的病症。肠道菌群作为一类环境因子，可通过肠-脑轴（microbiota-gut-brain axis）调控中枢神经系统与免疫应答，这一观点已获得越来越多的认可。肠道菌群组成或菌群相关因子的改变，已被证实与创伤性脊髓损伤（Spinal Cord Injury, SCI）等多种疾病的发生发展密切相关。目前学界对触发退行性颈脊髓病发病的分子机制，以及肠道菌群在此过程中的潜在作用仍知之甚少。 **结果：** 本研究通过在C57BL/6雌雄小鼠的C5-6椎板下方植入芳香族聚醚材料，构建退行性颈脊髓病模型。分别在造模后第6、9、12周三个时间点采集粪便样本，通过16S rRNA测序评估退行性颈脊髓病诱导的菌群组成改变（即菌群失调）程度。基于当前最大的小鼠肠道宏基因组来源基因组集，通过BLAST比对鉴定出多种细菌类群。与假手术组相比，雌雄小鼠均出现肠道菌群失调；但雄性小鼠的菌群失调程度较雌性更为显著：退行性颈脊髓病模型组中，毛螺菌科（Lachnospiraceae）与鼠杆菌科（Muribaculaceae）的多个细菌类群丰度发生显著改变。上述菌群改变还与肠道相关淋巴组织、血液中的免疫细胞组成变化，以及产丙酸、丁酸与乳酸的细菌类群的微生物代谢变化密切相关。 **结论：** 本研究首次证实，退行性颈脊髓病可导致肠道菌群随时间发生动态变化。此外，本研究还鉴定出退行性颈脊髓病进展过程中物种特异性的丰度变化。退行性颈脊髓病可显著降低产丁酸细菌的丰度，而对产乳酸细菌的丰度影响相对较小。基于序列的泛基因组学核心分析未能区分上述产乳酸细菌，但通过缺口填补反应与代谢建模，本研究成功鉴定出丙酮酸向丁酸转化的基因Buk，以及丙酮酸向丙酸转化的基因ACH1。本研究结果有助于进一步阐明雌雄小鼠中，随时间推移触发退行性颈脊髓病发病的分子机制与相关生物标志物。