Shumilov Kirill, Ni Allen, Garcia-Bonilla Maria, Celorrio Marta, Friess Stuart H
Virginia Commonwealth University.
Washington University in St. Louis School of Medicine.
Res Sq. 2024 Apr 24:rs.3.rs-4289147. doi: 10.21203/rs.3.rs-4289147/v1.
White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the modulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.
白质损伤（WMI）被认为是创伤性脑损伤（TBI）后长期认知功能障碍的主要原因。这种损伤部分是由于损伤后少突胶质细胞谱系细胞（OLCs）的凋亡死亡，这是由创伤直接引发或对轴突退变的反应所触发的。最近的研究表明，肠道微生物群通过调节TBI后外周免疫细胞浸润来调节炎症反应。此外，T细胞直接影响OLCs的分化和增殖。因此，我们假设肠道微生物群在调节OLCs对WMI的反应中起关键作用，影响T细胞的分化和激活。TBI后早期肠道微生物的耗竭长期减少了髓鞘再生，急性降低了OLCs的增殖，并与髓鞘碎片积累增加有关。令人惊讶的是，肠道微生物群耗竭的小鼠中T细胞的缺失恢复了TBI后OLCs的增殖和髓鞘再生。与来自对照损伤小鼠的T细胞相比，与来自肠道微生物群耗竭小鼠的T细胞共培养的OLCs导致增殖受损和MHC-II表达增加。此外，在肠道微生物群耗竭和TBI条件下，OLCs中MHC-II的表达似乎与增殖受损有关。我们的数据共同表明，TBI后肠道微生物群的耗竭损害了髓鞘再生，减少了OLCs的增殖，同时增加了OLCs MHCII的表达，并且这需要T细胞的存在。这些数据表明，T细胞是肠道微生物群调节TBI后少突胶质细胞反应和白质恢复的重要机制环节。
