Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
Jesse Brown VA Medical Center, Chicago, IL, USA.
Gut Microbes. 2024 Jan-Dec;16(1):2363880. doi: 10.1080/19490976.2024.2363880. Epub 2024 Jun 11.
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria , and increased , compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, , and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.
肌萎缩侧索硬化症（ALS）是一种神经肌肉疾病。表达人类突变的转录激活反应 DNA 结合蛋白 43kDa（hmTDP43）的 ALS 小鼠在出现神经肌肉症状之前表现出肠道功能障碍。我们假设通过细菌代谢产物或益生菌恢复肠道和微生物的动态平衡可以延迟 ALS 疾病的发作。我们研究了 ALS 进展过程中肠道和神经元、肠道和血脑屏障以及炎症的病理生理变化。然后，我们培养了从 TDP43 小鼠分离的肠神经胶质细胞（EGCs）进行机制研究。与年龄匹配的野生型小鼠相比，TDP43 小鼠的肠道运动明显减少，通透性增加，肌肉减弱。我们观察到 TDP43 小鼠结肠、脊髓和大脑中的 hmTDP43 和胶质纤维酸性蛋白（GFAP）增加，α-平滑肌肌动蛋白（α-SMA）、紧密连接蛋白（ZO-1 和 Claudin-5）表达减少。与 WT 小鼠相比，TDP43 小鼠的 Butyryl-coenzyme A CoA 转移酶减少，丁酸产生菌减少，而丁酸增加。TDP43 小鼠的血清炎症细胞因子（IL-6、IL-17 和 IFN-γ）和 LPS 升高。来自 TDP43 小鼠的 EGCs 显示 hmTDP43 聚集，同时 GFAP 和离子钙结合接头分子（IBA1，一种小胶质细胞标志物）增加。与未处理组相比，用丁酸或益生菌 VSL#3 处理的 TDP43 小鼠的旋转棒时间明显延长，肠道运动增加，通透性降低。丁酸或益生菌治疗降低了结肠、脊髓和大脑中 GFAP、TDP43 的表达，增加了 α-SMA、ZO-1 和 Claudin-5 的表达。此外，丁酸或益生菌治疗增强了 TDP43 小鼠的 Butyryl-coenzyme A CoA 转移酶，减少了炎症细胞因子。用丁酸或益生菌处理的 TDP43 EGCs 显示 GFAP、IBA1 和 TDP43 聚集减少。有益细菌和代谢产物通过恢复肠道和微生物的动态平衡为治疗 ALS 提供了一种潜在的治疗策略。
