Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.

IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gut Microbes Pub Date : 2024-01-01 Epub Date: 2024-06-11 DOI:10.1080/19490976.2024.2363880
Yongguo Zhang, Yinglin Xia, Jun Sun
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Abstract

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 Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, 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, Butyrivibrio fibrisolvens, 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.

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益生菌和微生物代谢物可维持屏障和神经肌肉功能,并清除蛋白质聚集,从而延缓 TDP43 突变小鼠的疾病进展。
肌萎缩性脊髓侧索硬化症(ALS)是一种神经肌肉疾病。表达人突变型转录反应 DNA 结合蛋白 43 kDa(hmTDP43)的 ALS 小鼠在出现神经肌肉症状之前就表现出肠道功能障碍。我们推测,用细菌代谢物或益生菌恢复肠道和微生物的平衡可延缓 ALS 发病。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 小鼠体内分离出来的肠胶质细胞(EGCs),进行机理研究。与年龄匹配的野生型小鼠相比,TDP43 小鼠的肠道流动性明显降低,渗透性增加,肌肉变弱。我们在 TDP43 小鼠的结肠、脊髓和大脑中观察到 hmTDP43 和神经胶质纤维酸性蛋白(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 小鼠的丁酰辅酶 A CoA 转移酶减少,丁酸菌 Butyrivibrio fibrisolvens 减少,脆弱拟杆菌 Bacteroides 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。TDP43小鼠的EGCs显示出hmTDP43的聚集,并伴有GFAP和电离钙结合适配分子(IBA1,一种小胶质细胞标记物)的增加。与未治疗组相比,接受丁酸盐或益生菌 VSL#3 治疗的 TDP43 小鼠的转体时间明显增加,肠道流动性增加,渗透性降低。丁酸盐或益生菌治疗可减少结肠、脊髓和大脑中 GFAP 和 TDP43 的表达,增加 α-SMA、ZO-1 和 Claudin-5 的表达。此外,丁酸盐或益生菌处理还能增强丁酰辅酶 A CoA 转移酶、丁酸纤维梭菌,并减少 TDP43 小鼠体内的炎性细胞因子。用丁酸盐或益生菌处理的 TDP43 EGCs 显示出 GFAP、IBA1 和 TDP43 聚集减少。通过有益菌和代谢产物恢复肠道和微生物的平衡为治疗渐冻人症提供了一种潜在的治疗策略。
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来源期刊
Gut Microbes
Gut Microbes Medicine-Microbiology (medical)
CiteScore
18.20
自引率
3.30%
发文量
196
审稿时长
10 weeks
期刊介绍: The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.
期刊最新文献
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