From the Neuroimmunology and MS Research (nims) (M.J.D., M.B., P.O., E.B.-C., M.H., A.L., R.M., M.S.), Department of Neurology, University Hospital and University Zurich; Institute for Implementation Science in Health Care (P.O.), University of Zürich; Cellerys AG (P.O., A.L., R.M., M.S.), Schlieren; Universitäts-Kinderspital Zürich (E.B.-C.); Neurozentrum Bellevue (M.H., A.L.); PharmaBiome AG (G.L.), Schlieren, Switzerland; and Therapeutic Immune Design (R.M.), Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Neurol Neuroimmunol Neuroinflamm. 2024 Sep;11(5):e200296. doi: 10.1212/NXI.0000000000200296. Epub 2024 Aug 6.
After the enormous health burden during the acute stages of the COVID-19 pandemic, we are now facing another important challenge, that is, long-COVID, a clinical condition with often disabling signs and symptoms of the neuropsychiatric, gastrointestinal, respiratory, cardiovascular, and immune systems. While the pathogenesis of this syndrome is still poorly understood, alterations of immune function and the gut microbiota seem to play important roles. Because affected individuals are frequently unable to work for prolonged periods and suffer numerous health compromises, effective treatments represent a major unmet medical need. Multiple potential therapies have been tried, but none is approved yet. Approaches that are able to influence the immune system and gut microbiota such as probiotics and paraprobiotics, i.e., nonviable probiotics, seem promising candidates. We, therefore, evaluated the clinical and immunologic effects of paraprobiotics in a small pilot study.
A total of 6 patients with long-COVID were followed systematically for more than 12 months after disease onset using standardized validated questionnaires, a smartphone app, and wearable sensors to assess neurocognitive function, fatigue, depressiveness, autonomic nervous system alterations, and quality of life. We then offered patients defined paraprobiotics for 4 weeks and evaluated them at the end of the treatment period using the same questionnaires, smartphone app, and wearable sensors. In addition, a comprehensive immunophenotyping and gut microbiota analysis was performed before and after treatment.
Improvements in several of the neurologic symptoms such as dysautonomia, fatigue, and depression were documented using both patient-reported outcomes and data from the smartphone app and wearable sensors. Of interest, the expression of activation markers on some immune cell populations such as B cells and nonclassical monocytes and the expression of toll-like receptor 2 (TLR2) on T cells were reduced after paraprobiotics treatment.
Our results suggest that paraprobiotics might exert positive effects in patients with long-COVID most likely by modulating immune cell activation and expression of TLR2 on T cells. Further studies with paraprobiotics should confirm the promising observations of this small pilot study and hopefully not only improve the outcome of long-COVID but also unravel the pathomechanisms of this condition.
This study provides Class IV evidence that paraprobiotics increase the probability of favorable changes of clinical and immunologic markers in patients with long-COVID.
在 COVID-19 大流行的急性阶段造成巨大健康负担之后，我们现在面临着另一个重要挑战，即长新冠，这是一种临床病症，常伴有神经精神、胃肠道、呼吸、心血管和免疫系统的致残迹象和症状。虽然这种综合征的发病机制仍不清楚，但免疫功能和肠道微生物群的改变似乎起着重要作用。由于受影响的个体经常长时间无法工作并遭受许多健康损害，因此有效的治疗方法代表了一个主要的未满足的医疗需求。已经尝试了多种潜在的治疗方法，但尚无一种方法获得批准。能够影响免疫系统和肠道微生物群的方法，例如益生菌和副益生菌，即非活性益生菌，似乎是有希望的候选方法。因此，我们在一项小型试点研究中评估了副益生菌对长新冠患者的临床和免疫影响。
对 6 名长新冠患者进行了系统随访，自疾病发病后超过 12 个月，使用标准化的验证问卷、智能手机应用程序和可穿戴传感器评估神经认知功能、疲劳、抑郁、自主神经系统改变和生活质量。然后，我们为患者提供了为期 4 周的副益生菌，并在治疗结束时使用相同的问卷、智能手机应用程序和可穿戴传感器对其进行评估。此外，在治疗前后进行了全面的免疫表型分析和肠道微生物群分析。
使用患者报告的结果以及智能手机应用程序和可穿戴传感器的数据，记录了一些神经系统症状（如自主神经功能紊乱、疲劳和抑郁）的改善。有趣的是，一些免疫细胞群体（如 B 细胞和非经典单核细胞）上的激活标志物表达以及 T 细胞上的 toll 样受体 2（TLR2）表达在副益生菌治疗后减少。
我们的结果表明，副益生菌可能通过调节免疫细胞激活和 T 细胞上 TLR2 的表达，对长新冠患者产生积极影响。使用副益生菌的进一步研究应证实这项小型试点研究的有希望的观察结果，并希望不仅改善长新冠的结局，还能揭示这种疾病的发病机制。
本研究提供了 IV 级证据，表明副益生菌增加了长新冠患者临床和免疫标志物有利变化的可能性。
