肠道微生物易位参与HIV相关认知功能障碍发病的机制研究

HIV-associated neurocognitive disorders (HAND) affect the quality of life of HIV patients significantly. However, the pathogenesis of HAND has not been fully understood. Recently, we found that the microbial translocation and the activation of kynurenine pathway, both of which were reported to have a role in the pathogenesis of HAND, are closely correlated in HIV-infected patients. It is well known that the metabolic products of kynurenine are toxic to neurons. Therefore, we hypothesize that microbial translocation plays an important role in the pathogenesis of HAND in HIV patients through activating the kynurenine pathway in microglia、astrocytes as well as circulating monocytes. To test our hypothesis, clinical surveys、cell studies as well as animal test will be performed. These results will help us to figure out whether HAND is associated with microbial translocation, if so, whether the activation of kynurenine pathway is required. Our study will not only provide new insights for people to understand the pathogenesis of HAND, but also has the potential to facilitate the clinical management and prevention of HAND in the future.

HIV 相关认知功能障碍 (HAND) 是严重影响HIV 患者生存质量的疾病，但其发病机制目前尚不清楚。本课题组根据前期实验数据发现，肠道微生物易位与犬尿氨酸代谢途径活化密切相关，而上述两者均已有报道可能与HAND 的发生相关。据此，我们提出假说：微生物易位通过活化小胶质细胞、星形胶质细胞以及外周血单核细胞中的犬尿氨酸代谢途径，提高体内犬尿氨酸浓度，从而促进HAND 发生。为验证我们的假说，我们将首先通过临床样本分析，分别验证HIV感染者肠道内微生物易位与血浆中犬尿氨酸浓度增加以及HIV感染者HAND 发生率升高的相关性；进而在细胞水平研究微生物易位激活犬尿氨酸代谢途径的分子机制；最后通过动物模型实验来进一步检验微生物易位是否与HAND 发生相关，以及其发生是否通过犬尿氨酸代谢途径活化实现。相关研究结果将有助于我们进一步明确HAND 的发病机制，以期为临床防治HAND 提供重要理论依据。

HIV相关认知功能障碍(HAND)是严重影响HIV患者生存质量的疾病，但其发病机制目前尚不清楚。我们前期研究认为，HIV感染者的IDO活性高于健康受试者，因此我们推测这或许是HIV感染者容易发生HAND的重要原因。本研究进一步证实HAND与IDO活性相关，但HAND与脂多糖并无关联，因此，本研究调整方案，针对受试者肠道菌群进行分析。通过对受试者肠道菌群多样性、门属水平构成、16s rRNA功能预测等分析，最终验证HIV感染者肠道菌群与的神经认知功能障碍不存在关联，为其他研究者少走弯路提供了基础。