The Effect of Microbial Metabolites on Immune Function Reconstruction of Aids Based on Mitochondrial Dysfunction
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摘要:
目的 基于线粒体功能障碍探讨菌群代谢产物对艾滋病免疫功能功能重建的影响。 方法 在2023年10月至2024年3月之间招募石家庄市第五医院42名接受4年抗逆转录病毒治疗（antiretroviral therapy，ART）的HIV感染者，包括20名免疫无应答者（immune non-responders，INR）、22名应答者（immune responder，IR）。同时，选择20名性别和年龄匹配的无感染男男性接触者作为对照组，他们的HIV、乙型或丙型肝炎病毒感染均为阴性。采用流式细胞术分析免疫参数。采用游离脂肪酸荧光测定试剂盒和铁比色测定试剂盒测定血浆中游离脂肪酸（free fatty acid，FFA）和亚铁（Fe2+）水平。 结果 INR组患者的CD4+ T细胞、CD4+CD45RA+ T细胞和CD4+CD45RA+CD31+ T细胞百分比低于对照组和IR组（P < 0.05）。与IR组相比，INR组CD4+T细胞的JC-1比值、脂质反应性氧簇（reactive oxygen species，ROS）水平及C11-BODIPY过氧化/抗氧化升高（P < 0.05）。IR组CD4+T细胞的脂质ROS水平高于对照组（P < 0.05）。INR组患者外周血FFA水平和Fe2+水平高于对照组和IR组（P < 0.05），CD4+CD36+ T细胞百分比低于对照组和IR组（P < 0.05），而对照组和IR组之间的差异无统计学意义。 结论 菌群代谢产物FFA升高伴随着CD4+ T细胞上的CD36受体表达降低，导致线粒体功能障碍的发生。 Abstract:objective To explore the effect of microbial metabolites on immune function reconstruction of AIDS based on mitochondrial dysfunction. Methods From October 2023 to March 2024, 42 HIV-infected people who received antiretroviral therapy （ART） for 4 years were recruited, including 20 immune non-responders （INR） and 22 responders （IR）. At the same time, 20 non-infected MSM matched by sex and age were selected as the control group, and their HIV, hepatitis B or hepatitis C virus infection were all negative. The immune parameters were analyzed by flow cytometry. The levels of free fatty acid （FFA） and ferrous （Fe2+） in plasma were determined by fluorescence assay kit and iron colorimetric assay kit. Results The percentages of CD4+ T cells, CD4+CD45RA+ T cells and CD4+CD45RA+CD31+ T cells in INR group were lower than those in control group and IR group （P < 0.05）. Compared with IR group, the JC-1 ratio of CD4+ T cells, the level of reactive oxygen species （ROS） and the peroxidation/antioxidation of C11-BODIPY in INR group increased （P < 0.05）. The lipid ROS level of CD4+ T cells in IR group was higher than that in control group （P < 0.05）. The FFA level and Fe2+ level in peripheral blood of patients in INR group were higher than those in control group and IR group （P < 0.05）, and the percentage of CD4+CD36+ T cells was lower than that in control group and IR group （P < 0.05）, but there was no significant difference between control group and IR group. Conclusion The increase of FFA, a metabolite of flora, is accompanied by the decrease of CD36 receptor expression on CD4+ T cells, leading to mitochondrial dysfunction. -
Key words:
- HIV /
- Oxidative stress /
- T lymphocytes /
- Mitochondria /
- Antiretroviral therapy /
- free fatty acids
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图 1 INR组胸腺迁出和幼稚CD4+T细胞亚群减少
A：幼稚CD4+T细胞亚群（CD4+CD45RA+）的流式细胞分析代表图；B：各组幼稚CD4+T细胞亚群（CD4+CD45RA+）定量分析；C：胸腺迁出CD4+T细胞亚群（CD4+CD45RA+CD31+）的流式细胞分析代表图；D：各组胸腺迁出CD4+T细胞亚群（CD4+CD45RA+CD31+）定量分析
Figure 1. Thymus emigration and naive CD4+T cell subsets decrease in INR group.
图 2 各组CD4+T细胞内JC-1（绿色/红色）的代表性染色和JC-1比值的定量分析
Figure 2. Typical staining of JC-1 （green/red） in CD4+T cells in each group and quantitative analysis of JC-1 ratio
图 3 各组脂质ROS和脂质过氧化分析
A：流式细胞分析脂质过氧化物染色的代表图；B：细胞内脂质ROS水平的定量分析；C：流式细胞分析C11-BODIPY荧光探针的代表图；D：细胞内脂质过氧化水平和抗氧化水平比值的定量分析。
Figure 3. Analysis of lipid ROS and lipid peroxidation in each group
图 4 各组患者外周血FFA水平和Fe2+水平比较
注：A：外周血FFA水平分析，B：外周血Fe2+水平分析
Figure 4. Comparison of FFA level and Fe2+ level in peripheral blood of patients in each group
图 5 各组患者CD4+T细胞表面脂肪酸转运蛋白（CD36）的表达
Figure 5. Expression of fatty acid transporter （CD36） on CD4+T cells in patients of each group
表 1 研究参与者的一般特征 [中位数（M1，M3）]
Table 1. General characteristics of study participants [M（M1，M3）]
特征 对照组（n=20） INR组（n=20） IR组（n=22） Z/χ2 P 年龄，岁 35（33，38） 39（33，43） 35（31，40） 0.917 0.405 CD4+ T细胞，细胞数/μL 842（535，958）* 284（225，323） 502（398，711）* 17.328 <0.001 CD8+ T细胞，细胞数/μL 639（463，870） 581（490，862） 665（505，896） 2.076 0.134 基线CD4+ T细胞，细胞数/μL 163（101，244） 242（193，347） 1.494 0.143 基线HIV RNA，拷贝数/mL 3.544 0.057 ˂105 12 20 ≥105 8 2 治疗方案 - 0.961 TDF + EFV + 3TC 19 22 其他 1 0 ART治疗持续时间，年 5.11（4.10，6.52） 5.02（4.15，7.01） 2.021 0.494 成功ART的时间，年 4.63（3.62，6.21） 4.52（3.63，6.52） 1.684 0.297 总胆固醇，mmol/L 4.20（3.65，4.43） 4.17（3.46，4.97） 0.062 0.991 甘油三酯，mmol/L 1.89（1.36，2.77） 1.39（1.01，2.06）* 4.240 <0.001 HLD，mmol/L 1.03（0.85，1.18） 0.96（0.89，1.26） 1.761 0.086 LDL，mmol/L 2.29（1.98，2.77） 2.41（1.85，3.37） 1.283 0.207 与INR组相比，*P < 0.05 
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