Systems biology analyses reveal enhanced chronic morphine distortion of gut-brain interrelationships in simian human immunodeficiency virus infected rhesus macaques.
Systems biology analyses reveal enhanced chronic morphine distortion of gut-brain interrelationships in simian human immunodeficiency virus infected rhesus macaques.
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DOI：
10.3389/fnins.2022.1001544
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发表时间：
2022
影响因子：
4.3
通讯作者：
Byrareddy, Siddappa N.
中科院分区：
文献类型：
--
作者：
Olwenyi, Omalla A.;Johnson, Samuel D.;Bidokhti, Mehdi;Thakur, Vandana;Pandey, Kabita;Thurman, Michellie;Acharya, Arpan;Uppada, Srijayaprakash;Callen, Shannon;Giavedoni, Luis;Ranga, Udaykumar;Buch, Shilpa J.;Byrareddy, Siddappa N.
常用的阿片类药物，如吗啡，已被牵连在增强的SIV/HIV持久性在中枢神经系统（CNS）。然而，不同脑区的髓样细胞极化和病毒持续存在的程度仍不清楚。此外，吗啡对SIV/HIV肠-脑串扰失调的累加效应仍有待研究。因此，研究重点是了解滥用药物（如吗啡）如何影响免疫动力学、病毒持久性和肠-脑相互关系。在总共9周的时间里，恒河猴被加速，并且每天两次注射吗啡（n = 4）或盐水（n = 4）。随后是SHIVAD 8 EO变体感染。尸检时，从不同的脑[额叶、小脑、髓质、壳核、海马（HIP）和室下区（SVZ）]和肠道[升结肠、十二指肠和回肠的固有层（LP）和肌层（MUSC）]区域分离单核细胞。使用多参数流式细胞术分析髓样细胞极性/活化，结果与间接免疫荧光测定相证实。借助数字滴聚合酶链反应（PCR）测定猿猴人类免疫缺陷病毒（SHIV）DNA水平。然后使用Luminex测定法评价可溶性血浆/CSF生物标志物水平。最后，在Illumina NovaSeq平台上使用16 S rRNA评估粪便微生物组的变化。基于流式细胞术的半监督分析显示，吗啡暴露导致跨越不同脑区的活化小胶质细胞中M1（CD 14/CD 16）/M2（CD 163/CD 206）极化加剧。这是伴随着升高的SHIV DNA内的神经发生的网站-HIP和SVZ。HIP/SVZ CD 16+活化的小胶质细胞与脑中SHIV DNA水平呈正相关（r = 0.548，p = 0.042）。同时，吗啡依赖耗尽丁酸盐产生细菌，包括瘤胃球菌属（p = 0.05）、毛螺菌属（p = 0.068）和Roseburia_sp_831b（p = 0.068）。最后，吗啡还通过降低IL 1受体拮抗剂（IL 1 Ra）的水平来改变CNS炎症的调节。这些发现表明，吗啡通过改变受体调节，增加髓样脑激活，扭曲肠-脑串扰，并导致选择性增强神经发生部位的SHIV持续性，从而促进CNS炎症。
Commonly used opioids, such as morphine have been implicated in augmented SIV/HIV persistence within the central nervous system (CNS). However, the extent of myeloid cell polarization and viral persistence in different brain regions remains unclear. Additionally, the additive effects of morphine on SIV/HIV dysregulation of gut-brain crosstalk remain underexplored. Therefore, studies focused on understanding how drugs of abuse such as morphine affect immune dynamics, viral persistence and gut-brain interrelationships are warranted. For a total of 9 weeks, rhesus macaques were ramped-up, and twice daily injections of either morphine (n = 4) or saline (n = 4) administered. This was later followed with infection with SHIVAD8EO variants. At necropsy, mononuclear cells were isolated from diverse brain [frontal lobe, cerebellum, medulla, putamen, hippocampus (HIP) and subventricular zone (SVZ)] and gut [lamina propria (LP) and muscularis (MUSC) of ascending colon, duodenum, and ileum] regions. Multiparametric flow cytometry was used to were profile for myeloid cell polarity/activation and results corroborated with indirect immunofluorescence assays. Simian human immunodeficiency virus (SHIV) DNA levels were measured with aid of the digital droplet polymerase chain reaction (PCR) assay. Luminex assays were then used to evaluate soluble plasma/CSF biomarker levels. Finally, changes in the fecal microbiome were evaluated using 16S rRNA on the Illumina NovaSeq platform. Flow Cytometry-based semi-supervised analysis revealed that morphine exposure led to exacerbated M1 (CD14/CD16)/M2 (CD163/CD206) polarization in activated microglia that spanned across diverse brain regions. This was accompanied by elevated SHIV DNA within the sites of neurogenesis–HIP and SVZ. HIP/SVZ CD16+ activated microglia positively correlated with SHIV DNA levels in the brain (r = 0.548, p = 0.042). Simultaneously, morphine dependence depleted butyrate-producing bacteria, including Ruminococcus (p = 0.05), Lachnospira (p = 0.068) genera and Roseburia_sp_831b (p = 0.068). Finally, morphine also altered the regulation of CNS inflammation by reducing the levels of IL1 Receptor antagonist (IL1Ra). These findings are suggestive that morphine promotes CNS inflammation by altering receptor modulation, increasing myeloid brain activation, distorting gut-brain crosstalk, and causing selective enhancement of SHIV persistence in sites of neurogenesis.
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影响因子：
4.7
作者：
Breit S;Kupferberg A;Rogler G;Hasler G
通讯作者：
Hasler G
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
6.7
作者：
Alvarez-Carbonell, David;Ye, Fengchun;Karn, Jonathan
通讯作者：
Karn, Jonathan
DOI：
10.1007/s11481-017-9775-0
发表时间：
2018-06
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Dave RS;Sharma RK;Muir RR;Haddad E;Gumber S;Villinger F;Nehra AP;Khan ZK;Wigdahl B;Ansari AA;Byrareddy SN;Jain P
通讯作者：
Jain P
影响因子：
7.3
作者：
Dave，Rajnish S.;Ali，Haider;Byrareddy，Siddappa N.
通讯作者：
Byrareddy，Siddappa N.