Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation
Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation
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DOI：
10.1126/scitranslmed.aav0537
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发表时间：
2019-04-03
影响因子：
17.1
通讯作者：
Prendergast, Andrew J.
中科院分区：
文献类型：
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作者：
Bourke, Claire D.;Gough, Ethan K.;Prendergast, Andrew J.
长期复方新诺明预防可降低HIV感染的死亡率和发病率，但这些临床益处的机制尚不清楚。在这里，我们研究复方新诺明对全身炎症的影响，这是HIV死亡率的独立驱动因素。在接受抗逆转录病毒治疗的艾滋病毒阳性乌干达和津巴布韦儿童中，我们发现，在随机化后继续（n = 144）与停止（n = 149）复方新诺明后，血浆炎症标志物较低。这不能用临床疾病、HIV进展或营养状况来解释。由于亚临床肠道病原体携带和肠病可以驱动全身性炎症，我们探讨了复方新诺明对肠道微生物组和肠道炎症生物标志物的影响。虽然全球微生物组组成没有变化，但继续服用复方新诺明（n = 36）的儿童中草绿色链球菌和链球菌甲羟戊酸途径酶低于停止服用复方新诺明（n = 36）的儿童。这些变化与较低的粪便髓过氧化物酶有关。为了将复方新诺明对免疫激活的直接作用与抗生素作用分离开来，我们建立了全身性和肠道炎症的体外模型。体外复方新诺明对HIV阳性（n = 16）和HIV阴性（n = 8）UK成人血液白细胞产生的促炎细胞因子具有适度但一致的抑制作用，并减少肠道上皮细胞系产生的IL-8。总的来说，我们证明复方新诺明通过对微生物组的抗生素作用间接减少全身和肠道炎症，并通过钝化免疫和上皮细胞活化直接减少全身和肠道炎症。这些途径之间的协同作用可以解释复方新诺明的临床益处，尽管抗生素耐药性很高，为扩大撒哈拉以南非洲艾滋病毒感染者的覆盖范围提供了进一步的理由。
Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.