背景:HIV感染者(PLWH),即使通过抗逆转录病毒治疗(ART)控制病毒复制,经历持续的炎症。这种炎症部分归因于肠道微生物菌群失调和易位,这可能导致非艾滋病相关的衰老相关的合并症。感染艾滋病毒的程度-受感染本身的影响,ART用法,性取向,或其他相关因素-影响肠道的生物学年龄尚不清楚。此外,微生物菌群失调和易位在PLWH生物老化中的作用仍有待阐明。为了研究这些不确定性,我们使用了系统生物学方法,分析结肠和回肠活检,血液样本,以及来自ART上的PLWH的粪便标本和无艾滋病毒感染者(PLWoH)作为对照。
结果:PLWH在结肠表现出加速的生物老化,回肠,和血,通过各种表观遗传衰老时钟来衡量,与PLWoh相比。研究微生物易位与生物衰老之间的关系,PLWH的肠道紧密连接蛋白水平降低,随着微生物易位的增加。这种肠通透性与更快的生物老化和增加的炎症相关。在研究微生物菌群失调与生物衰老之间的关系时,PLWH的肠道具有较高的特异性促炎细菌丰度,例如亚杆菌属和普雷沃氏菌属。这些细菌与加速的生物老化有关。相反,PLWH的肠道中产生抗炎短链脂肪酸的细菌丰度较低,例如亚硝石和丹毒科,这些细菌与缓慢的生物老化有关。相关网络揭示了结肠和回肠中特定微生物属(但不在粪便中)之间的显着联系,衰老加剧,促炎微生物相关代谢物的增加(例如,色氨酸代谢途径中的那些),和抗炎代谢物如马尿酸的减少。
结论:我们确定了与肠道和全身生物老化交织在一起的特定微生物组成和微生物群相关的代谢途径。这种生物老化的微生物特征可能反映了各种因素,包括HIV感染本身,ART用法,性取向,以及与艾滋病毒感染有关的其他方面。更深入地了解这些联系的潜在机制可以提供缓解加速衰老及其相关健康并发症的潜在策略。视频摘要。
BACKGROUND: People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV - influenced by the infection itself, ART usage, sexual orientation, or other associated factors - affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls.
RESULTS: PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid.
CONCLUSIONS: We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract.