Singh Shalini, Giron Leila B, Shaikh Maliha W, Shankaran Shivanjali, Engen Phillip A, Bogin Zlata R, Bambi Simona A, Goldman Aaron R, Azevedo Joao L L C, Orgaz Lorena, de Pedro Nuria, González Patricia, Giera Martin, Verhoeven Aswin, Sánchez-López Elena, Pandrea Ivona Vasile, Kannan Toshitha, Tanes Ceylan E, Bittinger Kyle, Landay Alan L, Corley Michael J, Keshavarzian Ali, Abdel-Mohsen Mohamed
The Wistar Institute.
Rush University Medical Center.
Res Sq. 2023 Oct 30:rs.3.rs-3492242. doi: 10.21203/rs.3.rs-3492242/v1.
People with HIV (PWH), even with controlled viral replication through antiretroviral therapy (ART), experience persistent inflammation. This is partly due to intestinal microbial dysbiosis and translocation. Such ongoing inflammation may lead to the development of non-AIDS-related aging-associated comorbidities. However, there remains uncertainty regarding whether HIV affects the biological age of the intestines and whether microbial dysbiosis and translocation influence the biological aging process in PWH on ART. To fill this knowledge gap, we utilized a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PWH on ART and their matched HIV-negative counterparts.
Despite having similar chronological ages, PWH on ART exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to HIV-negative controls. Investigating the relationship between microbial translocation and biological aging, PWH on ART had decreased levels of tight junction proteins in the colon and ileum, along with increased microbial translocation. This increased intestinal permeability correlated with faster intestinal and systemic biological aging, as well as increased systemic inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PWH on ART had higher abundance of specific pro-inflammatory bacterial genera, such as and . These bacteria significantly correlated with accelerated local and systemic biological aging. Conversely, the intestines of PWH on ART had lower abundance of bacterial genera known for producing short-chain fatty acids and exhibiting anti-inflammatory properties, such as and , and these bacteria taxa 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 microbial-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid and oleic acid.
We identified a specific microbial composition and microbiome-related metabolic pathways that are intertwined with both intestinal and systemic biological aging in PWH on ART. A deeper understanding of the mechanisms underlying these connections could potentially offer strategies to counteract premature aging and its associated health complications in PWH.
感染人类免疫缺陷病毒（HIV）的患者（PWH），即使通过抗逆转录病毒疗法（ART）实现了病毒复制的控制，仍会经历持续性炎症。这部分归因于肠道微生物群失调和易位。这种持续的炎症可能导致非艾滋病相关的与衰老相关的合并症的发展。然而，HIV是否会影响肠道的生物学年龄，以及微生物群失调和易位是否会影响接受ART治疗的PWH的生物学衰老过程，仍存在不确定性。为了填补这一知识空白，我们采用了系统生物学方法，分析了接受ART治疗的PWH及其匹配的HIV阴性对照的结肠和回肠活检组织、血液样本和粪便标本。
尽管接受ART治疗的PWH与HIV阴性对照的实际年龄相似，但通过各种表观遗传衰老时钟测量，他们在结肠、回肠和血液中表现出加速的生物学衰老。在研究微生物易位与生物学衰老之间的关系时，接受ART治疗的PWH结肠和回肠中的紧密连接蛋白水平降低，同时微生物易位增加。这种肠道通透性增加与更快的肠道和全身生物学衰老以及全身炎症增加相关。在研究微生物群失调与生物学衰老之间的关系时，接受ART治疗的PWH的肠道中特定促炎细菌属的丰度较高，如 和 。这些细菌与加速的局部和全身生物学衰老显著相关。相反，接受ART治疗的PWH的肠道中以产生短链脂肪酸和具有抗炎特性而闻名的细菌属的丰度较低，如 和 ，并且这些细菌分类群与较慢的生物学衰老相关。相关网络揭示了结肠和回肠（而非粪便）中特定微生物属之间的显著联系、衰老加速、促炎微生物相关代谢物（如色氨酸代谢途径中的代谢物）增加以及马尿酸和油酸等抗炎代谢物减少。
我们确定了一种特定的微生物组成和与微生物群相关的代谢途径，它们与接受ART治疗的PWH的肠道和全身生物学衰老相互交织。对这些联系背后机制的更深入理解可能会提供策略，以对抗PWH的过早衰老及其相关的健康并发症。
