Compromised Intestinal Barrier Resilience to Disruption in People with HIV [colon]

People living with HIV (PLWH) experience chronic intestinal barrier dysfunction (gut leakage), which persists despite viral suppression by antiretroviral therapy (ART) and contributes to chronic inflammation and its comorbidities. The mechanisms underlying this phenomenon remain unclear and are likely multifactorial. We hypothesize that living with HIV compromises the intestinal barrier's resilience to injurious agents, increasing susceptibility to leakage upon exposure to common exogenous or endogenous disruptors, such as alcohol or pro-inflammatory cytokines, respectively. Using 3D intestinal organoids (colonoids and enteroids) derived from PLWH on ART and HIV-negative controls, we assessed the impact of alcohol and inflammatory cytokines on barrier integrity. Organoids from PLWH exhibited reduced resilience to disruption compared to controls, correlating with alterations in pathways critical to epithelial integrity, including epithelial-mesenchymal transition, DNA repair, and oxidative stress-related pathways. These findings reveal a novel mechanism underlying intestinal dysfunction in PLWH and highlight potential molecular targets to mitigate these complications. Overall design: RNAseq profilling of organoids from colon biopsies from people living with HIV (PLWH) and people living without HIV (PLWoH)

HIV感染者（People living with HIV, PLWH）存在慢性肠道屏障功能障碍（gut leakage，即肠漏），即便通过抗逆转录病毒治疗（antiretroviral therapy, ART）实现病毒抑制，该障碍仍持续存在，并会促进慢性炎症及其共病的发生。目前这一现象的潜在机制仍不明确，且大概率为多因素共同作用的结果。我们提出如下假说：HIV感染会削弱肠道屏障对损伤因子的抵御能力，使得机体在暴露于常见外源性或内源性干扰物（分别为乙醇与促炎细胞因子）时，更易出现肠道渗漏。
本研究使用来自接受ART治疗的PLWH以及HIV阴性对照者的3D肠道类器官（3D intestinal organoids，包括结肠类器官colonoids与肠类器官enteroids），评估了乙醇与促炎细胞因子对肠道屏障完整性的影响。结果显示，与对照组相比，PLWH来源的类器官对屏障破坏的抵御能力显著降低，这一现象与上皮完整性关键通路的异常密切相关，包括上皮-间质转化、DNA修复以及氧化应激相关通路。本研究结果揭示了PLWH人群肠道功能障碍的全新机制，并为缓解此类并发症指明了潜在的分子靶点。
研究整体设计：对来自PLWH与HIV未感染者（People living without HIV, PLWoH）的结肠活检组织来源的类器官开展RNA测序（RNA-seq）分析。