Rocha Clarissa Santos, Alexander Katie L, Herrera Carolina, Weber Mariana G, Grishina Irina, Hirao Lauren A, Kramer Dylan J, Arredondo Juan, Mende Abigail, Crakes Katti R, Fenton Anne N, Marco Maria L, Mills David A, Kappes John C, Smythies Lesley E, Ziprin Paul, Sankaran-Walters Sumathi, Smith Phillip D, Dandekar Satya
Department of Medical Microbiology & Immunology, University of California Davis, Davis, CA, 95616, United States.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, UK.
Mucosal Immunol. 2025 Jan 31. doi: 10.1016/j.mucimm.2025.01.011.
Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are associated with mucosal barrier disruption and immune suppression. Administration of Lactiplantibacillus plantarum or Bifidobacterium longum subsp. infantis into the SIV-inflamed gut lumen in vivo resulted in rapid reprogramming of microbial TRP metabolism towards indole-3-lactic acid (ILA) production. This shift accelerated epithelial repair and enhanced anti-viral defenses through induction of IL-22 signaling in mucosal T cells and aryl hydrocarbon receptor activation. Additionally, ILA treatment of human colorectal tissue explants ex vivo inhibited HIV replication by reducing mucosal inflammatory cytokine production and cell activation. Our findings underscore the therapeutic potential of microbial metabolic reprogramming of TRP-to-ILA and mechanisms in mitigating viral pathogenic effects and bolstering mucosal defenses for HIV eradication.
肠道炎症性疾病会导致微生物群落失调。人类免疫缺陷病毒1型（HIV）感染会破坏肠道完整性，颠覆修复/更新途径，损害黏膜免疫并引发微生物群落失调。然而，驱动病毒感染引发炎症的肠道修复机制的微生物代谢机制尚未完全了解。我们采用多管齐下的方法研究了肠道微生物在病毒感染引发炎症的肠道中恢复上皮屏障和黏膜免疫的能力及机制：利用感染猿猴免疫缺陷病毒（SIV）的非人灵长类动物模型模拟HIV/AIDS进行体内研究、利用暴露于HIV的人结肠外植体进行体外研究以及利用原代人肠道上皮细胞进行研究。SIV感染使色氨酸（TRP）代谢重新编程，增加了与黏膜屏障破坏和免疫抑制相关的犬尿氨酸分解代谢产物水平。在体内向感染SIV引发炎症的肠道腔中施用植物乳杆菌或婴儿双歧杆菌亚种，会使微生物TRP代谢迅速重新编程，转向生成吲哚-3-乳酸（ILA）。这种转变通过诱导黏膜T细胞中的IL-22信号传导和芳烃受体激活，加速上皮修复并增强抗病毒防御。此外，体外对人结肠组织外植体进行ILA处理，通过减少黏膜炎性细胞因子的产生和细胞激活来抑制HIV复制。我们的研究结果强调了将TRP代谢重新编程为ILA的微生物代谢及其机制在减轻病毒致病作用和增强黏膜防御以根除HIV方面的治疗潜力。
