Indolelactic acid

Indolelactic acid (Indole-3-lactic acid) is a tryptophan-derived microbial metabolite primarily produced by the gut microbiota. Indolelactic acid functions as a signaling molecule to modulate host immune responses and maintain gut homeostasis, exhibiting anti-inflammatory properties and playing a significant role in metabolic pathways and gut-brain axis communication^[1]. Indolelactic acid has a structure that includes an indole ring and a lactic acid moiety. Indolelactic acid acts as a ligand for the aryl hydrocarbon receptor (AhR), regulating the differentiation of immune cells and the secretion of cytokines. ILA exhibits anti-inflammatory, antiviral, and anti-tumor activities^{[2, 3, 4]}.

In vitro experiments have shown that Indolelactic acid (100μM) can enhance the activation of AhR and the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) in human intestinal epithelial cells. Indolelactic acid reduces endotoxin-induced macrophage activation and the release and expression of IL-8 in intestinal epithelial cells^[5]. Indolelactic acid also accelerates the production of IL12a in dendritic cells by enhancing the binding of H3K27ac at the enhancer regions of IL12a, which contributes to priming CD8+ T cell immunity against tumor growth^[6].

In vivo, daily oral administration of Indolelactic acid (20mg/kg) to C57BL/6 mice with colitis downregulates the levels of TNF-α, IL-6, and IL-22, significantly alleviating intestinal inflammation and restoring the diversity of the gut microbiota^[7]. In mouse models, oral administration of Indolelactic acid (35mg/kg/day) reduces neuroinflammation and improves motor function through an aldehyde dehydrogenase (ALDH)-dependent pathway, exerting antidepressant effects^[8].

References:
[1] Yu K, Li Q, Sun X, et al. Bacterial indole-3-lactic acid affects epithelium-macrophage crosstalk to regulate intestinal homeostasis. Proc Natl Acad Sci U S A. 2023 Nov 7;120(45):e2309032120.
[2] Zhang FL, Chen XW, Wang YF, et al. Microbiota-derived tryptophan metabolites indole-3-lactic acid is associated with intestinal ischemia/reperfusion injury via positive regulation of YAP and Nrf2. J Transl Med. 2023 Apr 18;21(1):264.
[3] Kim H, Lee E, Park M, et al. Microbiome-derived indole-3-lactic acid reduces amyloidopathy through aryl-hydrocarbon receptor activation. Brain Behav Immun. 2024 Nov;122:568-582.
[4] Li Y, Li Q, Yuan R, et al. Bifidobacterium breve-derived indole-3-lactic acid ameliorates colitis-associated tumorigenesis by directing the differentiation of immature colonic macrophages. Theranostics. 2024 Apr 22;14(7):2719-2735.
[5] Ehrlich AM, Pacheco AR, Henrick BM, et al. Raybould HE. Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells. BMC Microbiol. 2020 Nov 23;20(1):357.
[6] Zhang Q, Zhao Q, Li T, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metab. 2023 Jun 6;35(6):943-960.
[7] Zhang S, Nie Q, Sun Y, et al. Bacteroides uniformis degrades β-glucan to promote Lactobacillus johnsonii improving indole-3-lactic acid levels in alleviating colitis. Microbiome. 2024 Sep 19;12(1):177.
[8] Qian X, Li Q, Zhu H, Chen Y, et al. Bifidobacteria with indole-3-lactic acid-producing capacity exhibit psychobiotic potential via reducing neuroinflammation. Cell Rep Med. 2024 Nov 19;5(11):101798.

Indolelactic acid（Indole-3-lactic acid）是一种由色氨酸衍生的微生物代谢物，主要由肠道菌群产生。它作为信号分子参与调节宿主免疫反应和维持肠道稳态，具有抗炎特性，并在代谢通路和肠-脑轴通讯中发挥重要作用^[1]。Indolelactic acid的结构包含吲哚环与乳酸基团，能够作为芳烃受体（AhR）的配体，调节免疫细胞分化和细胞因子分泌，具有抗炎、抗病毒以及抗肿瘤的活性^{[2, 3, 4]}。

体外实验中，Indolelactic acid（100μM）可增强人肠道上皮细胞的AhR和核因子（红细胞衍生2）相关因子2（Nrf2）的激活，Indolelactic acid降低内毒素诱导的巨噬细胞活化，以及肠上皮细胞中 IL-8 的释放和表达^[5]。Indolelactic acid通过增强 IL12a 增强子区域的 H3K27ac 结合来加速树突状细胞中 IL12a 的产生，这有助于激发 CD8 T 细胞对肿瘤生长的免疫力 ^[6]。

在体内，对结肠炎模型C57BL/6小鼠每日口服Indolelactic acid（20mg/kg），可下调TNF-α、IL-6和IL-22的水平，显著减轻肠道炎症，并恢复肠道菌群多样性^[7]。在小鼠模型中，口服Indolelactic acid（35mg/kg/day）通过乙醛脱氢酶（ALDH）依赖性通路减少神经炎症，改善运动功能，发挥抗抑郁的作用^[8]。