# Microbiome-Derived Indole-3-Lactic Acid Attenuates Cutibacterium Acnes-Induced Inflammation via the Aryl Hydrocarbon Receptor Pathway

## TL;DR

This study shows that a compound called indole-3-lactic acid (ILA) can reduce skin inflammation caused by a bacteria linked to acne by activating a specific receptor pathway.

## Contribution

The study identifies ILA as a novel postbiotic that reduces acne-related inflammation via the aryl hydrocarbon receptor (AHR) pathway.

## Key findings

- ILA and IPA significantly suppressed inflammatory mediators like TNF-α, IL-1β, and COX2 in C. acnes-stimulated keratinocytes.
- ILA treatment in mice reduced inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression.
- Transcriptomic analysis showed ILA upregulates AHR-responsive genes like CYP1A1 and CYP1B1 while reducing inflammatory signaling.

## Abstract

Acne vulgaris is a chronic inflammatory dermatosis where conventional therapies often face limitations in efficacy and safety, necessitating the development of microbiome-targeted interventions. This study investigated the immunomodulatory potential of microbiome-derived tryptophan metabolites as a novel therapeutic strategy for Cutibacterium acnes (C. acnes)-induced inflammation, focusing on the aryl hydrocarbon receptor (AHR) pathway. We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. acnes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model. In vitro, ILA and IPA significantly suppressed C. acnes-driven inflammatory mediators, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, and Cyclooxygenase-2 (COX2), whereas IAA demonstrated limited efficacy. In vivo, ILA treatment exhibited superior therapeutic activity, markedly reducing inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression. Transcriptomic analysis confirmed that ILA attenuates inflammatory signaling (e.g., IL-17 and TNF pathways) while upregulating AHR-responsive genes such as Cytochrome (CYP) 1A1 and CYP1B1. Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical formulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management.