read_status: annotated
type: paper
title: "Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity"
year: 2025
authors:
- "Jin, Wen-Bing"
- "Xiao, Leyi"
- "Jeong, Mingeum"
- "Han, Seong-Ji"
- "Zhang, Wen"
- "Yano, Hiroshi"
- "Shi, Huiqing"
- "Arifuzzaman, Mohammad"
- "Lyu, Mengze"
- "Wang, Daoming"
- "Tang, Yuelin Angelina"
- "Qiao, Shanshan"
- "Yang, Xiaoyu"
- "Yang, He S."
- "Fu, Jingyuan"
- "Sonnenberg, Gregory F."
- "Collins, Nicholas"
- "Artis, David"
- "Guo, Chun-Jun"
journal: "Cell"
doi: "10.1016/j.cell.2025.02.029"
url: "https://linkinghub.elsevier.com/retrieve/pii/S0092867425002569"
project:
- IGP
system:
- gut_microbiota
- bile_acid_pool
- cd8_t_cells
- tumor_microenvironment
disease:
- cancer
- solid_tumor
genes:
- androgen_receptor
- tcf7
processes:
- bile_acid_metabolism
- nuclear_receptor_antagonism
- cd8_t_cell_differentiation
- immune_checkpoint_response
methods:
- bile_acid_metabolomics
- microbial_genetic_screen
- nuclear_receptor_reporter_assay
- murine_tumor_models
- single_cell_rna_sequencing
key_findings:
- androgen_receptor_inhibition
- cd8_t_cell_stemness_induction
- anti_pd1_potentiation
- microbiota_host_metabolite_crosstalk
limitations:
- incomplete_receptor_binding_mechanism
- limited_human_intervention_data
- bile_acid_specificity
relevance:
- microbiota_immunotherapy_axis
- nuclear_receptor_reprogramming
- metabolite_based_therapy
concepts:
- Microbiota_Derived_Nuclear_Receptor_Ligands
- CD8_T_Cell_Stem_Like_States
- Bile_Acid_Structure_Function_Relationships
tags:
- microbiome
- bile_acids
- androgen_receptor
- cancer_immunity
Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions. We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant. As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.
Microbiota-derived oxo-bile acids directly antagonize androgen receptor (AR) signaling.
AR antagonism is necessary for tumor suppression and sufficient to potentiate anti-PD-1 therapy.
Anti-tumor effects require CD8⁺ T cell–intrinsic AR signaling.
AR-antagonizing bile acids promote stem-like CD8⁺ T cell differentiation (Tcf7⁺, CD62L⁺).
Effects are immune-mediated, not due to direct tumor cytotoxicity.
High-throughput microbial hydroxysteroid dehydrogenase (HSDH) functional screening.
Targeted and untargeted bile acid metabolomics (LC-MS).
AR luciferase reporter and ligand-binding assays.
Syngeneic murine tumor models with androgen manipulation.
CD8⁺ T cell depletion and adoptive transfer experiments.
Single-cell RNA-seq of tumor-infiltrating CD8⁺ T cells.
Demonstrates microbiota metabolites as functional steroid receptor ligands, not passive correlates.
Reframes bile acids as immune-reprogramming signals, not only metabolic detergents.
Connects sex hormone signaling directly to tumor immunotherapy efficacy.
Provides a mechanistic bridge between microbiome variability and heterogeneous immunotherapy response.
Figure 1–2: Functional mapping of microbiota HSDHs and novel bile acid structures.
Figure 3: Structure–activity relationship defining AR antagonism by oxo-bile acids.
Figure 4: Microbiota-dependent production and human relevance of AR-antagonizing bile acids.
Figure 5: Tumor suppression and anti-PD-1 potentiation in vivo.
Figure 6–7: CD8⁺ T cell–intrinsic AR requirement and stem-like differentiation trajectory.
Molecular details of AR–bile acid binding dynamics remain incomplete.
Limited direct human interventional validation.
Specificity across different bile acid species requires further resolution.