Pharmacological inhibition of Alistipes putredinis-derived indole-3-acetic acid by baicalin suppresses stress-driven breast cancer metastasis

Breast cancer patients often experience chronic stress disorders and gut dysbiosis. Baicalin has been demonstrated to have antitumor, antibacterial and microbiota regulatory functions and can be used for treating breast cancer and preventing metastasis; however, how baicalin regulates the gut microbiota to inhibit metastasis remains unexplored. Chronic stress promoted breast cancer lung metastasis mainly through Alistipes putredinis , which produced the tryptophan metabolite indole-3-acetic acid (IAA). Chronic stress did not affect tumor growth but enhanced metastasis and reshaped the immune environment at the metastatic site. Mechanistically, IAA promoted 4T1 cell migration through AhR-mediated oxidative stress, and the AhR inhibitor CH223191 inhibited migration and metastasis in vitro and in vivo. Notably, baicalin treatment inhibited lung metastasis and increased both the number and cytotoxicity of CD8 + T cells in the lungs. 16S rDNA sequencing and targeted tryptophan metabolomics revealed that baicalin treatment not only reduced the abundance of A. putredinis but also modulated the metabolism of tryptophan in A. putredinis, resulting in suppressing IAA production. Fecal microbiota transplantation was further used to confirm the effects of baicalin. Breast cancer patients with metastasis and severe depression showed an increased abundance of A. putredinis in feces and increased concentration of IAA in the serum. These findings reveal stress-driven microbiota and metabolite alterations, which may facilitate breast cancer metastasis, uncovering the underlying mechanism by which baicalin prevents metastasis. Video Abstract