Chemotherapy-driven intestinal dysbiosis and indole-3-propionic acid rewire myelopoiesis to promote a metastasis-refractory state

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. While early-stage disease can often be cured by surgery, most patients have microsatellite stable (MSS) tumors that do not respond to immune checkpoint inhibitors. For high-risk stage II and stage III CRC, adjuvant chemotherapy with fluoropyrimidines and oxaliplatin reduces recurrence and improves survival. However, 30–50% of patients still develop distant metastases, most commonly in the liver.

Growing evidence shows that the gut microbiota influences the effectiveness of chemotherapy. In preclinical models, microbial sensing is required for optimal responses to oxaliplatin, and chemotherapy-induced microbial translocation can stimulate anti-tumor CD4⁺ T cell responses. Clinically, patients often receive antibiotics around the time of chemotherapy, and a large retrospective study found that antibiotic use was associated with worse disease-free survival in CRC. Despite this, the mechanisms linking chemotherapy, microbiota changes, and metastatic relapse remain poorly understood.

Here is shown that standard chemotherapy with 5-FU and oxaliplatin induces a long-lasting, metastasis-resistant state by durably reshaping the gut microbiota. This remodeling increases production of the microbiota-derived tryptophan metabolite indole-3-propionic acid (IPA). IPA acts primarily on myeloid progenitors in the bone marrow, promoting macrophage differentiation while reducing immunosuppressive Ly6C^high^CCR2⁺ monocytes. This shift enhances anti-tumor CD4⁺ T cell responses and limits CRC liver metastasis.

These findings are supported by patient data showing that circulating IPA levels increase after chemotherapy in a subset of CRC patients and inversely correlate with monocyte abundance. Together, our results reveal a previously unrecognized systemic effect of chemotherapy mediated by the gut microbiota and identify IPA as a potential therapeutic strategy to counteract immunosuppression and metastasis.

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