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

## TL;DR

Chemotherapy causes gut changes that produce a compound called IPA, which helps prevent cancer from spreading to the liver by altering immune cell production.

## Contribution

The study reveals a chemotherapy-induced microbiota-metabolite-immune axis that prevents metastasis through indole-3-propionic acid.

## Key findings

- Chemotherapy-induced intestinal injury promotes the production of indole-3-propionic acid (IPA) by gut bacteria.
- IPA redirects myelopoiesis toward macrophages and away from immunosuppressive monocytes, enhancing antitumor immunity.
- In CRC patients, higher IPA levels after chemotherapy correlate with lower monocyte abundance and better survival.

## Abstract

The contribution of chemotherapy-induced tissue injury to individual susceptibility to metastasis remains largely unexplored. We report that chemotherapy indirectly prevents colorectal cancer (CRC) liver metastases by inducing a lasting systemic “chemomemory”. Chemotherapy-induced intestinal mucositis alters nutrient availability, promoting the expansion of tryptophan-metabolizing bacteria and production of the microbial metabolite indole-3-propionic acid (IPA). IPA reprograms bone marrow myelopoiesis by redirecting common myeloid progenitor fate toward the macrophage lineage, limiting generation of immunosuppressive Ly6ChighCCR2+ monocytes. This shift enhances CD4+ T cell antitumor function by promoting Th1 differentiation and spatially reorganizing CD8+ and CD4+ T cell interactions within the metastatic microenvironment. In a subset of CRC patients, circulating IPA levels increase after chemotherapy and inversely correlate with monocyte abundance, while high monocyte levels were associated with reduced survival. Our findings reveal that chemotherapy-induced intestinal injury normalizes pathological myelopoiesis through a microbiota-derived metabolite and identify IPA as a potential adjuvant to counteract monocyte-driven immunosuppression and metastasis.

The microbiota influences the cytotoxicity of chemotherapy in patients with colorectal cancer but the impact on metastatic relapse is less clear. Here, the authors report that chemotherapy-induced intestinal mucositis induces systemic immune changes via production the microbial metabolite, indole-3-propionic acid (IPA), preventing metastases.