The Gut Microbiota Lachnospiraceae and Its Bacterial Metabolite Vanillylamine Significantly Alleviate Myelosuppression Caused By Abdominal and Pelvic Tumor Chemotherapy

Acute and chronic myelosuppression occurs in up to 80% of abdomen pelvic tumor patients undergoing chemoradiotherapy, severely impacting survival outcomes and quality of life. Currently, treatments for chemotherapy-induced acute myelosuppression are limited and inadequate for prevention, highlighting the urgent need for novel preventative and therapeutic strategies.

We investigated the role of gut microbiota in a 5-fluorouracil (5-FU)-induced acute myelosuppression mouse model using a four-antibiotic cocktail to disrupt the gut microbiota. Metagenomics of intestinal contents and single-strain gavage mouse models identified key gut bacteria that mitigate myelosuppression. Untargeted metabolomics of intestinal contents and a metabolite gavage mouse model revealed key bacterial metabolites that alleviate myelosuppression. Bioinformatics analysis, in vitro whole gut microbial culturing, and LC-MS confirmed that Lachnospiraceae produce the critical metabolite vanillylamine. Molecular mechanisms were explored using HE staining, flow cytometry, colony assays, RNA sequencing, Western blot, qPCR, and siRNA gene knockdown to understand how Lachnospiraceae and vanillylamine alleviate myelosuppression and accelerate ST-HSC proliferation.

Our findings show that antibiotic-induced dysbiosis exacerbates 5-FU-induced myelosuppression and increases mortality in mice. Conversely, Lachnospiraceae and Akkermansiaceae significantly alleviate myelosuppression and accelerate ST-HSC proliferation. Metabolites such as vanillylamine and several indole-derived metabolites from gut bacteria also alleviate myelosuppression and promote ST-HSC proliferation. Lachnospiraceae positively correlates with vanillylamine production, and Lachnospiraceae-derived vanillylamine significantly activates the JNK pathway, accelerating ST-HSC proliferation.

In conclusion, gut bacteria such as Lachnospiraceae and their metabolites like vanillylamine accelerate ST-HSC proliferation through activating the JNK pathway and alleviate chemotherapy-induced acute myelosuppression, enriching our understanding of the gut-bone marrow axis.

No relevant conflicts of interest to declare.