Gut‐derived <i>Lactobacillus</i> from exceptional responders mitigates chemoradiotherapy‐induced intestinal injury through methionine‐driven epigenetic modulation

Acute chemoradiotherapy-induced intestinal injury (ACRIII) is a common and debilitating complication in patients with colorectal cancer, significantly impairing both quality of life and treatment outcomes. This study aimed to investigate the role of the gut microbiome in mitigating ACRIII. Through bioinformatics analysis of clinical fecal samples and fecal microbiota transplantation (FMT) experiments in mice, we identified a strong association between a high abundance of <i>Lactobacillus</i> species and the absence of ACRIII. From the fecal samples of rectal cancer patients who achieved complete remission without experiencing ACRIII during chemoradiotherapy, 10 novel <i>Lactobacillus</i> strains were isolated and characterized. Among these, <i>Lacticaseibacillus rhamnosus</i> DY801 exhibited a robust capacity to synthesize methionine through metB. This microbial methionine production modulated methionine metabolism in host gut lymphoid tissue inducer (Lti) cells, without diminishing the therapeutic efficacy of chemoradiotherapy. Supplementation with methionine increased intracellular levels of S-adenosylmethionine and enhanced histone H3 lysine 4 trimethylation (H3K4me3) in Lti cells. These epigenetic modifications led to the suppression of pro-inflammatory cytokines interleukin-17A (IL-17A) and interleukin-22 (IL-22), ultimately reducing ACRIII severity. Our findings suggest that specific <i>Lactobacillus</i> strains derived from patients with exceptional treatment responses may offer a novel therapeutic avenue for preventing or alleviating ACRIII. This microbiome-based approach holds significant potential for improving patient outcomes and enhancing the tolerability of chemoradiotherapy in colorectal cancer.