The impact of gut microbiota on chemotherapy-induced gastrointestinal toxicity in children with leukemia

Intestinal mucositis is a common side effect of chemotherapy leading to diarrhea, abdominal painand increased risk of infections. The intestinal microbiota has been recognized as a key regulator ofmucosal immune responses. Therefore, we hypothesized that intestinal microbial changes would beassociated with enterocyte loss and systemic inflammation during induction treatment for childhoodacute lymphoblastic leukemia (ALL). We prospectively included 51 children newly-diagnosed withALL treated in Denmark in 2015-2018. Plasma C-reactive protein (CRP), plasma citrulline (markerof functional enterocytes mass) measurements and fecal samplings were performed on treatmentdays 1, 8, 15, 22 and 29. Fecal samples in patients and 19 healthy siblings were analyzed by 16SrRNA gene sequencing (V3-V4 region). Bacterial alpha diversity was lower in patients compared tosiblings. It decreased from day 1 to days 8 ? 22 and increased on day 29. Shannon alpha diversityindex was correlated with CRP on days 15 ? 29 (rho=-0.33 ? -0.49; P<0.05) and with citrulline ondays 15 and 29 (although with P-values<0.06 , rho=0.32 ? 0.34). The abundance of Enterococcusspecies (spp.) was correlated with CRP on days 22 ? 29 (rho=0.42 ? 0.49; P<0.009), while theabundance of Lachnospiraceae spp. was correlated with citrulline on days 8 ? 15 (rho=0.48 ? 0.62,P<0.001). Systemic inflammation, enterocyte loss and Enterococcus spp. relative abundancereached a peak around day 15. Maintaining a diverse microbiota rich in butyrate-producingLachnospiraceae may reduce intestinal mucositis severity, while loss of diversity and enterococciovergrowth may exacerbate intestinal damage and inflammation.