Unravelling neutropenic enterocolitis: insights from gut microbiota, and intestinal barrier analyses.

Background: Neutropenic enterocolitis (NE) is a severe digestive complication of chemotherapy, primarily affecting patients with acute myeloid leukemia (AML). We hypothesized that NE is linked to intestinal barrier dysfunction and gut dysbiosis.

Methods: Sixty-five AML patients undergoing induction chemotherapy were included in this prospective monocentric cohort. Among them, 26 patients (40%) were diagnosed with NE. Stool samples were subjected to bacterial load quantification (all bacteria quantitative PCR), 16s rRNA metagenomic analysis, and short-chain-fatty-acids quantification. Additionally, fecal calprotectin and human 𝛃-defensin 2 along with plasmatic inflammatory cytokines, and citrulline levels were measured. Human transcriptomic analysis was conducted on samples obtained from anatomical specimens of colectomies of NE patients.

Results: Gut microbiota underwent significant alterations after chemotherapy, transitioning from a diverse and balanced enterotype to enterotypes exhibiting a reduced α-diversity, an increased abundance of Enterococcus faecalis, and a decreased abundance of butyrate-producing genera, which correlated with a decreased fecal concentration of butyrate. Simultaneously, post-chemotherapy, plasma citrulline concentrations decreased indicating enterocyte damages. Finally, human transcriptomic analysis found a significant upregulation of the JAK-STAT signaling KEGG pathway in the colons of NE patients encompassing cytokines (IL-6, OSM-OSMR) that play a pivotal role in sustaining local inflammation within the digestive tract.

Conclusions: This work reaffirms the significant influence of chemotherapy on the gut microbiota and the integrity of the enterocyte barrier. Severe NE is marked by the development of a local inflammatory response that may be induced by the reduction in butyrate levels.

Trial registration: The study was registered on Clinicaltrials.gov (identifier: NCT04438278).