Altered microbiota-host metabolic cross talk preceding neutropenic fever in patients with acute leukemia

Despite antibiotic prophylaxis, most patients with acute leukemia receiving mucotoxic chemotherapy develop neutropenic fever (NF), many cases of which remain without a documented etiology. Antibiotics disrupt the gut microbiota, with adverse clinical consequences, such as Clostridioides difficile infection. A better understanding of NF pathogenesis could inform the development of novel therapeutics without deleterious effects on the microbiota. We hypothesized that metabolites absorbed from the gut to the bloodstream modulate pyrogenic and inflammatory pathways. Longitudinal profiling of the gut microbiota in 2 cohorts of patients with acute leukemia showed that Akkermansia expansion in the gut was associated with an increased risk for NF. As a prototype mucolytic genus, Akkermansia may influence the absorption of luminal metabolites; thus, its association with NF supported our metabolomics hypothesis. Longitudinal profiling of the serum metabolome identified a signature associated with gut Akkermansia and 1 with NF. Importantly, these 2 signatures overlapped in metabolites in the γ-glutamyl cycle, suggesting oxidative stress as a mediator involved in Akkermansia-related NF. In addition, the level of gut microbial-derived indole compounds increased after Akkermansia expansion and decreased before NF, suggesting their role in mediating the anti-inflammatory effects of Akkermansia, as seen predominantly in healthy individuals. These results suggest that Akkermansia regulates microbiota-host metabolic cross talk by modulating the mucosal interface. The clinical context, including factors influencing microbiota composition, determines the type of metabolites absorbed through the gut barrier and their net effect on the host. Our findings identify novel aspects of NF pathogenesis that could be targets for precision therapeutics. This trial was registered at www.clinicaltrials.gov as #NCT03316456.