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

Abstract

Despite antibiotic prophylaxis,most patients with acute leukemia receivingmucotoxic chemotherapy develop neutropenic fever (NF), many cases of which remain without a documented etiology.Antibiotics disrupt the gutmicrobiota,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 themicrobiota.We hypothesizedthatmetabolitesabsorbedfromthe gut tothe bloodstreammodulatepyrogenicand inflammatorypathways.Longitudinalprofiling of the gutmicrobiotain2cohorts ofpatientswith acute leukemia showed thatAkkermansia expansion in the gutwas associatedwith an increased risk for NF. As a prototypemucolytic genus, Akkermansia may influence the absorption of luminalmetabolites; thus, its association with NF supported ourmetabolomics hypothesis. Longitudinal profiling of the serummetabolome identified a signature associated with gut Akkermansia and 1 with NF. Importantly, these 2 signatures overlapped inmetabolites in the g-glutamyl cycle, suggesting oxidative stress as amediator 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 inmediating the anti-inflammatory effects of Akkermansia, as seen predominantly in healthy individuals. These results suggest that Akkermansia regulatesmicrobiota-hostmetabolic cross talk bymodulating themucosal interface. The clinical context, including factors influencingmicrobiota composition, determines the type ofmetabolites absorbedthroughthe gut barrierandtheir net effect onthehost.Ourfindings identify novel aspects of NF pathogenesis that could be targets for precision therapeutics. This trial was registered at www.clinicaltrials.gov as #NCT03316456.