Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment

Fever in the setting of low white blood cell counts, also known as neutropenic fever, is considered an oncologic emergency. Only some 30% of patients with neutropenic fever have an identifiable source of infection, such as a bloodstream bacterial infection of intestinal origin. Whether other nonpathogenic intestinal bacteria can contribute to neutropenic fever is not known. In a cohort of 119 patients undergoing hematopoietic cell transplantation, a treatment with a high risk for neutropenic fever, the fecal microbiome was examined at onset of neutropenia. Over the next 4 days, 63 patients (53%) developed a fever, which was associated with increased Akkermansia muciniphila, a species of intestinal commensal bacteria with mucus-degrading capabilities (p=0.006, corrected for multiple comparisons). In mouse models, two cytotoxic therapies, irradiation and melphalan, each also produced an expansion of fecal A. muciniphila as well as thinning of the colonic mucus layer. Direct irradiation of fecal bacteria, however, did not lead to expansion of A. muciniphila, suggesting an indirect effect via the host. Irradiated mice displayed reduced oral food intake, and dietary restriction of unirradiated mice was sufficient to produce an expansion of A. muciniphila and thinning of the colonic mucus layer. Treatment of diet-restricted mice with several narrow-spectrum antibiotics demonstrated that azithromycin, which depleted intestinal A. muciniphila, led to preservation of the colonic mucus layer. Diet-restricted mice developed an increase in colonic luminal pH and reductions in acetate, propionate, and butyrate. Treatment of A. muciniphila in vitro with lower pH and increased propionate led to delayed growth and prevented utilization of mucin. Dietary restriction and low propionate also produced large changes in A. muciniphila gene expression, including upregulation of L-fucose isomerase, a member of glycosyl hydrolase family 109, and a member of the Idh/MocA family of oxidoreductases, which may play roles in mucin glycan utilization. Supplementing the drinking water of diet-restricted mice with propionate led to preservation of the colonic mucus layer. In the setting of irradiation, we found that by 6 days following treatment mice developed signs of systemic infection manifesting as hypothermia. Upon examination of colon tissues, we found that irradiated mice had elevated levels of inflammatory cytokines including IL-1b, CCL2, CCL7, IL-22, CXCL1, and CXCL10. Treatment with azithromycin or propionate lessened the severity of hypothermia, preserved the mucus layer, and mitigated elevations in inflammatory cytokines in the colon. In summary, we have found that clinical neutropenic fever is associated with increased intestinal abundance of mucolytic bacteria, and further experiments in mice have identified a pathway linking impaired diet and loss of bacterial metabolites as important mediators of this process.