Gut microbiome contributes to neutropenic fever.

Abstract

A primary contributor to neutropenic fever not caused by an infection in patients following cytotoxic cancer treatment may lie in the gut. A study published in Science Translational Medicine showed that patients treated by hematopoietic cell transplantation who developed neutropenic fever not caused by an infection had a significantly increased abundance of the species of the mucin-degrading bacteria Akkermansia muciniphila.1 Although it is well known that the gut microbiome is a common source of infections that can cause neutropenic fever, less understood is the cause of neutropenic fever without an identifiable infection. The study, led by investigators from The University of Texas MD Anderson Cancer Center in Houston, sheds some insight on the role the gut microbiome plays in this setting. “Interestingly, we found that mucus-degrading bacteria, which are naturally harbored within the gut microbiome and don’t directly cause infections, are the primary contributors to neutropenic fever,” says to neutropenic fever senior author Robert R. Jenq, MD, an associate professor in the Department of Genomic Medicine, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center. In the single-center study, investigators first looked at the link between the gut microbiome and fever in 119 patients who underwent hematopoietic cell transplantation. At the onset of severe neutropenia, the fecal microbiome of each patient was characterized. Of the 119 patients, 63 (53%) also developed a fever. The study found that patients who developed a fever had a significantly greater proportion of A muciniphila abundances greater than 0.1% in their fecal samples as compared to the patients who did not develop a fever (54% vs 32%, respectively; p = .02). Investigators also used preclinical mouse models to further understand the mechanisms underlying the pathophysiology of neutropenic fever. Through a series of in vivo and in vitro experiments, they examined the effects of various treatments on the gut microbiome of mice, including irradiation, chemotherapy, antibiotics, and caloric restriction. They found that irradiation and chemotherapy expanded A muciniphila and thinned the colonic mucus layer, as did caloric restriction of unirradiated mice. Caloric restriction reduced important metabolites in the gut necessary for maintaining intestinal homeostasis, including propionate, and led to increased expression of mucus-utilization enzymes in intestinal A muciniphila. Further testing showed that giving mice either antibiotics targeting A muciniphila or propionate (which is used as a food additive to prevent mold formation) preserved the mucus layer in irradiated mice and reduced inflammatory cytokines in the colon. Dr Jenq underscores that a key finding of the study was that caloric restriction is a major contributor to mucusdegrading behavior in the gut. “In mice, just as in patients, we found that radiation or chemotherapy can lead to a reduced appetite, and this decrease in dietary nutrition directly leads to increases in mucus-degrading behavior by the gut microbiome,” he says. He adds that the findings emphasize the need to encourage patients to continue to eat while receiving cancer treatment but acknowledges how difficult that can be for patients undergoing “tough” treatments. “In the future, targeted nutritional support strategies could be an effective approach to reduce toxicities of cancer treatment,” he says.