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

Abstract

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant ( n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila , a species of mucin-degrading bacteria ( P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.

The Microbiome and Its Impact on Allogeneic Hematopoietic Cell Transplantation

“…Given that the majority of bloodstream infections identified from patients with febrile neutropenia arise from an intestinal origin, the authors recently asked if the composition of intestinal bacteria could be associated with development of fever in HCT patients when they become neutropenic 42 . We found that patients who later developed fever had increased relative abundances of Bacteroides and Akkermansia muciniphila in their fecal samples collected at onset of neutropenia.…”

“…41 An examination of the intestinal microbiome of patients undergoing alloHCT conditioning before development of neutropenic fever, as well as the microbiome of mice following either total body irradiation (TBI) or treatment with melphalan in the absence of antibiotic treatment, both demonstrated that HCT conditioning alone can markedly modulate the composition of intestinal bacteria. 42 Interestingly, murine experiments demonstrated that mice, similar to humans, consume less food after TBI, and that much of the effects of HCT on the microbiome can be recapitulated with a simple 50% reduction in oral food intake in unirradiated mice. 42 Hence, nutritional supplementation strategies represent an approach that could mediate meaningful benefits on the intestinal microbiome and in turn improve clinical outcomes.…”

“…In addition to antibiotics, HCT conditioning is another common perturbator of the intestinal microbiome, with a direct correlation between HCT conditioning intensity and microbiome injury in clinical studies 41 . An examination of the intestinal microbiome of patients undergoing alloHCT conditioning before development of neutropenic fever, as well as the microbiome of mice following either total body irradiation (TBI) or treatment with melphalan in the absence of antibiotic treatment, both demonstrated that HCT conditioning alone can markedly modulate the composition of intestinal bacteria 42 . Interestingly, murine experiments demonstrated that mice, similar to humans, consume less food after TBI, and that much of the effects of HCT on the microbiome can be recapitulated with a simple 50% reduction in oral food intake in unirradiated mice 42 .…”

ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers

“…Interestingly, Schwabkey and colleagues have linked mucus-degrading bacteria in the gut to increased fever. These bacteria thin the mucus layer in mice, potentially exposing the hosts to further bacterial infections [69].…”

Gut microbiome contributes to neutropenic fever

“…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 …”