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.
Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16 S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium , which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8 + T cells, in the colon after FMT when compared with non-complete response patients ( n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.
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.
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