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

• DOI: 10.1126/scitranslmed.abo3445
• Publication Date: 2022-11-16T18:58:11Z
• Authors: Zaker I. Schwabkey; Diana H. Wiesnoski; Chia-Chi Chang; Wen-Bin Tsai; Dung Pham; Saira S. Ahmed; Tomo Hayase; Miriam R. Ortega ...; Rawan K. El-Himri; Christopher A. Sa...; Eiko Hayase; Annette C. Frenk ...; Takahiko Miyama; Taylor M. Halsey; Brooke E. Heckel; Alexandria N. Brown; Yimei Jin; Mathilde Raybaud; Rishika Prasad; Ivonne Flores; Lauren McDaniel; Valerie Chapa; Philip L. Lorenzi; Marc O. Warmoes; Lin Tan; Alton G. Swennes; Stephanie Fowler; Margaret Conner; Kevin McHugh; Tyler Graf; Vanessa B. Jensen; Christine B. Pete...; Kim-Anh Do; Liangliang Zhang; Yushu Shi; Yinghong Wang; Jessica R. Gallow...; Pablo C. Okhuysen; Carrie R. Daniel-...; Yusuke Shono; Marina Burgos da ...; Jonathan U. Peled; Marcel R.M. van d...; Nadim Ajami; Jennifer A. Wargo; Pavan Reddy; Raphael H. Valdivia; Lauren Davey; Gabriela Rondon; Samer A. Srour; Rohtesh S. Mehta; Amin M. Alousi; Elizabeth J. Shpall; Richard E. Champlin; Samuel A. Shelburne; Jeffrey J. Molldrem; Mohamed A. Jamal; Jennifer L. Karmouch; Robert R. Jenq
• Keywords: 0301 basic medicine; 570; 0303 health sciences; Medical Sciences; Neutropenia; Bioinformatics; Hematopoietic Stem Cell Transplantation; Mucins; 610; Biomedical Informatics; Gastrointestinal Microbiome; Diet; 3. Good health; Mice; Mucus; 03 medical and health sciences; Oncology; Verrucomicrobia; Neoplasms; Medical Specialties; Medicine and Health Sciences; Animals; Propionates

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.