TY - JOUR T1 - Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment JF - bioRxiv DO - 10.1101/2021.09.18.460647 SP - 2021.09.18.460647 AU - Zaker Schwabkey AU - Diana H. Wiesnoski AU - Chia-Chi Chang AU - Wen-Bin Tsai AU - Dung Pham AU - Saira S. Ahmed AU - Tomo Hayase AU - Miriam R. Ortega Turrubiates AU - Rawan K. El-Himri AU - Christopher A. Sanchez AU - Eiko Hayase AU - Annette C. Frenk Oquendo AU - Takahiko Miyama AU - Taylor M. Halsey AU - Brooke E. Heckel AU - Alexandria N. Brown AU - Yimei Jin AU - Philip L. Lorenzi AU - Marc O. Warmoes AU - Lin Tan AU - Alton G. Swennes AU - Vanessa B. Jensen AU - Christine B. Peterson AU - Kim-Anh Do AU - Liangliang Zhang AU - Yushu Shi AU - Yinghong Wang AU - Jessica R. Galloway-Pena AU - Pablo C. Okhuysen AU - Carrie R. Daniel-MacDougall AU - Yusuke Shono AU - Marina Burgos da Silva AU - Jonathan U. Peled AU - Marcel R.M. van den Brink AU - Nadim Ajami AU - Jennifer A. Wargo AU - Gabriela Rondon AU - Samer A. Srour AU - Rohtesh S. Mehta AU - Amin M. Alousi AU - Elizabeth J. Shpall AU - Richard E. Champlin AU - Samuel A. Shelburne AU - Jeffrey J. Molldrem AU - Mohamed A. Jamal AU - Jennifer L. Karmouch AU - Robert R. Jenq Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/09/18/2021.09.18.460647.abstract N2 - Not all cancer patients with severe neutropenia develop fever, and the fecal microbiome may play a role. In neutropenic hematopoietic cell transplant patients (n=119), 63 (53%) developed a subsequent fever and had increased fecal Akkermansia muciniphila, a mucus-degrading bacteria (p=0.006, corrected for multiple comparisons).In mouse models, two therapies, irradiation and melphalan, similarly expanded A. muciniphila. Dietary restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Azithromycin treatment depleted A. muciniphila and preserved colonic mucus.Dietary restriction raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila with lower pH and increased propionate prevented utilization of mucin. Treating irradiated mice with azithromycin or propionate preserved the mucus layer, lessened hypothermia, and reduced inflammatory cytokines in the colon. These results suggest that diet, metabolites and colonic mucus link the microbiome to neutropenic fever, and could guide future microbiome-based preventive strategies.Competing Interest StatementR.R.J. receives consultant role fees from Merck, Karius and Microbiome DX, advisory member role fees from Seres, Kaleido, MaaT Pharma, Prolacta, and LISCure, research funding from Kaleido, and patent licensing fees from Seres. ER -