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American Association for the Advancement of Science, Science Translational Medicine, 671(14), 2022

DOI: 10.1126/scitranslmed.abo3445

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

Journal article published in 2022 by Diana H. Wiesnoski ORCID, Marc O. Warmoes ORCID, Liangliang Zhang ORCID, Yinghong Wang ORCID, Marcel R. M. van den Brink ORCID, Jennifer A. Wargo ORCID, Raphael H. Valdivia ORCID, Zaker I. Schwabkey ORCID, Saira S. Ahmed, Miriam R. Ortega Turrubiates, Chia-Chi Chang ORCID, Rawan K. El-Himri, Wiesnoski Dh, Christopher A. Sanchez, Wen-Bin Tsai and other authors.
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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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.