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.
Subject(s)
Gastrointestinal Microbiome , Hematopoietic Stem Cell Transplantation , Neoplasms , Neutropenia , Mice , Animals , Propionates , Verrucomicrobia , Mucus/metabolism , Mucins/metabolism , Diet , Neutropenia/metabolism , Neoplasms/metabolismABSTRACT
In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript.
ABSTRACT
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
Subject(s)
Colitis/therapy , Fecal Microbiota Transplantation/methods , Gastrointestinal Microbiome/drug effects , Ipilimumab/adverse effects , Aged , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , CTLA-4 Antigen/therapeutic use , Colitis/chemically induced , Colitis/immunology , Colitis/microbiology , Female , Gastrointestinal Microbiome/immunology , Humans , Immune System/drug effects , Immune System/microbiology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Male , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/therapeutic use , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/microbiologyABSTRACT
Clinical evidence is accumulating for a role of the microbiome in contributing to or modulating severity of inflammatory diseases. These studies can be organized by various organ systems involved, as well as type of study approach utilized, whether investigators compared the microbiome of cases versus controls, followed patients longitudinally, or intervened with antibiotics, prebiotics, or bacterial introduction. In this review, we summarize the clinical evidence supporting the microbiome as an important mechanism in the onset and maintenance of inflammation.
