한빛사논문
- 조회2,523
SydneyLavoie1,*, Eunyoung Chun1,*, SenaBae1, Caitlin A. Brennan1, Carey Ann Gallini Comeau1, Jessica K.Lang1, Monia Michaud1, Hamid R. Hoveyda2, Graeme L. Fraser3, Miles H. Fuller4, Brian T. Layden4,5, Jonathan N. Glickman6,7, Wendy S. Garrett1,8,9,*,#
1Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
2Euroscreen SA, Gosselies, Belgium
3EPICS SA, Gosselies, Belgium
4Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois
5Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
6Department of Pathology, Harvard Medical School, Boston, Massachusetts
7Beth Israel Deaconess Medical Center, Boston, Massachusetts
8Broad Institute of Harvard and MIT, Cambridge, Massachusetts
9Department and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
*Authors share co-first authorship.
#Corresponding author
Abstract
Background & Aims
Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC.
Methods
We performed studies with ApcMin/+ mice, ApcMin/+Ffar2–/– mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas.
Results
ApcMin/+Ffar2–/– mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2–/– mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2–/– mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production.
Conclusions
Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC.
논문정보
- Research article
- 2020년 04월 (BRIC 등록일 2020-04-02)
- 국외 연구진
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