Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in ApcMin/+ Mice: Relation to Metabolism and Gut Microbiota Composition

Yi-Wen Huang; *; Chien-Wei Lin; *; Pan Pan; *; Carla Elena Echeveste; Athena Dong; Kiyoko Oshima; Martha Yearsley; Jianhua Yu; **; Li-Shu Wang; **

doi:10.15430/JCP.2021.26.1.32

Original Article

J Cancer Prev 2021; 26(1): 32-40

Published online March 30, 2021

https://doi.org/10.15430/JCP.2021.26.1.32

Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Apc^Min/+ Mice: Relation to Metabolism and Gut Microbiota Composition

Yi-Wen Huang¹,*, Chien-Wei Lin²,*, Pan Pan³,*, Carla Elena Echeveste³, Athena Dong³, Kiyoko Oshima⁴, Martha Yearsley⁵, Jianhua Yu⁶,**, Li-Shu Wang³,**

¹Department of Obstetrics & Gynecology, ²Division of Biostatistics, ³Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, ⁴Department of Pathology, Johns Hopkins University, Baltimore, MD, ⁵Department of Pathology, The Ohio State University, Columbus, OH, ⁶Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA, USA

Correspondence to :
Li-Shu Wang, E-mail: liswang@mcw.edu, https://orcid.org/0000-0002-6500-6943
Jianhua Yu, E-mail: jiayu@coh.org, https://orcid.org/0000-0002-0326-3223
*These authors contributed equally to this work as co-first authors.
**These authors contributed equally to this work as co-correspondence authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (Apc^Min/+). Ffar2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, Apc^Min/+, and Apc^Min/+-Ffar2^-/- mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the Apc^Min/+-Ffar2^-/- mice compared to the Apc^Min/+ mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, longchain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that Ffar2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.

Keywords: Ffar2, Apc^Min/+, Colorectal cancer, Metabolomics, Gut microbiota

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Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in Apc^Min/+ Mice: Relation to Metabolism and Gut Microbiota Composition

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