TY - JOUR
T1 - Pigs, unlike mice, have two distinct colonic stem cell populations similar to humans that respond to high-calorie diet prior to insulin resistance
AU - Charepalli, Venkata
AU - Reddivari, Lavanya
AU - Radhakrishnan, Sridhar
AU - Eriksson, Elisabeth
AU - Xiao, Xia
AU - Kim, Sung Woo
AU - Shen, Frank
AU - Vijay-Kumar, Matam
AU - Li, Qunhua
AU - Bhat, Vadiraja B.
AU - Knight, Rob
AU - Vanamala, Jairam K.P.
N1 - Funding Information:
We thank members of S.W. Kim's laboratory at North Carolina State University for their assistance with the pig study. We appreciate the help for the pig studies provided by members of the North Carolina State University Swine Education Unit, Raleigh, NC, Swine Evaluation Unit, Clayton, NC, and North Carolina State University Feed Mill, Raleigh, NC. Abigail Sido measured IL6 expression under the supervision of J.K.P. Vanamala, and these data were used for correlations performed in this study. We would also like to thank Dr. Na Xiong from Pennsylvania State University for providing thoughtful feedback on the manuscript draft. J.K.P. Vanamala is the principal investigator of USDA-NIFA NRI integrated grant 2009-55200-05197 that supported this work. L. Reddivari was partially supported by USDA-NIFA grant 2016-67017-24512 Gut bacterial analysis was partially funded by HHMI Early Career Scientist (awarded to R. Knight). Q. Li was partially supported by NIH R01GM109453 and 1UL1RR033184-01.
Publisher Copyright:
©2017 AACR.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics. We used a human-relevant pig model and developed an immunofluorescence technique to detect and quantify colonic stem cells. Pigs (n = 8/group) were provided either standard diet (SD; 5% fat) or HCD (23% fat) for 13 weeks. HCD- and SD-consuming pigs had similar total calorie intake, serum iron, insulin, and glucose levels. However, HCD elevated both colonic proliferative zone (KI-67) and stem cell zone (ASCL-2 and BMI-1). Proliferative zone correlated with elevated innate colonic inflammatory markers TLR-4, NF-κB, IL6, and lipocalin-2 (r ≥ 0.62, P = 0.02). Elevated gut bacterial phyla proteobacteria and firmicutes in HCD-consuming pigs correlated with proliferative and stem cell zone. Colonic proteome data revealed the upregulation of proteins involved in cell migration and proliferation and correlated with proliferative and stem cell zone expansion. Our study suggests that pig colon, unlike mice, has two distinct stem cells (ASCL-2 and BMI-1) similar to humans, and HCD increases expansion of colonic proliferative and stem cell zone. Thus, pig model can aid in the development of preventive strategies against gut bacterial dysbiosis and inflammation-promoted diseases, such as colon cancer.
AB - Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics. We used a human-relevant pig model and developed an immunofluorescence technique to detect and quantify colonic stem cells. Pigs (n = 8/group) were provided either standard diet (SD; 5% fat) or HCD (23% fat) for 13 weeks. HCD- and SD-consuming pigs had similar total calorie intake, serum iron, insulin, and glucose levels. However, HCD elevated both colonic proliferative zone (KI-67) and stem cell zone (ASCL-2 and BMI-1). Proliferative zone correlated with elevated innate colonic inflammatory markers TLR-4, NF-κB, IL6, and lipocalin-2 (r ≥ 0.62, P = 0.02). Elevated gut bacterial phyla proteobacteria and firmicutes in HCD-consuming pigs correlated with proliferative and stem cell zone. Colonic proteome data revealed the upregulation of proteins involved in cell migration and proliferation and correlated with proliferative and stem cell zone expansion. Our study suggests that pig colon, unlike mice, has two distinct stem cells (ASCL-2 and BMI-1) similar to humans, and HCD increases expansion of colonic proliferative and stem cell zone. Thus, pig model can aid in the development of preventive strategies against gut bacterial dysbiosis and inflammation-promoted diseases, such as colon cancer.
UR - http://www.scopus.com/inward/record.url?scp=85027051502&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027051502&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-17-0010
DO - 10.1158/1940-6207.CAPR-17-0010
M3 - Article
C2 - 28576788
AN - SCOPUS:85027051502
SN - 1940-6207
VL - 10
SP - 442
EP - 450
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 8
ER -