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Anti-neoplastic effects of non-digestible carbohydrates on Wnt signalling pathway gene expression and its functional outcomes in the large bowel: a human dietary intervention study

Published online by Cambridge University Press:  20 May 2014

F. Malcomson ,
N. D. Willis ,
I. McCallum ,
L. Xie ,
W. Leung ,
S. B. Kelly ,
M. Bradburn ,
N. J. Belshaw ,
I. T. Johnson  and
J. C. Mathers
F. Malcomson
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
N. D. Willis
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
I. McCallum
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
L. Xie
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
W. Leung
Affiliation:
Institute of Food Research, Norwich Research Park, Norfolk NR4 7UA, UK
S. B. Kelly
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
M. Bradburn
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
N. J. Belshaw
Affiliation:
Institute of Food Research, Norwich Research Park, Norfolk NR4 7UA, UK
I. T. Johnson
Affiliation:
Institute of Food Research, Norwich Research Park, Norfolk NR4 7UA, UK
J. C. Mathers
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
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Abstract

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Environmental factors, including diet, modify colorectal cancer (CRC) risk. Non-digestible carbohydrates (NDCs) such as resistant starch (RS) appear to be protective( Reference Bingham, Day and Luben 1 ). These beneficial effects may result from butyrate production, a short-chain fatty acid( Reference Lipkin, Reddy and Newmark 2 ), by colonic bacteria. The Wnt pathway is involved in the regulation of processes including proliferation and apoptosis in the large bowel. CRC can result from an imbalance in proliferation and apoptosis, and an abnormal crypt mitotic cell distribution is one of the earliest detectable alterations in the normal mucosa prior to CRC( Reference Terpstra, van Blankenstein and Dees 3 ). The Wnt pathway is implicated in the aetiology of sporadic and inherited CRCs( Reference Bienz and Clevers 4 ), and butyrate may modulate Wnt signalling( Reference Bordonaro, Lazarova and Sartorelli 5 ).

This study aimed to investigate the effects of supplementing healthy participants with NDCs on Wnt-related gene expression and its functional outcomes, such as proliferation, in the bowel. We hypothesised that NDC supplementation would increase colonic butyrate and positively modulate Wnt signalling.

Using a 2*2 factorial, double-blind RCT design, 75 participants were supplemented with RS and/or polydextrose or placebo for 7 weeks. Rectal mucosal biopsies were collected pre- and post-intervention and used to quantify Wnt-related gene expression in duplicate by quantitative PCR. Crypt cell proliferative state (CCPS) was assessed following whole crypt microdissection of stained biopsies as described by Mills et al. ( Reference Mills, Mathers and Chapman 6 ). The number of mitotic and apoptotic events per crypt were counted in 10 crypts per participant.

Although this study remains blinded, preliminary analyses of Wnt gene expression (Fig. 1) and CCPS (Fig. 2) suggest differences both post-intervention and between the intervention groups. In particular, we observed a statistically significant effect of treatment group on SFRP1 gene expression (Fig. 1) after the intervention. SFRP1 is a Wnt signalling antagonist and SFRP1 expression is down-regulated in CRCs. Possible correlations between post-intervention changes in gene expression and changes in the percentage of mitotic cells in the top half of the crypt are being investigated currently.

Fig. 1. Mean post-intervention expression of SFRP1 expressed as adjusted copies (2−ΔCt × 1000) relative to the geometric mean of 18S and β2M housekeeping genes (n = 45).

Fig. 2. Mean post-intervention % of mitotic cells in top half of the crypt (n = 24). Data is presented as least squares means.

This study was funded by the BBSRC (BB/H005013/1). Ethical approval for this project, as part of a larger application, was granted on 10th December 2009 (REC No. 09/H0907/77).

References

1. Bingham, SA, Day, NE, Luben, R et al. (2003) Lancet 361, 1496–1501.CrossRefGoogle Scholar
2. Lipkin, M, Reddy, B, Newmark, H et al. (1999) Annu Rev Nutr 19, 545–586.Google Scholar
3. Terpstra, OT, van Blankenstein, M, Dees, J et al. (1987) Gastroenterology 92, 704–708.Google Scholar
4. Bienz, M, Clevers, H (2000) Cell 103, 311–20.Google Scholar
5. Bordonaro, M, Lazarova, DL, Sartorelli, AC (2008) Cell Cycle 9, 1178–83.Google Scholar
6. Mills, SJ, Mathers, JC, Chapman, PD et al. (2001) Gut 48, 41–46.Google Scholar
Figure 0

Fig. 1. Mean post-intervention expression of SFRP1 expressed as adjusted copies (2−ΔCt × 1000) relative to the geometric mean of 18S and β2M housekeeping genes (n = 45).

Figure 1

Fig. 2. Mean post-intervention % of mitotic cells in top half of the crypt (n = 24). Data is presented as least squares means.