Abstract
Background: Hyperactive Wnt signaling is frequently observed in colorectal cancer. Higher intakes of dietary fiber [nondigestible carbohydrates (NDCs)] and the fermentation product butyrate are protective against colorectal cancer and may exert their preventative effects via modulation of the Wnt pathway.Objectives: We investigated the effects of supplementing healthy individuals with 2 NDCs [resistant starch (RS) and polydextrose] on fecal calprotectin concentrations and Wnt pathway–related gene expression. In addition, we determined whether effects on secreted frizzled-related protein 1 (SFRP1) expression are mediated via the epigenetic mechanisms DNA methylation and microRNA expression.Design: In a randomized, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study), 75 healthy participants were supplemented with RS and/or polydextrose or placebo for 50 d in a 2 × 2 factorial design. Pre- and postintervention stool samples and rectal mucosal biopsies were collected and used to quantify calprotectin and expression of 12 Wnt-related genes, respectively. The expression of 10 microRNAs predicted to target SFRP1 was also quantified by quantitative reverse transcriptase-polymerase chain reaction, and DNA methylation was quantified at 7 CpG sites within the SFRP1 promoter region by pyrosequencing.Results: NDC supplementation did not affect fecal calprotectin concentration. SFRP1 mRNA expression was reduced by both RS (P = 0.005) and polydextrose (P = 0.053). RS and polydextrose did not affect SFRP1 methylation or alter the expression of 10 microRNAs predicted to target SFRP1. There were no significant interactions between RS and polydextrose.Conclusions: RS and polydextrose supplementation did not affect fecal calprotectin concentrations. Downregulation of SFRP1 with RS and polydextrose could result in increased Wnt pathway activity. However, effects on Wnt pathway activity and downstream functional effects in the healthy large-bowel mucosa remain to be investigated. The DISC Study was registered at clinicaltrials.gov as NCT01214681.
Highlights
A large proportion of colorectal cancer (CRC)7 cases are linked to lifestyle factors [1], and it has been estimated that 70% of cases could be prevented by adopting a healthier diet [2]
We hypothesized that nondigestible carbohydrates (NDCs) may have protective effects in the large bowel by reducing inflammation, but we did not observe any effects of resistant starch (RS) and/or polydextrose on concentrations of fecal calprotectin, an indicator of inflammation in the large bowel
One study reported an inverse correlation between fiber intake and fecal calprotectin concentration [25], whereas another reported an increase in calprotectin with RS supplementation [26]
Summary
A large proportion of colorectal cancer (CRC) cases are linked to lifestyle factors [1], and it has been estimated that 70% of cases could be prevented by adopting a healthier diet [2]. Convincing evidence exists for reduced CRC risk with higher intakes of dietary fiber [3, 4], including nondigestible carbohydrates (NDCs) such as resistant starch (RS). Butyrate possesses anticancer properties through its anti-inflammatory and antiproliferative effects [5]. These effects may be mediated by regulation of gene expression through epigenetic mechanisms, primarily histone modifications [6]. Studies have shown that butyrate modulates Wnt signaling, a pathway frequently hyperactivated in CRC, providing an additional mechanism through which butyrate may protect against CRC [7]. Higher intakes of dietary fiber [nondigestible carbohydrates (NDCs)] and the fermentation product butyrate are protective against colorectal cancer and may exert their preventative effects via modulation of the Wnt pathway
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