Inulin results in increased levels of β-catenin and cyclin D1 as the adenomas increase in size from small to large in the Min/+ mouse

Abstract

The mechanism that drives the growth of some colonic adenomas towards malignancy, while permitting others to remain for decades in quiescence, remains unknown. Diets can alter the growth rate of intestinal tumours but it is still unknown whether diets are able to alter the molecular biology of these adenomas in a way that predicts further outcome. To address this issue we fed Min/þ mice with two diets known to lead to different adenoma outcomes: a high-fat control diet (n 15) or a high-fat inulin-enriched (10 % w/w) diet (n 13). To study the effect of diet on cell signalling during adenoma growth, the adenomas of each Min/þ mouse were divided into three size-categories, and the levels of b-catenin, E-cadherin, cyclin D1 and matrix metalloproteinase-9, which are known to be involved in colon tumorigenesis, were determined. The growth-promoting inulin diet resulted in more large adenomas than the control feeding (P¼ 0·003) and doubled the total area of the adenomas (P ¼ 0·008). The inulin diet increased the expression of nuclear b-catenin (P¼0·004) and its target cyclin D1 (P¼ 0·017) as the adenomas increased in size from small to large, indicating the presence of an accelerated cancerous process. Neither phenomenon was seen in the control group during adenoma growth. Our results suggest that in addition to the number, size, and growth rate of adenomatous polyps, the signalling pattern of the adenomas should also be considered when evaluating preventive dietary strategies.Intestinal tumorigenesis: Adenoma growth: E-cadherin: Adenomatous polyposis coli: Colon cancerThe incidence of colon cancer is increasing in the Western world and death from this malignancy is already the second leading cause of cancer mortality in the USA (1) . Ageing of the population and a Western-type life style, including dietary habits and low levels of physical activity, are the main reasons for this incidence. Progression of the disease from benign adenoma through early carcinoma to malignant metastatic cancer requires years or even decades. Due to a long asymptomatic period, all too often the disease is life-threatening before it is diagnosed. Every second person is estimated to have a benign colonic tumour during his or her lifetime and 10 % of these tumours are assumed to progress to malignancy (2) . Thus, for preventive strategies it is vitally important to understand the mechanisms that stimulate adenoma growth and development towards accelerated malignancy or, in contrast, attenuate them to remain in quiescence for periods as long as decades.Several animal models have shown that diet or its constituents can alter the growth rate of intestinal tumours (3) . Whether diet is able to alter the molecular biology of these adenomas, which could result in very early prediction of their eventual outcome, is however not known. To address this issue we continued with our previous study (4) where multiple intestinal neoplasia (Min/þ) mice were fed with a high-fat non-fibre diet and a fructo-oligosaccharide inulin diet that led to different aden...

Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer

“…This consideration is in accord with the “butyrate paradox,” which argues that the ability of this SCFA to promote or impede cell proliferation is contextually dependent on the cell-type, time, and the amount of exposure (Donohoe et al, 2012). The doses of SCFA exceeding the threshold tolerable by the host have been shown to aggravate colonic inflammation (Kaiko et al, 2016; Kim et al, 2013) and tumorigenesis (Belcheva et al, 2014; Misikangas et al, 2008; Pajari et al, 2003), induce urethritis and hydronephrosis (Park et al, 2016), and promote obesity by aggravating hepatic lipogenesis (Singh et al, 2015) and hyperphagia (Perry et al, 2016). Janssen et al (2017) reported that feeding of guar gum (a soluble fiber comprised of mannose [β 1,4-linked] and galactose [1,6-linked]) for 18 weeks protected mice from diet-induced obesity but eventuated hepatic inflammation and fibrosis associated with increased plasma TBA and disrupted enterohepatic circulation).…”

Effect of Dietary Fibers on Cecal Microbiota and Intestinal Tumorigenesis in Azoxymethane Treated A/J Min/+ Mice

“…Briefly, in models applying AOM, the AOM precursor dimethyl hydrazine (DMH) or AOM/dextran sodium sulfate (DSS) to induce carcinogenesis, anti-tumorigenic effects of inulin have been found in mice [ 21 , 50 ] and rats when administered prior and subsequent to the carcinogen [ 51 – 55 ]. In conventional C57BL/6J Min/+ mice, inulin has been reported to increase the genetically driven small intestinal tumor burden [ 56 – 58 ] except for one study reporting short chain FOS (which can be produced by degradation of inulin) to attenuate tumorigenesis [ 59 ]. These data may suggest a different role of fructose based fiber (inulin and FOS) in the genetically driven small intestinal tumorigenesis in C57BL/6J Min mice compared with carcinogen induced colon tumorigenesis.…”

Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma

“…Mice that developed hyperbilirubinemia upon ICD diet displayed loss in gut bacteria richness and diversity, reduced Tenericutes, and increased abundance of Proteobacteria and Clostridia, which are capable of producing butyrate and secondary bile acids. Notably, butyrate is involved in the promotion or inhibition of cell proliferation based on the amount and duration of exposure and the type of target cell 107 and excessive doses may exert oncogenic effects, promote liver steatosis and intestinal inflammation, 108–112 whereas secondary bile acids have known hepatotoxic activity. 113 The metabolomic analysis showed that an increase in butyrate cecal content characterized mice with hyperbilirubinemia and HCC.…”