Nature|Ketogenic diet can prevent cancer! New research reveals mechanism

Colorectal cancer (CRC) is one of the most common cancers, and its incidence is associated with specific dietary patterns. For example, a Western diet enhances the tumorigenicity of intestinal progenitor cells and suppresses antitumor immunity. Likewise, a high-sugar diet and high blood sugar predispose to CRC. In addition, excessive intake of animal protein, especially red meat, also increases the risk of developing CRC.

Ketogenic Diet (KD)is a A variety of high-fat, low-carbohydrate, protein and other nutritional elements in the appropriate proportions diet plan, initially it is an effective treatment for children with refractory epilepsy non-drug therapy.

Recently, scientists from the University of Pennsylvania reported in Nature that< /span>The ketogenic diet showed strong tumor suppressive effect. The ketone body beta-hydroxybutyrate (BHB) recapitulates these properties of a ketogenic diet, reducing colonic crypt cell proliferation and effectively inhibiting intestinal tumor growth.

The researchers designed mouse diets with defined macronutrient sources, constant protein content, and varying fat-to-carbohydrate ratios (Fig. Cyclical dextran sodium sulfate (DSS) induced colorectal cancer (Fig. 1a), thereby identifying dietary interventions affecting intestinal tumor growth.

The results showed thattumor numbers and tumor numbers increased with increasing fat to carbohydrate ratios. Size was suppressed (Fig. 1c). Not only that,ketogenic diet (KD) can also inhibitCdx2CreERTApcfl/fl tumor progression in CRC model mice and mice with CRC development, recovery from KD feeding to normal Diet can cause CRC recurrence. These results indicated that,KD could not only prevent the occurrence of CRC in mice, but also inhibit the progression of CRC.

Figure 1. a, Schematic representation of dietary exposure in AOM/DSS-treated mice. b , Macronutrient composition of the diet. c, Tumor scores in AOM/DSS-treated mice fed six different diets. d, Schematic representation of dietary exposure in Cdx2 CreERT Apc fl/fl mice. e, Tumor scores in Cdx2 CreERT Apc fl/fl mice fed KD or control diets. f-k, Schematic of dietary exposure (f, i) and colonoscopy-based tumor quantification (g, h, j, k) AOM/DSS-treated KD-fed mice in treated model (f-h) and stopped model (i-k) .

Next, the researchers explored the mechanisms by which KD affects colon tumor development.

The experiment first ruled out differences in caloric intake. In the AOM/DSS model, cancer progression is driven by immune cells, however adaptive immune cells are not functionally required for dietary protection. At the same time, the NLRP3 inflammasome has also been shown to be unrelated to the mechanism of tumor development. Additionally, they used an organoid system recapitulating stem cell-derived growth of the intestinal epithelium to study the effects of KD on intestinal stem cells (ISCs),showing that diet inhibited crypt cell proliferation.

The ketogenic diet (KD) can stimulate the liver to produce the ketone body acetoacetate (AcAc) and the ketone body β-hydroxybutyrate ( BHB), which is the body’s physiological response to hunger. To determine whether the inhibitory effect of KD on epithelial growth was mediated by ketone bodies, the experiments monitored intestinal organoids cultured in the presence of AcAc or BHB (Fig. 2a). Although the growth of organoids was unchanged in the presence of AcAc (Fig. 2b,c), BHB reduced the size of the organoids in a concentration-dependent manner (Fig. 2d,e). This effect of BHB was also observed in tumor organoids (Fig. 2f,g). In addition to inducing hepatic ketosis, KD confers health benefits by reducing systemic glucose levels and enhancing insulin sensitivity.

To determine the relative contributions of BHB supplementation and glucose limitation, we treated organoids with BHB using different glucose concentrations. The results suggest that glucose restriction and BHB supplementation may act through different mechanisms.

Figure 2.a, class cultured with AcAc or BHB Schematic diagram of organ growth. b, c, Representative images (b) and quantification (c) of organoids exposed to AcAc or BHB. d–g, Representative images (d, f) and quantification (e, g) of wild-type (d, e) and AKS organoids (f, g) cultured with BHB. h, Serum concentrations of BHB in AOM/DSS-treated mice fed diets with the indicated fat content. i–k, serum BHB (i), colonoscopy-based tumor quantification (j), and histological tumor counts (k) in KD-fed or BHB-treated Cdx2 CreERT Apc fl/fl mice.

Next, the researchers investigated the mechanism of tumor suppression mediated by the ketone body beta-hydroxybutyrate (BHB). They performed RNA sequencing (RNA-seq) on BHB-treated organoids and found that BHB induced significant changes in global gene expression (Figure 3a). One of the tumor-suppressing transcription factors, Hopx, whose expression is concentrated at the base of colonic crypts, a marker of slow division of intestinal stem cells, was significantly increased.

Exposure to an organoid model by culturing stem cells from Hopx-deficient mice and wild-type littermates Under BHB, BHB reduced the growth of wild-type organoids (Fig. 3c,d), whereas Hopx-deficient organoids were resistant to BHB treatment (Fig. 3e,f). Thus, BHB reduced epithelial proliferation in wild-type organoids, but not in the absence of Hopx. Hopx overexpression in organoids was sufficient to reduce the growth of wild-type and tumor organoids (Fig. 3g-j). Mice receiving KD had elevated levels of Hopx in colon tissue (Fig. 3k), which were further exacerbated after induction of colon tumors (Fig. 3l). This effect is unique to the colon. Whereas after induction of CRC in Hopx-deficient mice and wild-type littermates on KD, the diet was ineffective in Hopx-deficient mice, although the wild-type group had significantly reduced tumor growth after KD feeding (Fig. 3m,n). ). In conclusion, the tumor suppressor effect of KD and BHB requires the expression of Hopx.

Figure 3.a, BHB-treated and control organoids Heatmap of differentially expressed genes. b, Hopx expression in BHB-treated organoids. c–f, Representative images (c,e) and quantification (d,f) of wild-type (c,d) and Hopx-deficient (e,f) organoids treated with BHB. g–j, Representative images (g, i) and quantification (h, j) of wild-type (g, h) and AKS (i, j) Hopx-overexpressing organoids. k, l, Colonic transcript levels of Hopx in KD-fed mice under steady-state conditions (k) and after tumor induction (l). m, n, Colonoscopy-based tumor quantification (m) and histological tumor counts (n) in KD-fed Hopx-deficient mice and controls.

The article also discusses whether the BHB-HOPX pathway is equally effective in inhibiting human intestinal epithelial proliferation (Fig. 4a). Indeed, BHB reduced organoid growth in healthy donors (Fig. 4b,c) and in CRC patients, suggesting a BHB-mediated inhibitory effect of tumor organoids. Similar to the findings in mice, BHB treatment resulted in elevated Hopx expression in human organoids (Fig. 4d).

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