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Stem cells

Dietary fat promotes intestinal dysregulation

Nature volume 531, pages 4243 (03 March 2016) | Download Citation

In mice, a high-fat diet has now been found to induce intestinal progenitor cells to adopt a more stem-cell-like fate, altering the size of the gut and increasing tumour incidence. See Article p.53

Excess food intake causes obesity and is linked to many life-threatening diseases, including cardiovascular disease and cancer1. Ingested dietary components cause a well-understood physiological response that readjusts metabolism and restores energy balance, and that is controlled by nutrients, hormones and systemic factors2. But little is known about how dietary components might affect stem-cell biology to alter tissue function or tumour development3. On page 53 of this issue, Beyaz et al.4 show that an increase in dietary fat directly promotes the proliferation of intestinal stem cells (ISCs) and the progenitor cells to which they give rise, perhaps resulting in more 'seeds' that can develop into cancer.

Tissue homeostasis in the gut requires that resident ISCs maintain a dynamic balance between self-renewal, which expands the stem-cell pool, and differentiation into daughters — intestinal progenitors that eventually give rise to all the mature lineages of the intestinal epithelium (the intestinal lining). Nutrients cause changes in a variety of circulating factors that influence adult stem-cell biology, affecting this balance and so altering tissue remodelling and regeneration2. In addition, ISCs are in close contact with dietary constituents undergoing digestion, and so are directly regulated by molecular components of ingested food.

Beyaz et al. report that a high-fat diet (HFD) elevates the number and proliferation rate of both ISCs and progenitors in mice. This alteration led to elongation and regeneration of pits in the epithelium called crypts, in which these cell types are located. The HFD augmented the ability of intestinal crypts to give rise to mini-gut-like structures called organoids when cultured in vitro — an approach that is widely used to assay ISC activity. Progenitors from HFD mice could also form organoids, suggesting that they become more stem-cell-like under HFD conditions (Fig. 1). Rather than being a result of obesity per se, these changes in ISC and progenitor behaviour were caused by certain fatty acids in the HFD.

Figure 1: Dietary fats remodel the intestine.
Figure 1

Intestinal stem cells (ISCs) and their daughters, intestinal progenitors, reside at the bottom of structures called crypts, and give rise to all the cell types of the mature intestine, including Paneth cells and absorptive cells. When mice are fed a balanced diet, signals released by Paneth cells (grey arrows) promote ISC regeneration. Beyaz et al.4 report that some of the fatty acids in a high-fat diet (HFD) activate a signalling cascade that involves the nuclear receptor protein PPAR-δ and the protein β-catenin. The cascade increases ISC and progenitor proliferation, makes progenitors more stem-cell-like and enables ISCs to grow in the absence of signals from Paneth cells. This HFD-mediated expansion of the stem and progenitor pool promotes tumour formation.

Despite the changes in ISC and progenitor function, Beyaz and colleagues found that the overall length and weight of the intestine were reduced in mice fed an HFD, compared with control animals. And, explaining this finding, the number of certain mature cell types — absorptive cells and Paneth cells, which defend against harmful bacteria in the gut — was lower in HFD mice. Together, these findings imply that an undifferentiated ISC pool is maintained despite the expanded numbers and increased regenerative potential of the ISCs.

Stem cells normally reside in a specialized environment called a niche, in which communication with neighbouring cells ensures their precise regulation. Paneth cells are an essential part of the niche5, and are interspersed throughout it. A previous study6 from the same group revealed that calorie restriction increases the number of niche Paneth cells, promoting ISC self-renewal and subsequent intestinal regeneration. By contrast, in the current study, the authors demonstrated that an unrestricted HFD uncoupled the ISCs from their niche, allowing them to adjust to the decrease in Paneth-cell numbers. For instance, several signalling proteins (such as Jag1 and Jag2) that are normally produced by Paneth cells are upregulated in HFD-derived ISCs, sustaining niche-independent growth.

The incidence of human colorectal cancer correlates with diet-induced obesity7. Furthermore, adult stem cells are speculated to be the origin of some cancers8. Beyaz et al. showed that the increased pool of ISCs and ISC-like progenitors induced by an HFD predisposed mice to intestinal tumours. By contrast, calorie restriction — which also increases ISC numbers6 — is associated with reduced tumour initiation1. The mechanistic differences underlying altered stem-cell function in each condition may partially explain this discrepancy. Calorie restriction is associated with increased interactions between the niche and ISCs, whereas HFD-associated, niche-independent growth allows stem cells to escape physiological regulation. How the molecular pathways modulated by these two dietary regimens intersect and communicate in ISCs remains to be investigated, and might identify putative therapeutic targets.

Gene-expression profiles often provide clues to the state of a cell. Nuclear receptors such as PPAR and LXR proteins sense nutrients and regulate gene expression, providing a connection between diet-induced metabolic changes and these profiles9. Beyaz and colleagues analysed gene expression and found that genetic targets of one PPAR, PPAR-δ, were upregulated in ISCs in HFD mice compared to ISCs in control mice. PPAR-δ is linked to a signalling cascade called the Wnt–β-catenin pathway10, which is involved in the development of intestinal tumours. In the current study, genetic and pharmacological experiments revealed that activation of PPAR-δ and Wnt–β-catenin signalling mediates, at least in part, the effects of dietary fats on ISC and progenitor function and intestinal tumour formation.

This work provides a plausible cellular and molecular explanation for how an excess of dietary fat remodels the intestine. However, questions remain about how the basic mechanisms of action of dietary fat affect systemic energy metabolism and other gastrointestinal diseases apart from cancer. For instance, it is known that diet can influence immune and metabolic activities by directly modulating the diversity and functions of the gut microbiota (the population of microorganisms that inhabit the gut), but it remains unclear whether and how such changes in the microbiota integrate with the PPAR-δ pathway. Because the microbiota differs between individuals, the interplay between microbiota and ISCs under HFD conditions might modulate an individual's tumour risk.

It would be interesting to investigate the contribution of ISCs to gut inflammatory disorders such as Crohn's disease because, as with cancer, an HFD accelerates the progress of these disorders independently of obesity11. Furthermore, it is not known whether an HFD affects the gut's neuroendocrine system (the hormone-releasing cells that receive input from neurons), perhaps through its effects on ISCs and progenitors, to contribute to the metabolic alterations associated with obesity, type 2 diabetes or cardiovascular diseases.

The current study does not address whether the effects of an HFD on gut architecture are reversible. Moreover, it is unclear how changes in dietary regimens affect ISC function. Finally, further investigation will be needed to determine whether dietary or pharmacological interventions that target ISCs could maintain healthy intestinal function and reduce the incidence of tumours or other HFD-associated human diseases. Such research, building on the foundation provided by the current study, will be important for defining future steps in personalized human nutrition and health.



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  1. Chi Luo and Pere Puigserver are in the Department of Cell Biology, Harvard Medical School, and in the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

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Correspondence to Pere Puigserver.

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