Untangling the Contribution of Fructose Metabolism to Obesity and Colorectal Cancer: A Tale of Adaptation to Hypoxia in the Gut

Taylor SR, Ramsamooj S, Liang RJ, et al. Dietary fructose improves intestinal cell survival and nutrient absorption. Nature 2021;597(7875):263–267. Fructose consumption has increased dramatically in the past 50 years in Western countries, mainly in the form of sucrose and sweeteners such as high-fructose corn syrup (HFCS) used in sugar-sweetened beverages. This increase in fructose consumption has been paralleled by an epidemic of obesity and metabolic disorders (eg, type 2 diabetes mellitus and hypertriglyceridemia), as well as an increased incidence of early-onset colorectal cancer (CRC), suggesting a potential link between excess fructose, obesity, metabolic syndrome, and development of early-onset CRC. In this study, the authors aimed to elucidate the effects of fructose on the normal intestinal epithelium. To this end, they fed mice HFCS for 4 weeks and quantified the mean intestinal villus length using a high-throughput, unbiased image-segmentation–based approach. They found that animals on an HFCS diet showed a 25%–40% increase in intestinal villus length in the duodenum and proximal jejunum vs controls. Moreover, this villus hypertrophy was associated with higher weight gain, fat accumulation, and increased lipid absorption. Next, they performed label-tracing experiments to elucidate whether the longer intestinal villi observed in mice fed HFCS were due to an increase in cell proliferation or prolonged cell survival. They found similar migration rates in the control vs HFCS-fed group, but more than twice as many cells surviving longer than 72 hours in the latter. As hypoxia is a driver of cell death in intestinal villi, they analyzed hypoxia patterns in HFCS-treated mice vs controls. Although both groups showed similar hypoxia patterns, they found an increase in hypoxia-inducible factor-1α (HIF-1α) targets and strong up-regulation of the fructolytic proteins GLUT5 and ketohexokinase (KHK) in the intestinal epithelium of HFCS-treated mice. To examine whether fructose could promote hypoxic cell survival in other contexts, they examined human CRC cell lines cultured in hypoxia and hypoxic mouse intestinal organoids. The addition of fructose did not affect proliferation in either cells or organoids, but improved cell survival in both. They found that in hypoxic intestinal cells, fructose 1-phosphate, a metabolite of fructose generated by the enzyme KHK in the intestinal mucosa, inhibits PKM2 (the M2 isoform of pyruvate kinase) to promote cell survival. Finally, they demonstrated that genetic ablation of KHK or pharmacologic activation of PKM2 diminished the effect of fructose on hypoxia survival, thus preventing villus elongation, increased nutrient absorption, and tumor growth. The authors concluded that fructose promotes hypoxic cell survival in the intestine, which leads to an increase in villus length in the normal epithelium, resulting in improved nutrient absorption and weight gain. This finding may help to explain the obesogenic properties of a Western-style diet and is a compelling explanation for the promotion of tumor growth by HFCS. Comment. In the past several decades, patterns of human feeding and food production have changed dramatically, and for many years it has been known that diet plays a key role as a risk factor for many chronic diseases and malignancies. In this sense, fructose uptake has increased significantly in the last 50 years to ≥9% of daily caloric intake in developed countries, mainly in the form of sucrose and sweeteners such as HFCS used in sugar-sweetened beverages (Food Chem Toxicol 2011;49:2875–2882). This increase in fructose consumption is associated with obesity, metabolic disorders (eg, type 2 diabetes mellitus, insulin resistance, nonalcoholic fatty liver disease, and hypertriglyceridemia), and a rise in the incidence of early-onset CRC. These observations suggest a potential link between excess fructose, obesity, metabolic syndrome, and development of early-onset CRC. Several studies have reported that excessive consumption of sugary beverages causes obesity and that being obese increases the risk of CRC, especially in men (Gut 2013;62:933–947). The health implications of fructose consumption have received growing attention in recent years. Although the liver has traditionally been considered as primarily responsible for fructose metabolism, current evidence supports that the intestinal metabolism of this carbohydrate is of great relevance (Cell Metab 2018;27:351–361). The small intestine can metabolize 90% of fructose when ingested in low doses so that only traces of fructose are detected in the portal blood along with large amounts of glucose, lactate, and glycerate derived from its metabolism. However, high doses of fructose (≥1 g/kg) exceed intestinal absorption and clearance, allowing fructose to reach both the liver and colon intact. It has been suggested that the intestinal metabolism of fructose constitutes a physiological mechanism that protects the liver and colon from coming into contact with fructose (Nat Metab 2020;2:586–593). It should be noted that the intestinal microbiota modifies its composition when it comes into contact with this nutrient. Furthermore, colonic neoplastic lesions possess both fructose receptors (GLUT5) capable of transporting fructose directly from the intestinal lumen, and the enzymes necessary to metabolize it. In fact, when colonic tumors are present, the amount of fructose reaching the liver and the peripheral circulation decreases considerably. Previous evidence in genetic mouse models supports that high fructose intake promotes growth in intestinal tumors (Science 2019;363:1345–1349). Indeed, mice fed HFCS showed a more severe tumor burden and more profound anemia (a complication associated with severe disease and worse survival in genetic CRC models). In humans, epidemiological data support the role of the Western diet in general and excessive fructose intake in particular as risk factors for early-onset CRC. The results of a recent prospective epidemiologic study that analyzed data from 41,272 nurses aged 25–42 years support that excessive consumption of sugar-sweetened beverages in adolescence and young adulthood may explain, at least in part, the rapid increase in early-onset CRC (Gut 2021;70:2330–2336). Likewise, another recently published study reported an increase in colorectal precursor lesions (advanced adenomas) before the age of 50 years in individuals with high consumption of sugar-sweetened beverages (J Natl Cancer Inst 2021;113:543–552). Therefore, current evidence supports that excessive consumption of fructose might play a role in the development of early-onset CRC. However, the potential functional mechanism linking fructose intake with obesity and/or CRC development remained poorly understood. Moreover, we lacked information regarding the potential effect of fructose on the normal intestinal epithelium. The present study convincingly demonstrated that high fructose consumption enhances hypoxic cell survival in both intestinal villi and intestinal tumors. This finding may help to explain obesity associated with a Western-style diet and the promotion of tumor growth observed in mice fed HFCS. Moreover, this study reinforces the potential role of fructose metabolism as an important component of oxygen sensing in diverse biological contexts. By testing dietary interventions in mouse models, the authors found that mice of both sexes and a variety of ages and genetic backgrounds showed a remarkable increase (25%–40%) in intestinal villus length in the duodenum and proximal jejunum when treated with HFCS compared with control mice. Moreover, this structural change, which led to an expansion of the intestinal surface area, was associated with weight gain, fat accumulation, and increased lipid absorption. By performing trace experiments using 5-bromo-2′-deoxyuridine and 5-ethynyl-2′-deoxyuridine injections, they were able to demonstrate that cell survival rather than cell proliferation was a major determinant of the hypertrophy of villi secondary to high fructose intake. In this sense, it is worth mentioning that tissue hypoxia is a key factor involved in intestinal epithelial cell death as cells migrate away from their blood supply during transit along the villus. In this regard, similar hypoxia patterns between HFCS-treated and control mice were observed using pimonidazole (a hypoxia marker) staining. Despite this similarity of hypoxia patterns, mice fed HFCS showed up-regulation of (1) HIF-1α target proteins, such as ENO1 (enolase-1) and LDHA (lactate dehydrogenase A), and (2) fructolytic proteins GLUT5 and KHK. These results support that fructose metabolism promotes hypoxemic cell survival in the intestine. Moreover, the author confirmed these findings in human CRC cell lines cultured in hypoxia, as well as in hypoxemic mouse intestinal organoids. Regarding the functional mechanism linking fructose and decreased sensitivity to hypoxia, they found that the fructose metabolite F1P (fructose-1-phosphate) robustly inhibited PKM2, which is very sensitive to changes in the intracellular metabolome and highly expressed in intestinal villi, by stabilizing the enzyme in its low active monomeric form. Monomeric PKM2 is able to transactivates HIF1-α, a key transcription factor in the prevention of hypoxic cell death. Finally, they demonstrated that genetic ablation of KHK or pharmacologic activation of PKM2 using TEPP-46 diminished the effect of fructose on hypoxia survival, thus preventing villus elongation, increased nutrient absorption, and tumor growth. In summary, the authors shed light on the mechanisms linking high fructose intake to obesity and CRC growth. Their results suggest that exposition to dietary fructose might serve as a highly specific signal for reprogramming cellular metabolism in response to hypoxia in both intestinal villi and intestinal tumors. It will be important to confirm how well these observations translate to humans. In the meantime, this study adds to a growing body of evidence supporting the importance of reducing dietary fructose consumption as a strategy for preventing obesity and CRC.