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Sickeningly Sweet”…. High-Fructose Corn Syrup-Caveat Emptor!

Johnson, David A. MD, MACG, FASGE, MACP1

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The American Journal of Gastroenterology: October 2021 - Volume 116 - Issue 10 - p 1970-1971
doi: 10.14309/ajg.0000000000001335
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Clearly, a suboptimal diet is a modifiable risk factor for noncommunicable diseases, including most gastrointestinal (GI) illnesses (1). There is increasing evidence that the intake of highly processed foods known as the Western pattern diet induces a hyperimmune response and systemic inflammation particularly through inflammasome activation. These effects promote inflammation and immune response, thereby decreasing an appropriate defensive response to pathogens, antigens, metabolic or cellular stress, and neoplasia (2). The adverse inflammatory and immune responses through proinflammatory cytokines are increasingly recognized as important pathogenic factors in a wide array of inflammatory, neoplastic, and autoimmune diseases: including: cardiovascular disease, obesity, diabetes, inflammatory bowel disease, colorectal neoplasia, and nonalcoholic fatty liver disease (NAFLD) (1).

High-fructose corn syrup (HFCS), also known as glucose-fructose, is produced from corn starch which is enzymatically processed to convert some of the glucose into fructose (Figure 1). As it is cheaper, sweeter, and easier to use than cane sugar, whereby it has become a common component in the Western pattern diet and is used in most sugary beverages and processed foods. Notably, a key problem with HFCS is the overall prevalence of use, including foods that do not taste sweet, such as pizza and crackers. The global market for HFCS is projected to grow from $5.9 billion in 2019 to $7.6 billion in 2024. There are several types of HFCS with the dry weight percentage fructose indexed, whereas the remaining percentage is glucose (Table 1). The most common forms used, however, are HFCS 42 or HFCS 55. A rising concern is that HFCS has been implicated in the growing epidemic of obesity, diabetes, and metabolic syndrome in the United States (3). More recent data have highlighted the additional risks for GI diseases driven through inflammasome/cytokine upregulation (1).

Figure 1.
Figure 1.:
Structural forms of fructose and glucose.
Table 1.
Table 1.:
Formulations of high-fructose corn syrup and common dietary processed foods/drinks
Table 1-A.
Table 1-A.:
Formulations of high-fructose corn syrup and common dietary processed foods/drinks


Glucose is transported by intestinal epithelial cells in a very active manner through sodium-coupled glucose transporters. The fructose pathway however, is mediated via a passive transporter called GLUT5. As little as 5 g of fructose (notably 20 g in regular 12-ounce soda) can overwhelm this passive transporter (4). Rather than being absorbed, the fructose instead is delivered to the colon.

Using mice predestined to develop colonic neoplasms (bioengineered knockout of the adenoma polyposis coli gene), researchers administered the weight-adjusted equivalent of 20 g of HFCS daily. At 1 month, the HFCS-exposed mice showed significant acceleration into advanced, high–grade-type colonic neoplasms (4). No associated risks of obesity or diabetes were evident as confounding variables. There was notable uptake in fructose within the intestinal tumors identifiable through carbon labeling. The HFCS group also demonstrated accelerated de novo fatty acid–generated synthesis facilitating membrane stabilization, energy storage, and intestinal growth of these lesions. This suggests that the tumors rewire the metabolic pathways in favor of fatty acid synthesis promoting further growth. Further data have focused the influence of fructose metabolism in a number of cancers, with pathogenic association for cancer development and outcome (5).

Recognizably, there has been an emerging health concern in the United States with a dramatic increase in colorectal cancer (CRC) in relatively younger patients. By 2030, it has been projected that CRCs will increase by 90%–125% in 20- to 34-year-olds and by 28%–46% in 35- to 49-year-olds (6). Although the rising obesity and diabetes rates are often cited as the reason behind this increase, the implications for a pathogenic role of HFCS is provocative. Notably, HFCS increased by 100× from the 1970s to 1990s in the United States (6). Conceptually, this may be causal with a coincident birth cohort effect relative to early age onset of CRC.


Alteration of the intestinal microbiome has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Dietary effects of a non-WFD have demonstrated efficacy in IBD treatment (7). Specific dietary-related adverse effects of HFCS have been demonstrated based on animal studies (8,9). In a murine model using a high fructose, compared with a high glucose diet, there was worsening of drug-induced colitis associated with changes in composition, metabolic functions, and distribution of the intestinal microbiota (10). Alterations of bacterial bile acid metabolism, which have been associated with IBD, were evident in this HFCS murine model as well (10). Specific alterations in the microbiome were evident and requisite for the associated adverse effects. Reductions of intestinal mucous integrity were evident, with demonstrable increased bacterial access to the mucosa. Reducing or eliminating bacteria by concomitant antibiotics or use in germ-free mice attenuated or eliminated the HFCS-related adverse effects.


Fructose is a lipogenic substrate. Although the pathogenesis of NAFLD is multifactorial, HFCS consumption is recognized to be a key inducing factor in both humans and animals (11). Excessive consumption leads to de novo hepatic lipogenesis and induces oxidative stress through several mechanistic adverse effects. Notably, compared with glucose, fructose generates 100× more hepatic reactive oxygen species, which are free radicals with associated adverse effects of damage to DNA and/or RNA and may cause cell death (12). Fructose-induced NAFLD effects are associated with intestinal microbiome changes that alter the gut barrier function and consequent endotoxin translocation. In a murine model, these cytokine-related inflammatory changes induced NAFLD and liver cancer (13).

Caloric soft drinks are the leading source of added fructose worldwide and have been linked to obesity, diabetes, and metabolic syndrome. Notably, the consumption can increase the prevalence of NAFLD independently of metabolic syndrome (14). The data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity, which recognizably is quite limited.


  1. The clinical data support that added fructose, in particular HFCS, is a major risk factor for the development of common GI diseases, including NAFLD, IBD, and advanced colorectal neoplasia. Unfortunately, many processed foods contain HFCS, and most people cannot estimate how much fructose they actually consume. A recent report suggested that HFCS ingestion should be considered a “public health crisis” (15). Notably, the corn industry had an unsuccessful petition to the FDA to change the name of HFCS to “corn sugar” (
  2. The recognition of the effects of dietary components influencing the microbiome, as well as inflammatory and immune responses, is rapidly increasing. Although extrapolation from animal data in some of these associations may be premature, the scientific premise regarding the potential evils of HFCS is compelling….Caveat emptor!


Guarantor of the article: David Johnson, MD, MACG, FASGE, MACP.

Specific author contributions: All authors.

Financial support: None to report.

Potential competing interests: None to report.


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