N-glycolylneuraminic acid, or Neu5Gc, is a sialic acid – a nine carbon sugar molecule – produced by most nonhuman mammals. Sialic acids serve diverse roles, such as mediating cell-to-cell interactions, triggering cell signaling cascades, and binding to pathogens. Humans do not produce Neu5Gc; however, trace amounts of the compound are commonly present in human urine, suggesting that Neu5Gc is obtained in the diet. Foods highest in Neu5Gc include red meat, eggs, and milk. It is rarely present in fish or poultry.
Neu5Gc is similar in structure to Neu5Ac, a sialic acid produced in the human body. Due to this similarity, Neu5Gc is handled by the body's biochemical pathways as native. However, the body's immune system recognizes Neu5Gc as foreign and produces antibodies to it. Therefore, the consumption of foods that contain Neu5Gc may elicit an immune response, triggering inflammation, and potentially providing a unique dietary link between the consumption of animal products and chronic disease.
Animal product consumption as a unique source of Neu5Gc
In the human body, Neu5Gc is typically bound to a sugar molecule and is incorporated into cell membranes within multiple tissues.  For reasons that are not well understood, accumulation of dietary Neu5Gc in human tissues is not uniform and tends to occur preferentially in epithelial cells (cells that line hollow organs) or in the endothelium (the lining of blood vessels where atherosclerosis may occur). Evidence demonstrates that Neu5Gc also accumulates in human lung, pancreatic, and ovarian tumors.
Dietary Neu5Gc is abundant in beef, lamb, and pork as well as other animal products such as goat cheese, caviar, and fish eggs.  For comparison, beef contains approximately 500 picomoles of bound Neu5Gc per milligram; goat cheese contains approximately 250 picomoles per milligram; and caviar contains approximately 1,500 picomoles per milligram. A standard serving size of ground beef in the United States is 3 to 4 ounces (85 to 115 grams), providing approximately 50,000 micromoles (16 grams) of Neu5Gc per serving.
Potential evidence for a role in atherosclerosis and cancer
Some studies suggest that the body’s immune response to Neu5Gc provides a mechanistic explanation for why frequent consumption of animal products has been associated with an increased risk of developing various diseases such as atherosclerosis and cancer. For example, one study demonstrated that when endothelial cells are treated with approximately 1 gram of Neu5Gc, they undergo endothelial activation, a common feature of vascular disease, as well as increased cytokine secretion. In the same study, Neu5Gc accumulated in atherosclerotic plaques lining the blood vessels of human aortas. Taken together, these findings suggest a mechanism whereby dietary consumption of Neu5Gc can initiate or exacerbate an inflammatory response at the endothelium, potentially playing a role in the pathogenesis of atherosclerosis.
A study that investigated the development and progression of diet-related cancer found that Neu5Gc can accumulate in human lung, pancreatic, and ovarian tumors. Using a human-like Neu5Gc-deficient mouse model, the investigators found that injecting antibodies targeted to Neu5Gc – a scenario that would mimic the immune response to Neu5Gc in humans – enhanced the growth of tumor cells. A similar study found that human-like Neu5Gc-deficient mice fed 0.25 grams of Neu5Gc per gram of food and challenged with Neu5Gc-targeted antibodies developed systemic inflammation as evidenced by increased circulating IL-6, a pro-inflammatory molecule. Long-term exposure to Neu5Gc (approximately 21 months) produced a five-fold increase in the incidence of carcinomas and an association with Neu5Gc accumulation in the tumors. Thus, the accumulation of Neu5Gc may promote an immune response, and this chronic inflammation can increase cancer incidence (at least in animals).
Translating animal studies to humans
While the hypotheses proposed by animal studies are interesting and suggest a mechanistic element to the observational studies connecting red meat and health risks, drawing conclusions about how these findings translate to humans is challenging. Humans and rodents are vastly dissimilar organisms, particularly concerning Neu5Gc metabolism. Mice, like most mammals, produce Neu5Gc and absorb 98 percent of the Neu5Gc that they ingest. However, humans do not produce Neu5Gc, absorb little of it from the diet, and eliminate it rapidly from the body. Lastly, the experimental system involving mice that were genetically engineered to be incapable of producing Neu5Gc and then injected with anti-Neu5Gc antibodies is not reflective of the Neu5Gc situation in the human body.
Although the studies described above suggest a correlation between eating animal products and an increased incidence of cancer and atherosclerosis, other studies have found these findings only held true if other cancer-promoting lifestyle factors were also present, including obesity, smoking, excessive alcohol consumption, and lack of exercise. Additional evidence demonstrates that in the absence of unhealthy lifestyle factors, meat consumption is not tightly linked to an increase in death rates. For example, a large, population-based study that drew data from more than 170,000 men and women between the ages of 30 and 75 years showed that animal protein intake was associated with increased death rates only when the participants had at least one unhealthy lifestyle risk factor such as smoking, heavy alcohol consumption, physical inactivity, or being overweight or obese.
It is also noteworthy that other studies show different results. For example, a recent meta-analysis of 24 randomized controlled trials suggests that eating red meat every day did not influence biomarkers of cardiovascular disease risk.
While consuming very large quantities of red meat might not be optimal for health, avoiding it altogether could raise other health concerns. For example, women who don't consume red meat are at higher risk for iron deficiency, which can impact their overall health and, if they are pregnant, can have serious consequences for fetal brain development. The important connection between iron and the developing brain suggests that there might be an evolutionary reason why humans can tolerate the antigenic sugar Neu5Gc.
More clinical research is needed to determine to which degree Neu5Gc might drive the development of cardiovascular disease and cancer – and how direct a role it plays. Furthermore, well-controlled studies that consider lifestyle factors might yield more conclusive evidence.
A COMPREHENSIVE OVERVIEW OF NEU5GC
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