Abstract
BackgroundHigh consumption of red and processed meat is commonly associated with increased cancer risk, particularly colorectal cancer. Antibodies against the red meat-derived carbohydrate N-glycolylneuraminic acid (Neu5Gc) exacerbate cancer in “human-like” mice. Human anti-Neu5Gc IgG and red meat are both independently proposed to increase cancer risk, yet how diet affects these antibodies is largely unknown.MethodsWe used world global data to demonstrate that colorectal cancer incidence and mortality are associated with increased national meat consumption. In a well-defined large cohort, we used glycomics to measure daily Neu5Gc intake from red meat and dairy, and investigated serum as well as affinity-purified anti-Neu5Gc antibodies. Based on 24-h dietary records, daily Neu5Gc intake was calculated for 19,621 subjects aged ≥ 18 years of the NutriNet-Santé study. Serum and affinity-purified anti-Neu5Gc antibodies were evaluated by ELISA and glycan microarrays in representative 120 individuals, each with at least eighteen 24-h dietary records (aged 45–60, Q1–Q4; aged > 60, Q1 and Q4; 10 men/women per quartile).ResultsWe found that high-Neu5Gc diet, gender, and age affect the specificity, levels, and repertoires of anti-Neu5Gc IgG immune responses, but not their affinity. Men consumed more Neu5Gc than women, mostly from red meat (p = 0.0015), and exhibited higher overall serum anti-Neu5Gc IgG levels by ELISA (3.94 ng/μl versus 2.22 ng/μl, respectively; p = 0.039). Detailed glycan microarray analysis against 56 different glycans revealed high Neu5Gc-specificity with increased anti-Neu5Gc IgG and altered repertoires, associated with higher consumption of Neu5Gc from red meat and cow dairy. Affinity purification of serum anti-Neu5Gc antibodies revealed increased levels and biased array repertoire patterns, without an increase in antibody affinity, in individuals consuming higher Neu5Gc levels. Furthermore, in a high-meat diet, antibody diversity patterns on glycan microarrays shifted towards Neu5Gcα3-linked glycans, increasing the α3/α6-glycans ratio score.ConclusionsWe found a clear link between the levels and repertoire of serum anti-Neu5Gc IgG and Neu5Gc intake from red meat and dairy. These precise rational methodologies allowed to develop a Gcemic index to simplify the assessment of Neu5Gc in foods that could potentially be adapted for dietary recommendations to reduce cancer risk.
Highlights
High consumption of red and processed meat is commonly associated with increased cancer risk, colorectal cancer
We found a clear link between the levels and repertoire of serum anti-Neu5Gc IgG and Neu5Gc intake from red meat and dairy
We investigated the dietary effects on the global burden of world colorectal cancer, and the effects of dietary Neu5Gc on the levels and repertoires of circulating antiNeu5Gc antibodies in humans using the French NutriNet-Santé cohort based on detailed 24-h dietary records, in order to provide a mechanistic explanation for the cancer risk associated with red meat consumption
Summary
High consumption of red and processed meat is commonly associated with increased cancer risk, colorectal cancer. Human anti-Neu5Gc IgG and red meat are both independently proposed to increase cancer risk, yet how diet affects these antibodies is largely unknown. Circulating anti-Neu5Gc antibodies continuously encounter Neu5Gc-containing epitopes on human tissues and have been proposed to lead to xenosialitis [11], which in mice have been shown to exacerbate cancer [11, 12] and cardiovascular disease [13]. In human studies, glycan microarray analysis revealed that certain antiNeu5Gc antibodies can serve as a carcinoma biomarker [15] and that high levels of total anti-Neu5Gc IgG are associated with increased colorectal cancer risk, but not with red meat intake [16]. The co-existence and interactions between Neu5Gc on cells with circulating anti-Neu5Gc antibodies have been suggested to modulate inflammatory response characteristics to meditate diseases [5, 17]; a direct correlation between anti-Neu5Gc antibodies and the diet in humans has been elusive
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