Low calcium intake and colorectal cancer: Mechanistic integration, heterogeneity, and precision prevention

Ma Fenglan; Ma Hong; Zhao Yue

doi:10.16689/j.cnki.cn11-9349/r.2026.04.017

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Electronic Journal of Metabolism and Nutrition of Cancer ›› 2026, Vol. 13 ›› Issue (4) : 576-581. DOI: 10.16689/j.cnki.cn11-9349/r.2026.04.017

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Low calcium intake and colorectal cancer: Mechanistic integration, heterogeneity, and precision prevention

¹Ma Fenglan, ¹Ma Hong, ²Zhao Yue

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Abstract

CRC is one of the most common and highly lethal malignancies worldwide. Epidemiological studies consistently demonstrate an inverse association between dietary calcium intake and CRC risk; however, several RCTs have failed to confirm a protective effect of calcium supplementation, giving rise to a “clinical paradox.” Taking this paradox as a starting point, this article proposes a “four-level cascade” framework linking low calcium intake to CRC pathogenesis: at the luminal level, low calcium weakens the chelation and detoxification of bile acids and free fatty acids, leading to damage to the intestinal mucosal barrier; at the molecular level, low calcium inactivates the CaSR, relieving its dual negative regulation of the Wnt/β-catenin pathway; at the synergistic level, the vitamin D-VDR axis and CaSR form a bidirectional positive feedback loop, and low calcium and low vitamin D create a “bidirectional lock” effect that amplifies the loss of tumor suppressor signals; at the microbiota level, gut dysbiosis and its metabolic byproducts reciprocally exacerbate the damage to the previous three layers, forming a vicious cycle. Based on this integrative framework, this article systematically examines how three sources of heterogeneity—vitamin D status, CaSR genotype, and microbial metabolic load—modify calcium signaling, thereby providing a plausible explanation for the inconsistent results of RCTs. Finally, we distill four testable hypotheses, offering an integrated theoretical foundation and verifiable directions for the precision prevention of CRC.

Key words

Colorectal cancer / Low calcium intake / Calcium-sensing receptor / Wnt/β-catenin signaling pathway / Vitamin D / Gut microbiota / Heterogeneity / Mechanism integration

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Ma Fenglan, Ma Hong, Zhao Yue. Low calcium intake and colorectal cancer: Mechanistic integration, heterogeneity, and precision prevention[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2026, 13(4): 576-581 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.04.017

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