Dietary natural methylxanthines and colorectal cancer: a systematic review and meta-analysis.

Some evidence suggests that caffeine, theophylline, and theobromine, as natural methylxanthines (MTXs), possess anti-cancer effects. We systematically reviewed the animal and human studies investigating the effect of (or association between) dietary natural MTXs on (and) colorectal cancer (CRC) and performed a meta-analysis of epidemiological studies. Relevant studies were identified by searching MEDLINE, Embase, Scopus, and Web of Knowledge through September 2020. The overall relative risk (RR) and confidence interval (CI) were determined using a random-effects model. Eight animal and eight epidemiological investigations met our inclusion criteria. Animal studies indicated detrimental effects of high levels of caffeine intake on the initiation and promotion of CRC, while showing beneficial or non-significant effects at lower doses. The meta-analysis of six epidemiological studies found no association between dietary caffeine intake and the risk of CRC (RR = 0.98 (95% CI = 0.88-1.10)). Subgroup analysis revealed a direct association between caffeine intake and risk of CRC only in the studies with a moderate risk of bias and a lack of adjustment for smoking. The results of the only epidemiological study investigating the association between the serum levels of MTXs and the risk of CRC showed an inverse association. In conclusion, some animal studies underlined the beneficial effects of caffeine, at regular doses consumed by humans, on CRC. However, current epidemiological evidence does not support an association between caffeine intake and the risk of CRC.