The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

Abstract

Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a β-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention.

Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review

“…In a prostate cancer model, folate was found to be directly involved in oncogenic signaling pathways, specifically the PI3K-AKT-mTOR cascade [246]. Similarly, in a colon carcinogenesis mouse model, a significant increase in mTOR signaling was recorded in mice supplemented with folic acid compared with those without supplementation [20]. In addition to the observed effects on gene expression, FA was found to impact posttranslational modifications and protein-protein interaction [241].…”

“…In rodent studies, excess folate can be defined as exceeding the accepted standard baseline supplementation of 2 mg/kg diet. However, the optimal folate requirements for animals may be lower, and the activity of rate-limiting one-carbon metabolism enzymes is typically much higher in rodents compared with humans [20][21][22][23]. Chow diets fed to laboratory rodents can contain a variable amount of FA ranging from 2 to 15 mg/kg diet and averaging about 8 mg/kg diet [22].…”

The regulation function of intestinal microbiota by folate‐producing Lactiplantibacillus plantarumLZ227

“…10 As an important probiotic in the human intestine, LABs can play an auxiliary or even major role in the prevention and treatment of diseases such as colitis, mucositis, and even the immunostimulation properties of colon cancer. 11 Their catabolism can produce a variety of vitamins for body growth, such as folic acid and riboflavin. 12 LeBlanc et al found that recombinant Lactococcus lactis with high folate-producing production can significantly improve folate levels in folate-deficient mice and partially restore macrocyte anemia caused by folate deficiency.…”

“…As an important probiotic in the human intestine, LABs can play an auxiliary or even major role in the prevention and treatment of diseases such as colitis, mucositis, and even the immunostimulation properties of colon cancer 11 . Their catabolism can produce a variety of vitamins for body growth, such as folic acid and riboflavin 12 .…”

High Dietary Folic Acid Intake Is Associated with Genomic Instability in Peripheral Lymphocytes of Healthy Adults

“…Elevated FA levels are known for masking and exacerbating vitamin B12 deficiency [ 5 , 9 , 18 ], and are controversially implicated in increased cancer onset, progression, and mortality rate [ 5 , 18 , 19 , 20 ]. The controversies surrounding FA supplementation extend to a number of other diseases and conditions such as metabolic disorders [ 21 ], immunity [ 22 , 23 ], colon cancer [ 20 , 24 , 25 ], and autism spectrum disorders [ 26 , 27 ].…”