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Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Although many insect-based foods are nutritious and often an inexpensive option for human and domesticated animal consumption, there remains a negligible market for such foods in many countries. Several environmental and economic considerations underscore the potential value of insect-based foods, and emerging science suggests that diets incorporating such foods might also convey some genuine health benefits. However, if expanded markets for insect-based foods in cultures naïve to entomophagy are to be pursued, it will be important to develop multifaceted and coordinated strategies to 1) delineate authentic health benefits, 2) explore means of optimizing insect husbandry and food processing, 3) examine cultural barriers to acceptance, 4) formulate workable approaches to marketing, and 5) address relevant food regulations. We sought to construct a multidisciplinary coalition whose goals are to investigate the above-mentioned 5 issues. Eighteen individuals from government, industry, and academia, with collective expertise in the fields of entomology, insect husbandry, human nutrition, sustainable agriculture, entomophagy, consumer product development and marketing, food-processing technologies, food regulatory affairs, and the anthropology of food selection, convened a 1-d summit and formed a tripartite organization to integrate their varied perspectives. Collaborative efforts are underway among members of this coalition to accomplish these multiple goals. Coordinating efforts between accomplished experts in relevant fields of academia, government, and industry will greatly expand our knowledge of and appreciation for the potential benefits of insect-based foodstuffs to individuals, to society, and to the sustainability of the global food supply, and thereby inform us as to how to proceed in a judicious and intelligent manner.

The Short Bowel Syndrome (SBS) Registry (NCT01990040) is a multinational real-world study evaluating the long-term safety of teduglutide in patients with SBS and intestinal failure (SBS-IF) in routine clinical practice. This paper describes the study methodology and baseline characteristics of adult patients who have (ever-treated) or have never (never-treated) received teduglutide. A total of 1411 adult patients (679 ever-treated; 732 never-treated) were enrolled at 124 sites across 17 countries. The mean (standard deviation [SD]) age at enrollment was 55.4 (15.46) years, and 60.2% of patients were women. Crohn's disease was the most common cause of major intestinal resection in both ever-treated (34.1%) and never-treated patients (20.4%). A similar proportion of ever-treated and never-treated patients had a prior history of colorectal polyps (2.7% vs. 3.6%), whereas proportionally fewer ever-treated patients reported a history of colorectal cancer (1.8% vs. 6.2%) or any malignancy (17.7% vs. 30.0%) than never-treated patients. Never-treated patients received a numerically greater mean (SD) volume of parenteral nutrition and/or intravenous fluids than ever-treated patients (12.4 [8.02] vs. 10.1 [6.64] L/week). Ever-treated patients received a mean teduglutide dosage of 0.05 mg/kg/day. This is the first report of patient baseline characteristics from the SBS Registry, and the largest cohort of patients with SBS-IF to date. Overall, ever-treated and never-treated patients had similar baseline characteristics. Differences between treatment groups may reflect variations in patient selection and degree of monitoring. [ABSTRACT FROM AUTHOR]

Background: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. Objectives: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. Results: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. Conclusion: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses. Plain language title: Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications? Plain language summary: It has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12. [ABSTRACT FROM AUTHOR]

Evidence indicates that an abundant intake of foodstuffs rich in folate conveys protection against the development of colorectal cancer, and perhaps some other common cancers as well. The issue is complex, however, since some observations in animal and human studies demonstrate that an overly abundant intake of folate among those who harbor existing foci of neoplasia might instead produce a paradoxical promotion of tumorigenesis. The pharmaceutical form of the vitamin, folic acid, might affect the process in a manner that is distinct from natural forms of the vitamin, although this remains a speculative concept. Our limited understanding of this complex relationship is impeding efforts to move ahead with widespread folic acid fortification, but this delay may be necessary to ensure that such programs are instituted in a safe manner.

Preclinical and clinical studies suggest that diminished folate status increases the risk of colorectal carcinogenesis. However, many biochemical functions of folate are dependent on the adequate availability of other 1-carbon nutrients, including riboflavin, vitamin B-6, and vitamin B-12. Aberrations in the Wnt pathway are thought to play an important role in human colorectal cancers. This study therefore investigated if mild depletion of folate combined with depletion of riboflavin, vitamin B-6, and vitamin B-12 could induce alterations in the Wnt pathway in the colonic mucosa. Ninety-six mice were pair-fed diets with different combinations of B vitamin depletion for 10 wk. Genomic DNA methylation and uracil misincorporation were measured by LC/MS and GC/MS. Gene-specific methylation, strand breaks, and expressions were measured by real-time PCR and immunoblotting. Proliferation and apoptosis were determined by immunohistochemistry. DNA strand breaks within the Apc mutation cluster region were induced by folate depletion combined with inadequacies of riboflavin, vitamin B-6, and vitamin B-12 (P < 0.05), but such effects were not induced by folate depletion alone. Similarly, minor changes in the expression of Apc, [beta]-catenin, and cyclin DI produced by mild folate depletion were significantly magnified by multiple vitamin depletion. Apoptosis, which can be suppressed by increased Wnt-signaling, was attenuated by the combined deficiency state (P < 0.05) but not by singlet or doublet deficiencies. These findings indicate that a mild depletion of folate that is of insufficient magnitude by itself to induce alterations in components of the Wnt pathway may produce such effects when present in conjunction with mild inadequacies of other 1-carbon nutrients. J. Nutr. 137: 2701-2708, 2007.

Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/[micro]g DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/[micro]g DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations.

Older age and inadequate folate intake are strongly implicated as important risk factors for colon cancer and each is associated with altered DNA methylation. This study was designed to determine the effects of aging and dietary folate on select features of DNA methylation in the colon that are relevant to carcinogenesis. Old (18 mo; n = 34) and young (4 mo; n = 32) male C57BL/6 mice were randomly divided into 3 groups and fed diets containing 0, 4.5, or 18 [micro]mol folate/kg (deplete, replete, and supplemented groups, respectively) for 20 wk. Genomic DNA methylation and p16 promoter methylation in the colonic mucosa were analyzed by liquid chromatography/electrospray ionization/MS and methylation-specific PCR, respectively. p16 gene expression was determined by real-time RT-PCR. Old mice had significantly lower genomic DNA methylation compared with young mice at each level of dietary folate (4.5 [+ or -] 0.2, 4.8 [+ or -] 0.1, and 4.9 [+ or -] 0.1 vs. 6.0 [+ or -] 0.1, 5.3 -+ 0.2, and 5.9 [+ or -] 0.2%, in folate-deplete, -replete, and -supplemented groups, respectively, P< 0.05) and markedly higher p16 promoter methylation (61.0 [+ or -] 2.7, 69.7 [+ or -] 6.9, and 87.1 [+ or -] 13.4 vs. 10.8 [+ or -] 3.6, 8.4 [+ or -] 1.8, and 4.9 [+ or -] 1.7 %, respectively, P < 0.05). In old mice, genomic and p16 promoter DNA methylation each increased in a manner that was directly related to dietary folate ([P.sub.trend] = 0.009). Age-related enhancement of p16 expression occurred in folate-replete (P = 0.001 ) and folate supplemented groups (P = 0.041), but not in the folate-deplete group. In conclusion, aging decreases genomic DNA methylation and increases promoter methylation and expression of p16 in mouse colons. This effect is dependent on the level of dietary folate.

Folate is among the most strongly implicated dietary components to convey protection against colon cancer, and diminished folate status is associated with an enhanced risk of colon cancer. Age is also regarded as one of the most important risk factors for colonic carcinogenesis. It is therefore of considerable interest to determine whether the process of aging influences folate metabolism in the colon and whether folate supplementation might prevent the procarcinogenic effects associated with aging. Recent studies in our laboratory demonstrated that the colonic mucosa of elder rats is more susceptible to folate depletion than that of young rats. Depletion of folate results in a shift in the forms of folate in the colon as well as increased uracil incorporation into DNA, a purported mechanism for colonic carcinogenesis. However, modest folate supplementation eliminates evidence of inadequate folate status in the colons of elder rats, suggesting that the relation between age and folate status in the colon might be one mechanism by which aging modulates colorectal cancer risk. Interactions between folate and aging also affect a spectrum of epigenetic and genetic phenomena such as uracil misincorporation, DNA methylation, protein methylation, mitochondrial deletion, and critical gene expression, which could be related to carcinogenesis. Aging and inadequate dietary folate may interact and collectively induce derangements in folate metabolism, thereby provoking subsequent molecular aberrations, which may enhance carcinogenesis. However, folate supplementation appears to reverse these adverse effects of aging, which is potentially of substantial import because the latter is an unmodifiable risk factor. KEY WORDS: * folate * aging * 1-carbon metabolism * DNA methylation * uracil misincorporation

Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats. Weanling male Sprague-Dawley rats (n = 30) were divided into 2 groups and fed either a vitamin B-12-deficient diet or a similar diet containing adequate amounts of the vitamin. Rats from each group were killed at 6 and 10 wk. Uracil misincorporation into DNA was measured by GC/MS and genomic DNA methylation was measured by LC/MS. Plasma vitamin B-12 concentrations in deficient rats were below detectable limits at 6 and 10 wk; in control rats, concentrations were 0.46 [+ or -] 0.07 and 0.42 [+ or -] 0.10 nmol/L at those times. Although the colon total folate concentration did not differ between the groups, the proportion that was methylfolate was marginally greater in the deficient rats at 10 wk (P = 0.05) compared with control, consistent with the 'methylfolate trap' that develops during vitamin B-12 deficiency. After 10 wk, the colonic DNA of the deficient rats displayed a 35% decrease in genomic methylation and a 105% increase in uracil incorporation (P < 0.05). This vitamin B-12-deficient diet, which was of insufficient severity to cause anemia or illness, created aberrations in both base substitution and methylation of colonic DNA, which might increase susceptibility to carcinogenesis. KEY WORDS: * vitamin B-12 * DNA methylation * uracil misincorporation * rats * colon

Elder adulthood and diminished folate status are each associated with an enhanced risk of colorectal carcinogenesis. We therefore examined whether these two factors are mechanistically related. Weanling male Sprague-Dawley rats (n = 44) and l-y-old rats (n = 44) were each divided into three groups and fed diets containing 0, 4.5 or 18 [micro]mol folic acid/kg (deplete, replete and supplemented groups, respectively). Rats were killed at 0, 8 and 20 wk. The folate concentrations, the distribution of the different coenzymatic forms of folate, uracil incorporation into DNA and genomic DNA methylation were measured in the colonic mucosa. Folate-deplete and folate-replete elder rats had 30-45% lower colonic folate concentrations than young rats. Furthermore, 5-methyltetrahydrofolate was uniformly depleted in colons of the elder, folate-deplete rats, whereas this depletion occurred in only a minority of the younger rats. By the end of the experiment, the folate-deplete and folate-replete elder rats had ~50% more uracil incorporated into their colonic DNA than the corresponding young groups (P < 0.05). In elder rats, this uracil misincorporation was incremental across the three diet groups (P-test for trend < 0.05), whereas no excess uracil incorporation was observed in young rats. Neither age nor dietary folate affected genomic DNA methylation in the colon. In conclusion, the colon of elder rats is more susceptible to biochemical and molecular consequences of folate depletion than that of young rats. However, folate supplementation is as effective at sustaining adequate colonic folate status in elder rats as it is in the young. J. Nutr. 133: 1206-1212, 2003. KEY WORDS: * folate * colon cancer * aging * rats * uracil misincorporation

One-carbon metabolism is a network of interrelated biochemical reactions that involve the transfer of one-carbon groups from one compound to another. The coenzymes necessary for several of these reactions include the B-vitamins, folate, vitamin B-12, vitamin B-6 and riboflavin (vitamin B-2), whereas important intermediary compounds in this schema include methionine and choline. There has been renewed interest in one-carbon metabolism during the past several years, engendered by recent insights that indicate that modest dietary inadequacies of the abovementioned nutrients, of a degree insufficient to cause classical deficiency syndromes, can still contribute to important diseases such as neural tube defects, cardiovascular disease and cancer. Traditional means of assessing nutrient exposure with food frequency questionnaires, and nutrient status with plasma and urine vitamin assays, has some genuine validity and utility. Assessing the concentration of appropriate intermediary compounds, such as plasma homocysteine for folate and methylmalonic acid for vitamin B-12, provides further insights because they appear to add a degree of sensitivity that does not exist with the more traditional assays. There may also be value in developing measures that integrate the status of all these nutrients and express it as a functional 'methylation capacity' of the individual. Plasma or tissue concentrations of S-adenosylmethionine and S-adenosylhomocysteine, and genomic DNA methylation are two potential candidates in this regard although much work is yet to be done to define the nature of these relationships. KEY WORDS: * biomarkers * diet assessment * epidemiology * folate * nutrition * one-carbon metabolism

Vitamin E, part of the body's primary lipid-soluble defense against free radicals and reactive oxygen molecules, has been suggested to reduce the risk for some cancers. However, the role of vitamin E in the etiology and prevention of colon cancer, especially in the highest risk group, the aged, is not clear. Thus, this study was conducted to elucidate the effect of vitamin E supplementation on susceptibility to colon cancer by examining azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation, a surrogate biomarker of colon cancer. Young (3-4 mo) and old (19-20 mo) C57BL/6JNIA mice were fed either a control diet (30 mg dl-[alpha]-tocopheryl acetate/kg diet) or a vitamin E-supplemented diet (500 mg dl-[alpha]-tocopheryl acetate/kg diet) for 16 wk. After 6 wk of dietary supplementation, young and old mice were injected with saline or AOM weekly for 5 wk to receive the same total dose of AOM (2.2 mg) and killed 10 wk after the first AOM injection. Vitamin E supplementation had no effect on the number of AOM-induced ACF in young or old mice. In addition, vitamin E supplementation did not have an effect on splenocyte interferon-[gamma], interluekin-6 and tumor necrosis factor-[alpha] levels, natural killer cell killing activity or colonic cell proliferation in young or old mice. Thus, [alpha]-tocopherol does not seem to affect the initiation and early promotion stages of AOM-induced colon carcinogenesis in young or old mice. Whether vitamin E supplementation might be effective in reducing AOM-induced colon tumors is unclear. KEY WORDS: * vitamin E * colon cancer * aberrant crypt foci * mice