Sunday, 16 June 2013

Gastrointestinal consequences of folate deficiency

Folate (a.k.a. folic acid and vitamin B9) is an essential vitamin obtained from diet. Folate is also synthesised by some colonic bacteria such as Bifidobacteria spp. which may further contribute to host pools 1. In the body folate plays an essential role as a carrier of one-carbon molecules involved in DNA synthesis and methylation. Folate metabolism is further inextricably linked with that of vitamin B12 which recycles folate during the remethylation of homocysteine.

Deficiency of B12/folate has been associated with several conditions such as inflammatory bowel disease (IBD), cancer, cardiovascular disease, neurodegenerative conditions, depression and autism. In addition B12/folate deficiency may occur in some patients with CFS 2,3. The involvement of B12/folate in fundamental cellular processes means deficiency is of particular consequence to cell-types with rapid growth characteristics such as immune, blood and epithelial cells. However while deficiency of these vitamins is often considered with reference to haematological and immunological changes, those in the gut are rarely considered. Of note, serum and red blood cell (RBC) folate levels correlate with colonic folate levels 4,5.

Folate deficiency in the gut
The gut is lined by a single heterogeneous layer of epithelial cells which renew approximately every 4-5 days. This life cycle starts in the crypts with stem cells which migrate bi-directionally on the villus and differentiate into various cell types (i.e. enterocytes, goblet, enteroendocrine and paneth cells) 6. At the villus tip their life ends and they are cast off into the intestinal lumen.

Maintenance of this rapid life-cycle and consequently the integrity of the gut lining are heavily dependent upon adequate B12/folate. Initial studies reported that robust folate deficiency disrupts epithelial cell membranes 7 and induces villus atrophy 8,9. Other studies have shown that methotrexate, an anti-folate drug used in chemotherapy, induces intestinal inflammation and lesions accompanied by oxidative stress, disruption of tight junctions, increased paracellular permeability 10–12 and bacterial translocation 13. Recently a methyl-deficient diet (i.e. no folate, B12 or choline) was found to induce a global wall hypotrophy in the small bowel with increased crypt apoptosis, loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production 14. This diet also decreased the levels of paneth cells, goblet cells and mucus production 14.

Several studies have looked at the effects of folate deficiency on digestive function. Folate deficiency has been reported to decrease pancreatic digestive enzyme secretion 15,16. In addition folate deficiency impairs the digestive and absorptive function of the epithelium 7,17. The enzymes involved suggest compromised protein and carbohydrate digestion occurs under folate deficiency.

Folate status has further been shown to influence immune and inflammatory activity in the gut. In one study folate depletion was found to down-regulate pathways relating to immune and inflammation in the colon, while the opposite was true of folate supplementation 18. The authors concluded that even modest changes in folate delivery create substantial changes in the colon 18. Another study reported that folate deficiency greatly aggravated experimental colitis, while supplementation ameliorated its severity 19. More recently folate was shown to act as a survival factor for Treg cells expressing folate receptor 4 in the intestine 20,21. Tregs are involved in the generation of immunological tolerance by preventing excessive inflammation and immune activation; Treg abolition leads to autoimmune diseases. Together these studies suggest there may be a happy medium regarding folate, methylation and inflammation in the intestine.

Closing thoughts
While robust folate deficiency has adverse effects on intestinal structure and function, less is known about milder forms of deficiency. From an immunological point of view both low or high folate levels may be undesirable 18. With regards to therapeutic use of folate it would be interesting to see if it had any value in the increasing number of conditions associated with increased intestinal permeability (i.e. leaky gut). Many of these conditions also feature dysbiosis and it would further be interesting to see if there are any correlations between folate status and folate-producing bacteria such as Bifidobacteria.

References
1.         Rossi, M., Amaretti, A. & Raimondi, S. Folate production by probiotic bacteria. Nutrients 3, 118–34 (2011).
2.         Van Konynenburg, R. A. & Nathan, N. Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia. (2009).
3.         Regland, B. et al. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scandinavian journal of rheumatology 26, 301–7 (1997).
4.         McGlynn, A. P. et al. Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum. The Journal of nutrition 143, 27–33 (2013).
5.         Kim, Y. I. et al. Colonic mucosal concentrations of folate are accurately predicted by blood measurements of folate status among individuals ingesting physiologic quantities of folate. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 10, 715–9 (2001).
6.         Circu, M. L. & Aw, T. Y. Redox biology of the intestine. Free radical research 45, 1245–66 (2011).
7.         Singla, A., Kaushik, S. & Kaur, J. Folate deficiency results in alteration in intestinal brush border membrane composition and enzyme activities in weanling rats. Journal of nutritional science and vitaminology 52, 163–7 (2006).
8.         Hermos, J. A., Adams, W. H., Liu, Y. K., Sullivan, L. W. & Trier, J. S. Mucosa of the small intestine in folate-deficient alcoholics. Annals of internal medicine 76, 957–65 (1972).
9.         Dawson, D. W. Partial villous atrophy in nutritional megaloblastic anaemia corrected by folic acid therapy. Journal of clinical pathology 24, 131–5 (1971).
10.       Beutheu Youmba, S. et al. Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways. Journal of pediatric gastroenterology and nutrition 54, 463–70 (2012).
11.       Hamada, K., Shitara, Y., Sekine, S. & Horie, T. Zonula Occludens-1 alterations and enhanced intestinal permeability in methotrexate-treated rats. Cancer chemotherapy and pharmacology 66, 1031–8 (2010).
12.       Maeda, T. et al. Oxidative stress and enhanced paracellular permeability in the small intestine of methotrexate-treated rats. Cancer chemotherapy and pharmacology 65, 1117–23 (2010).
13.       Song, D. et al. Confirmation and prevention of intestinal barrier dysfunction and bacterial translocation caused by methotrexate. Digestive diseases and sciences 51, 1549–56 (2006).
14.       Bressenot, A. et al. Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats. The British journal of nutrition 1–11 (2012).doi:10.1017/S0007114512001869
15.       Balaghi, M., Horne, D. W., Woodward, S. C. & Wagner, C. Pancreatic one-carbon metabolism in early folate deficiency in rats. The American journal of clinical nutrition 58, 198–203 (1993).
16.       Balaghi, M. & Wagner, C. Folate deficiency inhibits pancreatic amylase secretion in rats. The American journal of clinical nutrition 61, 90–6 (1995).
17.       Ansari, S., Dudeja, P. K. & Mahmood, A. Effect of folate deficiency on the digestive and absorptive functions of intestinal epithelium in rats. Acta vitaminologica et enzymologica 3, 12–6 (1981).
18.       Protiva, P. et al. Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis. Cancer prevention research (Philadelphia, Pa.) 4, 530–43 (2011).
19.       Kominsky, D. J. et al. An endogenously anti-inflammatory role for methylation in mucosal inflammation identified through metabolite profiling. Journal of immunology (Baltimore, Md. : 1950) 186, 6505–14 (2011).
20.       Kunisawa, J., Hashimoto, E., Ishikawa, I. & Kiyono, H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PloS one 7, e32094 (2012).
21.       Kinoshita, M. et al. Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. Journal of immunology (Baltimore, Md. : 1950) 189, 2869–78 (2012).

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