Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”4289″ img_size=”full”][vc_column_text single_style=””]Intestinal absorption of dietary folates is an important, complex, and fascinating process in human metabolism. Folates (Vitamin B9) are critical nutrients that are essential for numerous cellular processes, including cell division and DNA synthesis. The absorption and distribution of folates in the human body involves many intricate steps and we attempt to elucidate this in the following blog.<\/p>\n Figure 1. The Intestinal Absorption and Transport of Dietary Folates. (a)<\/b>\u00a0Most dietary folates are polyglutamate derivatives (Fol-PG–<\/sup>) and are hydrolyzed to monoglutamate (Fol–<\/sup>) by the enzyme glutamate carboxypeptidase II (GCII) in the gut before absorption across the intestinal mucosa, and then transported into cells through the proton-coupled folate transporter (PCFT).\u00a0(b)<\/b>\u00a0Both the process of hydrolysis and PCFT-mediated transport have low pH optima and are favored by the low pH within the microenvironment at the jejunal microvilli (green zone) that is generated by Na+<\/sup>\/H+<\/sup>\u00a0exchangers (Na+<\/sup>\/H+<\/sup>).\u00a0(C)<\/b>\u00a0Reduced folate carrier 1 (RFC1) is expressed at the apical brush-border membrane; however, it may not be functional at the pH in this region at usual folate dietary levels.\u00a0(d)<\/b>\u00a0Cellular folates exit through the basolateral membrane by a mechanism that probably involves a member of the multidrug-resistance-associated protein (MRP) family of ATP-binding-cassette (ABC) exporters, for instance, MRP2, 3, 5 and\/or breast cancer resistance protein (BCRP\/ABCG2).\u00a0(e)<\/b>\u00a0Finally, the folates that are absorbed from the intestine are delivered to the liver via the hepatic portal vein and enter the so-called enterohepatic circulation. (ATP, adenosine triphosphate; ADP, adenosine diphosphate; OP–<\/sup>, organic phosphate gradient; OATP2B1\/SLCO2B1, organic anion-transporting polypeptide 2B1).[\/vc_column_text][vc_custom_heading text=”Introduction” use_theme_fonts=”yes” el_id=”introduction”][vc_column_text single_style=””]<\/p>\n Dietary folates exist predominantly in the polyglutamyl form containing up to seven glutamate residues. Nearly two-thirds of total folate intake from a mixed unfortified diet is in the polyglutamyl form, derived mainly from vegetables [1]. The intestinal absorption of dietary folates is a two-step process that involves\u00a0(Figure 1, 2):<\/b><\/p>\n [\/vc_column_text][vc_custom_heading text=”Intestinal Hydrolysis of Folate Polyglutamates” use_theme_fonts=”yes” el_id=”blog-scroll-point-1″][vc_column_text single_style=””]<\/p>\n The mechanism by which the dietary folates cross the enterocyte (mucosal cell) and are released across the basolateral membrane into the portal circulation is not fully understood, nevertheless some critical features have been clarified recently (Figure 1)<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]Hydrolysis of the polyglutamyl chain is an obligatory step in folate absorption because only monoglutamyl forms are able to cross cell membranes. The hydrolysis of polyglutamyl folates occurs in the proximal part of the jejunum with the involvement of the brush-border enzyme viz., glutamate carboxypeptidase II<\/b> {GCPII or GCII; aka – folate hydrolase, folylpolyglutamate hydrolase, pteroylpolyglutamate hydrolase, pteroylpoly-\u03b3-glutamate carboxypeptidase, or \u03b3 \u2013 glutamyl hydrolase}<\/i>.[\/vc_column_text][vc_column_text single_style=””]GCPII acts as an exopeptidase, cleaving terminal \u03b3-linked glutamate residues from polyglutamyl folates in a systematic and progressive stepwise way to release folates with different glutamate chain lengths. GCPII has an optimal pH of 6.5. Research studies have shown that the maintenance of this optimal pH is critical for the complete deconjugation of polyglutamyl folates in the jejunum [2] PCFT and RFC1 are not expressed on the\u00a0basolateral membrane of the intestinal mucosal cells<\/i><\/b>, and naturally folate efflux into the portal circulation is apparently believed to be mediated by multidrug-resistance-associated protein (MRPs) family of ATP-binding-cassette (ABC) exporters, for example, MRP3 and\/or MRP5, one of the low-affinity, high-capacity transporters [3].<\/p>\n Mechanisms of Folate Absorption Across the Apical Brush-Border Membrane of the Intestinal Mucosa<\/b>\u00a0Folate monoglutamates are absorbed in the intestine through saturable and non-saturable transport mechanisms\u00a0(Figure 2)<\/b>.<\/p>\n The\u00a0saturable transport<\/b>\u00a0operates at the dietary range of folate intake {concentrations < 10 \u03bcmol \/ L<\/b>} mainly in the duodenum and upper part of jejunum [4]. It is a carrier-mediated process with a pH optimum within the mildly acidic range (pH 6.0). In addition, evidence shows that oxidized and reduced folates are transported with similar affinity. RFC1 and PCFT are considered to be the transmembrane proteins involved in this process.<\/p>\n A\u00a0nonsaturable transport<\/b>\u00a0of folate functions at concentrations of folate within the supraphysiological and pharmacological range of intake {concentrations > 10 \u03bcmol \/ L<\/b>}, mainly occurring in the ileum without the direct involvement of any specific transporter [5]. At present, there are no data evidently showing that nonsaturable transport is affected by any dietary or physiological factors; consequently, it is considered as an important route for folate absorption in patients with impaired saturable transport, such as hereditary folate malabsorption and celiac disease.[\/vc_column_text][vc_single_image image=”4592″ img_size=”full”][vc_column_text single_style=””]Figure 2. A schematic representation of intestinal hydrolysis and absorption of folates. Step (1) – Intestinal hydrolysis:<\/b>\u00a0The hydrolysis of folate polyglutamates (Polyglu-Fol–<\/sup>) to the corresponding monoglutamyl (Monoglu-Fol–<\/sup>) derivatives.\u00a0Step (2) – Transmembrane transport:<\/b>\u00a0Followed by their saturable or non-saturable transport through the intestinal membranes into the enterocytes. (GCPII, glutamate carboxypeptidase II; PCFT, proton-coupled folate transporter; RFC1, reduced folate carrier 1, OP–<\/sup>, organic phosphate gradient.) [Adapted and modified from: Alemdaroglu NC, et al., Biopharma Drug Dispos 2008, 29:335-48. PMID: 18551467]<\/p>\n A variable proportion of plasma folate is bound to low-affinity protein binders,\u00a0primarily the albumin,<\/b>\u00a0which accounts for about 50% of bound folate. This proportion is increased in folate deficiency conditions or syndrome. In addition,\u00a0plasma also contains low concentrations of a soluble form of the folate receptor (FR).<\/b>\u00a0Notably, the levels of this high-affinity, low-capacity binder are elevated in pregnancy and are demonstrably very high in patients suffering from certain leukemias. Generally, increased concentrations of the high-affinity binder may reflect tissue damage or incidental release from tissues, and the effect of plasma protein binding on folate availability for tissues remains as an open question.[\/vc_column_text][vc_custom_heading text=”Enterohepatic Circulation of Folates (Transport in- and Storage in- the Liver)” use_theme_fonts=”yes” el_id=”blog-scroll-point-3″][vc_column_text single_style=””]<\/p>\n Pteroylmonoglutamates, primarily 5-methyl-tetrahydrofolate (5-methyl-THF), are the circulating forms of folates in plasma, moreover, mammalian cells are not believed to transport polyglutamates of chain length three and above. After folate absorption into the portal circulation, much of this folate can be taken up by the liver, where it is either:<\/p>\n An enterohepatic circulation of folate has been described involving release of hepatic 5-methyl-THF into bile via MRP2 with reabsorption in the small intestine. The preponderance of 5-methyl-THF in plasma probably reflects that this is the major cytosolic folate in mammalian tissues and consequently is the major form that would be released. The extent, if any, of the release of short chain folylpolyglutamates from tissues is unknown. Plasma contains \u03b3-glutamyl hydrolase (\u03b3-GH\/GCPII) activity, and any polyglutamate released into plasma would be hydrolyzed into the monoglutamate [6].<\/p>\n To summarize, folates that enter the liver have three potential destinations as follows [3]:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_custom_heading text=”Clinical Significance” use_theme_fonts=”yes” el_id=”blog-scroll-point-4″][vc_column_text single_style=””]<\/p>\n HFM is a rare autosomal recessive disorder caused by loss-of-function mutations in the PCFT gene, resulting in systemic folate deficiency and impaired transport of folate into the brain with very low folate levels in the cerebrospinal fluid (CSF) [7, 8].\u00a0CSF folate concentrations are normally higher than in plasma.<\/i><\/b>\u00a0Symptoms develop several months after birth and that include mainly:<\/p>\n Infants can be treated with high doses of oral folates such as methyl-THF or with low much smaller doses of parental folate, suggesting that some intestinal transport can occur through RFC1 carrier, but also revealing that PCFT is normally responsible for the bulk of folate transport in the intestine. Thus, normalization of CSF folate levels in subjects with HFM disorder requires very high plasma folate concentrations [9].<\/li>\n<\/ol>\n [\/vc_column_text][vc_custom_heading text=”Conclusions” use_theme_fonts=”yes” el_id=”conclusion”][vc_column_text single_style=””]In a nutshell, here we have highlighted some essential features that govern the intestinal absorption and transport of dietary folates; and addressed simultaneously a number of critical questions pertaining to intestinal absorption of dietary folates, for instance: (1) What is mechanism(s) of folate absorption across the apical brush-border membrane of the intestine under physiological conditions? (2) What role could PCFT, RFC1, and potentially other transporters play? (3) Where are folates absorbed within the small intestine in the presence or absence of PCFT? (4) Which MRP protein(s) is required for transport of folates across the serosal membrane of the human intestine? And finally, (5) How folate is transported and stored in liver, including the so-called enterohepatic circulation of folates.<\/p>\n To summarize, food folates (polyglutamate derivatives) are hydrolyzed to monoglutamate forms in the gut before absorption across the intestinal mucosa. The cleavage is accomplished by the enzyme GCPII (\u03b3-GH). The monoglutamate form of folate is actively transported across the proximal small intestine by a saturable pH-dependent process. When pharmacological doses of the monoglutamate form of folate are consumed, it is also absorbed by a non-saturable mechanism involving passive diffusion.<\/p>\n Monoglutamates, mainly 5-methyl-THF, are present in portal circulation. Much of this folate can be taken by the liver, where it is metabolized to polyglutamate derivatives and retained or released into the blood or bile. Approximately two-thirds of the folate in plasma is protein bound.[\/vc_column_text][vc_column_text single_style=”” el_class=”blog-banner-section”]<\/p>\n Folate (vitamin B9) is very important for your child\u2019s brain development!<\/p>\n During pregnancy, it helps prevent neural tube defects and plays a big role in forming a normal and healthy baby\u2019s brain and spinal cord. Folate also helps cells divide and assists in both DNA and RNA synthesis.<\/p>\n Emerging research suggests that the presence of FRAAs negatively impacts folate transport into the brain.<\/p>\n Yes, there is a test – The Folate Receptor Antibody Test (FRAT\u00ae<\/sup>) has emerged as a diagnostic tool for detecting the presence of FRAAs.<\/p>\n It is important to screen at an early age or as soon as possible as there may be corrective measures available. Please consult your physician for further information.<\/p>\n To request a test kit, click on the button below.<\/p>\n Request Now<\/a><\/p>\n<\/div>\n<\/div>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”text-gray-23″]For information on autism monitoring, screening and testing please read our blog<\/a>.[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”references”][vc_column][vc_custom_heading text=”References”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n","protected":false},"excerpt":{"rendered":" Intestinal absorption of dietary folates is an important, complex, and fascinating process in human metabolism…<\/p>\n","protected":false},"author":3,"featured_media":4289,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[80,64],"tags":[],"yoast_head":"\n\n
\n<\/a><\/li>\n\n
\n(Figure 2)<\/b>.[\/vc_column_text][vc_column_text single_style=””]Remarkable differences have been reported in the activity of intestinal GCPII among different animal species. In general, a high GCPII activity was observed in humans and pigs, whereas a very low to no enzyme was detected in monkeys and rats.[\/vc_column_text][vc_custom_heading text=”Intestinal Transport of Folate Monoglutamates” use_theme_fonts=”yes” el_id=”blog-scroll-point-2″][vc_column_text single_style=””]Both proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC1) are expressed on the\u00a0apical membranes of the intestinal mucosa<\/i><\/b>, and their respective mRNAs are upregulated under circumstances of folate depletion. Despite the fact, transport into the mucosal cell appears to occur primarily through the PCFT carrier. The enterocytes mucosal surface is bathed by an acid microclimate. An optimal pH of about 5.5 is required for intestinal folate transport, and folic acid is transported as effectively as reduced folate monoglutamates. All of these are consistent with transport by PCFT carrier. Consequently, RFC1 could not be an effective transporter under these conditions.<\/p>\n\n
\n
Box-1<\/b><\/h4>\n
\n
\n
\n
Did You Know? Folate Receptor Autoantibodies (FRAAs) may impede proper folate transport.<\/h4>\n
\n
Is there a test for identifying Folate Receptor Autoantibodies (FRAAs)?<\/h4>\n
![\"FRAT](\"https:\/\/autism.fratnow.com\/blog\/wp-content\/uploads\/2023\/12\/frat-mascot-image.webp\")
<\/div>\n<\/div>\n\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/?term=halsted+ch+1989<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/2867095\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/19173758\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/3907863\/<\/a><\/li>\n
\nhttps:\/\/www.ncbi.nlm.nih.gov\/books\/NBK114310\/?term=Dietary%20Reference%20Intakes%20for%20Thiamin%2C%20Riboflavin%2C%20Niacin%2C%20Vitamin%20B6%2C%20Folate%2C%20Vitamin%20B12%2C%20Pantothenic%20Acid%2C%20Biotin%2C%20and%20Choline%20%2C%2020232<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/24512081\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/11807405\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/17129779\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/20301716\/<\/a><\/li>\n<\/ol>\n