Changes in iron transporter divalent metal transporter 1 in proximal jejunum after gastric bypass.
World J Gastroenterol. 2014 June; 20(21): 6534-40.
Marambio A, Watkins G, Castro F, Riffo A, Zúñiga R, Jans J, Villanueva ME, Díaz G.
Department of Surgery University of Chile Clinical Hospital. Department of Gastroenterology Chilean Air Force Clinical Hospital. Department of Pharmacological and Toxicological Chemistry, University of Chile Chemistry and Pharmacy Faculty. Pathology Service University of Chile Clinical Hospital.
AIM: To describe the variation that divalent metal transporter 1 (DMT1) shows in patients after Roux-en-Y gastric bypass (RYGB) surgery.
METHODS: Prospective and analytical study of DMT1 level at the brush border of proximal jejunum in patients having undergone RYGB surgery. The mucosa of proximal jejunum forming the gastrojejunal anastomosis was biopsied during surgery and after 6 mo later with an endoscopic biopsy. All the patients received precise instructions regarding feeding and nutritional supplementation. Both samples were processed at the same time by immunohistochemistry and western blot. Samples were analysed by a pathologist. For statistical analysis, the χ(2) and Wilcoxon tests were used.
RESULTS: Sixteen patients were recruited, 13 of whom completed the study. Twelve were women. Average age and body mass index (BMI) were 44.1 and 40.4, respectively. Both body weight and BMI decreased significantly during the study period, with an average percent excess weight loss (%EWL) of 60% ± 13.3% and an average percent excess BMI loss (%EBMIL) of 79.6% ± 21.6%. Only two patients presented with mild anaemia 6 mo after surgery, but their ferritin levels stayed within normal ranges. Staining for DMT1 showed a significant increase in the cytoplasm of enterocytes located at the tips of the villi (χ(2) = 6.03; P = 0.049). Nevertheless, the total quantity of DMT1 decreased significantly (Z = 2.04; P = 0.04). Associated with these results, we observed a significant increase in goblet cells in the villi 6 mo postoperatively (Z = -2.47; P = 0.013).
CONCLUSION: Six months after RYGB surgery, patients exhibit an increase in DMT1 expression in the enterocytes of the tips of the villi at the proximal jejunum.
Despite the importance and impact of nutritional deficiencies, especially the occurrence of anemia in patients undergoing bariatric surgery (gastric bypass), the efforts needed to understand its pronounced occurrence in some patients have not been done. Furthermore, molecular mechanisms of adaptation that allow most of these patients adapt to this new gastrointestinal physiology, which as we understand should cause a deep iron deficiency in all of them, have not been fully clarified. We followed a group of patients undergoing a gastric bypass and compare the levels of the main receptor responsible for the absorption of iron at the apical membrane of the enterocyte, the divalent metal transporter 1 (DMT1) and demonstrated, among other things, a redistribution of it, given by an increase in the expression level at the tip of the villi of the proximal jejunum 6 months after surgery, which impresses correspond to a physiological and adaptive effort to capture a larger amount of iron from the intestinal lumen. It is described that DMT1 expression would be determined by the iron bioavailability 1 occurring overexpression in iron deficiency states, however, this will be associated with a variation in the distribution of DMT1 in the villi. This has been described for DMT1 and ferroportin (FPN), a transmembrane protein located in the basolateral membrane of the enterocyte, responsible of iron transport from the enterocyte through the body. It has been reported that if there is an iron overload occurance, there will be a redistribution of DMT1 to basal areas of the villi. This is associated with an internalization of FPN, occurring thus a repositioning of DMT1 and FPN depending on the availability of iron 2.
Figure 1. Proximal jejunum villi of the alimentary limb 6 months after surgery in patients submitted to a laparoscopic Roux-en-Y gastric bypass. In A immunohistochemical staining for DMT1, in B for Dcytb, in C for Ferroportin and in D for Hephaestin.
Several groups are investigating the molecular mechanisms that regulate the metabolic pathways controlling iron absorption, complex mechanism not well known. We have focused our study on the most important receptors described and its variation in patients undergoing laparoscopic Roux-en-Y gastric bypass, the bariatric surgery most frequently performed 3. We have successfully demonstrated that in patients undergoing gastric bypass who are properly supplemented by international standards, 6 months after surgery there is not only an increased DMT1 expression but also of FPN with these two transmembrane transporters as the main mediators and regulators of iron influx through the enterocyte (not published yet). According to our results, the co-transporters, Dcytb and Hephaestin, are not significant variations over the first six months after surgery, which may fulfill a secondary adaptive role (not published yet). Staining of each of these transporters can be seen in Figure 1. Associated with this, there is a significant decrease in serum Hepcidin levels (not published yet). This have been recognized as the main mediator between systemic sensors of iron (liver) and effectors (intestine). In Figure 2 we can observe the classic scheme of iron metabolism, the enterocyte and main receptors plus the interaction with the liver through Hepcidin.
Figure 2. Main mechanisms of intestinal iron absorption and its interaction with the liver. In red circles the main receptors studied. DMT1: divalent metal transporter 1; Dcytb: duodenal cytochrome B; FPN: Ferroportin; HEPH: Hephaestin (modified from: Anderson GJ. Iron absorption and metabolism. Curr Opin Gastroenterol 2009; 25: 129-35)
Consequently, patients undergoing gastric bypass would experience the expected systemic changes of an iron deficient state and the proximal jejunum which form the alimentary limb, not only plays a role in diverting food from duodenum, featuring the necessary adaptive changes already mentioned, but also would allow these patients not to present a deep nutritional deficit soon after surgery.
- Zoller H, Koch RO, Theurl I, Obrist P, Pietrangelo A, Montosi G et al. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 2001; 120: 1412-9.
- Núñez MT, Tapia V, Rojas A, Aguirre P, Gómez F and Nualart F. Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1. Am J Physiol Cell Physiol 2010; 298: C477-85.
- Buchwald H and Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg 2013; 23: 427-36.
Andrés Marambio, MD, MSc
Hospital Clínico Metropolitano La Florida
Froilán Roa 6542, La Florida, Santiago, Chile, 8242238
Pontificia Universidad Católica de Chile
Marcoleta 352, Santiago, Chile, 8330024