As a clinically commonly used organic iron supplement, ferrous gluconate is mainly absorbed in the upper small intestine (primarily the duodenum and proximal jejunum). This absorption process relies on the mediation of specific transport proteins on the surface of intestinal mucosal cells and is simultaneously regulated by the chemical form of iron ions, the intestinal internal environment, and the body’s iron nutritional status. The core functions of intestinal transport proteins in its absorption are analyzed below from three key links: pre-absorption iron ion form transformation, the role of core transport proteins, and intracellular metabolism after transport.
I. Pre-Absorption Transformation of Iron Ion Forms
After dissolving in the intestine, ferrous gluconate releases divalent iron ions (Fe²⁺, ferrous ions)—the key form that enables its effective absorption by the intestine. Compared with inorganic iron supplements (e.g., ferrous sulfate), Fe²⁺ in ferrous gluconate is less affected by factors such as intestinal pH and anti-nutritional factors (e.g., phytic acid, tannic acid) in the diet. It is more likely to maintain a stable absorbable form, laying the foundation for the subsequent binding and transport by transport proteins. However, if there is excessive oxygen or oxidants in the intestine, part of Fe²⁺ may be oxidized to trivalent iron ions (Fe³⁺, ferric ions). Since Fe³⁺ cannot be directly absorbed by the intestine, it needs to be reduced back to Fe²⁺ by "duodenal cytochrome b (Dcytb)" secreted by intestinal mucosal cells before entering the next transport process.
II. Mediating Role of Core Intestinal Transport Proteins
The absorption of Fe²⁺ from ferrous gluconate by the intestine is mainly accomplished through the cooperation of two key transport proteins, corresponding to the two core pathways of "physiological iron absorption." These two pathways function flexibly according to the intestinal iron concentration and the body’s needs.
(I) Main Transport Pathway: Divalent Metal Transporter 1 (DMT1)
DMT1 is the primary transport protein for Fe²⁺ absorption in small intestinal mucosal cells. It is widely distributed on the brush border (the side facing the intestinal lumen) of mucosal cells in the duodenum and proximal jejunum, and its transport function has clear specificity and dependence:
Substrate specificity: DMT1 has an affinity for divalent metal ions, with a particular preference for binding Fe²⁺. It can also transport other divalent metal ions such as zinc, manganese, and cadmium. Therefore, if these metal ions are present in excess in the intestine, they may compete with Fe²⁺ for binding sites on DMT1, slightly affecting the absorption efficiency of ferrous gluconate.
Dependence on transport conditions: The activity of DMT1 strictly relies on the acidic environment in the intestine, with an optimal pH of approximately 5.0. The upper small intestine (especially the duodenum) naturally maintains an acidic environment due to the inflow of gastric acid—this is an important reason why ferrous gluconate is mainly absorbed in this region. The acidic environment not only stabilizes the form of Fe²⁺ but also activates the transport function of DMT1.
Linkage with the body’s iron needs: The expression level of DMT1 is regulated by the body’s iron nutritional status. When the body is iron-deficient (e.g., in iron-deficiency anemia), intestinal mucosal cells upregulate the synthesis of DMT1 and increase its distribution on the brush border, thereby enhancing the ability to absorb Fe²⁺. Conversely, when the body’s iron reserves are sufficient, the expression of DMT1 is downregulated, reducing Fe²⁺ absorption and avoiding excessive iron accumulation. This regulatory mechanism endows the absorption of ferrous gluconate with the characteristic of "on-demand adjustment."
(II) Auxiliary Transport Pathway: Ferroportin (FPN, Iron Transporter)
FPN does not directly participate in the process of Fe²⁺ entering mucosal cells from the intestinal lumen; instead, it is responsible for transporting Fe²⁺ from within mucosal cells into the bloodstream. It serves as the key "exit protein" for Fe²⁺ to complete the process of "intestinal absorption – entry into the circulatory system," and its role forms a "relay" with DMT1:
Intracellular Fe²⁺ transformation and transport: Fe²⁺ that enters intestinal mucosal cells via DMT1 is first oxidized to Fe³⁺ by "ceruloplasmin" or "hephaestin" (a membrane iron transport accessory protein)—this step facilitates binding with iron carriers in the blood. Subsequently, Fe³⁺ binds to FPN, and through FPN’s transport function, it crosses the basolateral membrane of mucosal cells (the side facing blood vessels) and is released into the extracellular tissue fluid.
Synergy with blood iron carriers: Fe³⁺ entering the tissue fluid quickly binds to "transferrin (Tf)" in the plasma, forming a "transferrin-iron complex." This complex is then transported via the bloodstream to various tissues and organs throughout the body (e.g., bone marrow, liver, muscles), where it is taken up and utilized by cells (e.g., the bone marrow uses it for hemoglobin synthesis, while the liver uses it for iron storage).
Regulated activity: The activity of FPN is also regulated by the body’s iron status, and its expression level changes in synergy with DMT1. When the body is iron-deficient, FPN expression is upregulated, accelerating the release of intracellular Fe²⁺ into the bloodstream; when iron is sufficient, FPN expression is downregulated, reducing Fe²⁺ entry into the bloodstream. Meanwhile, untransported Fe²⁺ within mucosal cells binds to "ferritin" and remains in the cells in a stored form, eventually being excreted with the shedding of mucosal cells, further preventing iron excess.
III. Summary: Core Value of Transport Proteins in Ferrous Gluconate Absorption
Intestinal transport proteins (DMT1 and FPN) constitute the core mechanism for ferrous gluconate absorption through "division of labor and cooperation + on-demand regulation":
DMT1 acts as the "entrance," responsible for efficiently taking Fe²⁺ from the intestinal lumen into mucosal cells. Its activity depends on an acidic environment and is regulated by iron demand.
FPN acts as the "exit," responsible for transporting Fe²⁺ from within cells into the bloodstream, and cooperates with transferrin to complete the systemic transport of iron.
The synergistic effect of the two not only ensures the efficient absorption of Fe²⁺ from ferrous gluconate but also achieves dynamic balance in iron absorption through linkage with the body’s iron status, avoiding the risks of iron deficiency or excess. This is also an important physiological basis for ferrous gluconate, as an organic iron supplement, to have relatively high absorption efficiency and low intestinal irritation.
