Iron deficiency anemia (IDA) is one of the most common nutritional deficiency diseases worldwide, and oral iron supplements are the first-line clinical treatment. Ferrous Sulfate, a traditional first-generation oral iron supplement, was once widely used due to its low cost and high iron content (20%). However, it causes significant gastrointestinal side effects (e.g., nausea, vomiting, abdominal pain, constipation), leading to poor patient compliance. Ferrous Gluconate, a second-generation organic iron supplement, has a lower iron content (12%) but shows better gastrointestinal tolerance in clinical observations. Starting from the chemical structure, solubility characteristics, and absorption mechanism of iron supplements, this article systematically compares the incidence, manifestations, and differential mechanisms of gastrointestinal side effects between the two iron supplements. Combined with clinical research data and application recommendations, it provides a reference for the selection of iron supplements in the treatment of IDA.

I. Chemical Properties of the Two Iron Supplements and the Basis for Gastrointestinal Effects

The gastrointestinal side effects of iron supplements essentially result from "irritation of the gastrointestinal mucosa by unabsorbed free iron ions". The solubility characteristics and free iron ion release capacity, determined by chemical structure, are the core prerequisites for the differences in side effects between the two iron supplements:

(I) Ferrous Sulfate: High Free Iron Ion Release and Strong Mucosal Irritation

Ferrous Sulfate is an inorganic iron salt with the chemical formula FeSO₄·7H₂O. Its core characteristics are high water solubility and high dissociation degree:In the acidic environment of the stomach (pH 1.5–3.0), Ferrous Sulfate dissolves quickly and completely, dissociating into a large amount of free Fe²⁺ (divalent iron ions). The unabsorbed free Fe²⁺ (not absorbed in the upper small intestine, i.e., duodenum and jejunum) enters the lower intestinal tract (ileum and colon) with intestinal peristalsis and directly contacts the gastrointestinal mucosal cells.

On one hand, Fe²⁺ damages the integrity of the cell membrane of mucosal epithelial cells, impairing the mucosal barrier function and triggering local inflammatory reactions (e.g., mucosal congestion and edema).

On the other hand, Fe²⁺ stimulates the nerve endings of the gastrointestinal tract, activating the vomiting reflex center or signals of intestinal peristalsis disorders. This ultimately manifests as acute irritative symptoms such as nausea, vomiting, and abdominal pain, as well as chronic reactions such as constipation (Fe²⁺ inhibits intestinal peristalsis) or diarrhea (increased exudation due to mucosal inflammation).

In addition, the dissociation property of Ferrous Sulfate makes it prone to binding with food components in the gastrointestinal tract (e.g., tannic acid, phytic acid, calcium) to form insoluble precipitates. This not only reduces iron absorption rate (bioavailability approximately 10%–15%) but also may increase the sense of foreign body in the intestines, exacerbating constipation or bloating.

(II) Ferrous Gluconate: Low Free Iron Ion Release and Mild Mucosal Irritation

Ferrous Gluconate is an organic iron supplement with the chemical formula C₁₂H₂₂FeO₁₄. Its core characteristics are moderate water solubility and low dissociation degree:The gluconate group (a hydrophilic organic group) in the molecule binds to Fe²⁺ through coordinate bonds, forming a relatively stable chelate structure. In the acidic environment of the stomach, Ferrous Gluconate dissolves but dissociates slowly, releasing only a small amount of free Fe²⁺; most Fe²⁺ enters the small intestine in the form of "Ferrous Gluconate chelate".

This chelate can be directly absorbed by the "organic iron transporters" of small intestinal mucosal cells (without first dissociating into free Fe²⁺), resulting in higher absorption efficiency (bioavailability approximately 20%–30%).

The unabsorbed chelate does not release free Fe²⁺ and is excreted in feces as an intact molecule, significantly reducing direct irritation to the gastrointestinal mucosa.

At the same time, Ferrous Gluconate has weak interactions with food components (the chelate structure is not easily bound to tannic acid or phytic acid), which not only reduces precipitate formation but also minimizes local irritation (e.g., bloating, flatulence) caused by food interactions, resulting in better gastrointestinal tolerance.

II. Clinical Comparison of Gastrointestinal Side Effects: Differences in Incidence and Manifestations

Numerous clinical studies and meta-analyses have shown significant differences between Ferrous Gluconate and Ferrous Sulfate in the "incidence", "severity", and "type" of gastrointestinal side effects, which directly affect patient medication compliance:

(I) Side Effect Incidence: Significantly Lower in Ferrous Gluconate

Data from randomized controlled trials (RCTs) in patients with IDA show:

Ferrous Sulfate: At the conventional therapeutic dose (100–150 mg elemental iron per day, equivalent to approximately 500–750 mg Ferrous Sulfate), the total incidence of gastrointestinal side effects is as high as 60%–80%. Among these, the incidence of mild side effects (e.g., mild nausea, bloating) is approximately 40%–50%, moderate side effects (e.g., vomiting, abdominal pain, constipation) is 15%–25%, and severe side effects (e.g., severe abdominal pain, severe constipation/diarrhea requiring drug discontinuation) is 5%–10%.

Ferrous Gluconate: To achieve the same elemental iron dose (100–150 mg elemental iron per day, equivalent to approximately 830–1250 mg Ferrous Gluconate), the total incidence of gastrointestinal side effects is only 20%–35%. Among these, the incidence of mild side effects is approximately 15%–20%, moderate side effects is 5%–10%, and severe side effects is < 2% (drug discontinuation due to side effects is almost unnecessary).

For example, a clinical study involving 200 patients with IDA (published in Nutrients in 2019) showed:

72% of patients taking Ferrous Sulfate experienced at least one gastrointestinal side effect, and 21% required dose adjustment or drug discontinuation due to side effects.

Only 28% of patients taking Ferrous Gluconate experienced side effects, 3% required dose adjustment due to side effects, and no patients discontinued treatment.

(II) Side Effect Manifestations: Mildersymptoms in Ferrous Gluconate

The two iron supplements cause similar types of gastrointestinal side effects (mainly nausea, vomiting, abdominal pain, constipation, and diarrhea), but their severity differs significantly:

Nausea and vomiting: Nausea caused by Ferrous Sulfate is mostly persistent (occurring 1–2 hours after medication and lasting 4–6 hours), and some patients experience vomiting (vomitus may contain undissolved iron supplement particles). Nausea caused by Ferrous Gluconate is mostly intermittent (only mild discomfort for a short time after medication), and the incidence of vomiting is < 5% (compared to 15%–20% for Ferrous Sulfate).

Abdominal pain and bloating: Abdominal pain caused by Ferrous Sulfate is mostly spasmodic pain in the lower abdomen (related to intestinal mucosal irritation and peristalsis disorders), and the incidence of bloating is approximately 30% (related to increased intestinal gas production caused by iron supplement precipitates). Abdominal pain caused by Ferrous Gluconate is mostly mild upper abdominal discomfort (related to mild irritation from a small amount of free Fe²⁺ in the stomach), and the incidence of bloating is < 10%.

Constipation and diarrhea: The incidence of constipation with Ferrous Sulfate is 35%–45% (free Fe²⁺ inhibits intestinal peristalsis, and precipitates increase fecal hardness), and the incidence of diarrhea is 10%–15% (increased intestinal secretion due to mucosal inflammation). The incidence of constipation with Ferrous Gluconate is 10%–15% (the chelate does not affect intestinal peristalsis, and there is no significant change in fecal hardness), and the incidence of diarrhea is < 5% (mild mucosal irritation and slight inflammatory response).

In addition, Ferrous Sulfate may cause "black stools" (free Fe²⁺ combines with intestinal sulfides to form ferrous sulfide). Although this poses no health risk, some patients may worry about gastrointestinal bleeding due to black stools, increasing psychological burden. Ferrous Gluconate also causes black stools, but the color is lighter (less ferrous sulfide is produced), leading to better psychological acceptance among patients.

(III) Dose Dependence: Flatter "Dose-Side Effect" Curve for Ferrous Gluconate

The incidence of gastrointestinal side effects is positively correlated with the dose of iron supplements (higher dose leads to more significant side effects), but the strength of the "dose-side effect" correlation differs between the two iron supplements:

Ferrous Sulfate: When the dose exceeds 100 mg elemental iron per day, the incidence of side effects increases "exponentially". When the dose increases to 200 mg elemental iron per day, the incidence of severe side effects can rise to more than 20%, which is almost intolerable for patients.

Ferrous Gluconate: Even when the dose increases to 200 mg elemental iron per day (requiring approximately 1670 mg Ferrous Gluconate), the incidence of side effects only rises to about 40%, and most are mild side effects (no severe side effects). Its "dose-side effect" curve is flatter, and clinically, side effects can be further reduced by adjusting the dose (e.g., divided administration).

III. Core Mechanisms of Side Effect Differences: A Full-Process Analysis from Absorption to Mucosal Action

The differences in gastrointestinal side effects between the two iron supplements essentially stem from chain differences in three links: "free iron ion release", "absorption efficiency", and "mucosal action mode". The specific mechanisms can be divided into three levels:

(I) Free Iron Ion Release: The "Source Difference" Determining Irritation Intensity

Free Fe²⁺ is the direct cause of gastrointestinal mucosal irritation, and the dissociation characteristics of the two iron supplements determine the amount of free Fe²⁺ released:

Ferrous Sulfate dissociates rapidly in the stomach, with a high peak concentration of free Fe²⁺ (the concentration of free Fe²⁺ in the stomach can reach 100–200 μmol/L within 1 hour after medication) and a long duration (4–6 hours).

Ferrous Gluconate dissociates slowly, with a low peak concentration of free Fe²⁺ (only 20–50 μmol/L), and most Fe²⁺ exists in the form of chelate. The "direct irritation dose" of free Fe²⁺ to the mucosa is significantly reduced.

This "source difference" results in Ferrous Sulfate having a 3–5 times stronger mucosal irritation intensity than Ferrous Gluconate, which is the core reason for the difference in side effects.

(II) Absorption Efficiency: The Key Link Affecting "Unabsorbed Iron Amount"

Unabsorbed iron supplements are the main cause of irritation in the lower intestinal tract, and absorption efficiency determines the amount of unabsorbed iron:

Ferrous Sulfate has low bioavailability (10%–15%), meaning 85%–90% of the iron supplement is unabsorbed. This unabsorbed free Fe²⁺ reaches the lower intestinal tract with intestinal peristalsis, continuously irritating the colonic mucosa and causing symptoms such as constipation and diarrhea.

Ferrous Gluconate has high bioavailability (20%–30%), with only 70%–80% of the iron supplement being unabsorbed. The unabsorbed portion exists in the form of chelate (does not release free Fe²⁺), causes no irritation to the colonic mucosa, and is only excreted in feces.

In addition, the absorption of Ferrous Gluconate is less affected by food (the chelate can be directly absorbed by transporters without competing with food components), so patients can take it after meals (further reducing gastric mucosal irritation). In contrast, Ferrous Sulfate needs to be taken on an empty stomach (e.g., 1 hour before meals or 2 hours after meals), as food significantly reduces its absorption. The gastric mucosa is more sensitive on an empty stomach, making side effects more likely to occur.

(III) Mucosal Action Mode: From "Destructive Irritation" to "Mild Contact"

The two iron supplements interact with the gastrointestinal mucosa in different ways, leading to differences in the nature of side effects:

The free Fe²⁺ of Ferrous Sulfate has strong oxidizing properties and can undergo redox reactions with lipids and proteins in mucosal cells, destroying the cell membrane structure (e.g., causing oxidative breakage of the phospholipid bilayer) and triggering mucosal cell necrosis or inflammatory reactions (e.g., releasing inflammatory factors such as interleukin-6 and tumor necrosis factor-α). This is classified as "destructive irritation".

The chelate molecule of Ferrous Gluconate has no oxidizing properties and only has "physical contact" with mucosal cells, without damaging the cell membrane or triggering inflammatory reactions. Only a small amount of free Fe²⁺ dissociated in the stomach may cause mild irritation, which is classified as "mild contact".

This difference in action mode explains why Ferrous Sulfate causes more severe side effects (e.g., abdominal pain, diarrhea) often accompanied by mucosal inflammation-related symptoms (e.g., mucous stools), while Ferrous Gluconate mostly causes mild discomfort without inflammatory reactions.

IV. Clinical Application Recommendations: Iron Supplement Selection and Usage Optimization Based on Side Effect Differences

Combined with the side effect characteristics of the two iron supplements, clinically, the appropriate iron supplement should be selected and the usage plan optimized based on the patient’s tolerance, disease severity, and medication compliance needs:

(I) Iron Supplement Selection Principles

Priority selection scenarios: For patients with gastrointestinal sensitivity (e.g., the elderly, children, pregnant women, patients with gastrointestinal diseases (gastritis, irritable bowel syndrome)) or those who previously discontinued Ferrous Sulfate due to side effects, Ferrous Gluconate is preferred to reduce the risk of side effects and improve compliance.

Alternative selection scenarios: For young patients with limited economic conditions and good gastrointestinal tolerance, Ferrous Sulfate can be selected. However, it should be started at a low dose (e.g., 50 mg elemental iron per day) and gradually increased to the therapeutic dose to reduce side effects. If moderate or severe side effects occur, switch to Ferrous Gluconate in a timely manner.

(II) Usage Plan Optimization

Administration time: Ferrous Gluconate can be taken 30 minutes after meals (food does not affect absorption and can further reduce gastric mucosal irritation). Ferrous Sulfate needs to be taken on an empty stomach (e.g., 1 hour before meals or 2 hours after meals); if side effects are significant on an empty stomach, it can be adjusted to post-meal administration (accepting the cost of approximately 30% reduced absorption efficiency).

Divided administration: Both iron supplements are recommended to be taken in "divided doses" (e.g., 2–3 times a day) to avoid excessive side effects caused by a single high dose. For example, 150 mg elemental iron per day of Ferrous Gluconate can be divided into 3 doses (50 mg elemental iron each time, equivalent to approximately 415 mg Ferrous Gluconate per dose).

Combination medication: If constipation still occurs while taking Ferrous Sulfate, a mild laxative (e.g., lactulose, polyethylene glycol 4000) can be used in combination. If nausea or abdominal pain occurs, a gastric mucosal protective agent (e.g., hydrotalcite) can be used in combination. However, note that gastric mucosal protective agents may reduce iron absorption and should be taken 2 hours apart from iron supplements.

Dietary coordination: During iron supplement administration, avoid simultaneous intake of foods high in tannic acid (e.g., strong tea, coffee) or phytic acid (e.g., whole grains, legumes) (to reduce precipitate formation). Appropriate intake of vitamin C (e.g., fresh fruits, vitamin C tablets) can promote Fe²⁺ absorption, reduce the amount of unabsorbed iron, and indirectly reduce side effects.

The differences in gastrointestinal side effects between Ferrous Gluconate and Ferrous Sulfate stem from three-fold differences in "free iron ion release", "absorption efficiency", and "mucosal action mode" determined by chemical structure:

Ferrous Sulfate has a high incidence of side effects (60%–80%) and significant symptoms due to high free Fe²⁺ release, low absorption efficiency, and destructive mucosal irritation.

Ferrous Gluconate has a low incidence of side effects (20%–35%) and mild symptoms due to low free Fe²⁺ release, high absorption efficiency, and mild mucosal contact.

In clinical application, iron supplements should be selected based on the patient’s gastrointestinal tolerance and economic conditions, and the plan should be optimized through "post-meal administration, divided doses, and combined dietary adjustment" to reduce side effects while ensuring efficacy and improving patient compliance. For the long-term treatment of IDA, Ferrous Gluconate is a more recommended oral iron supplement due to its better gastrointestinal tolerance.