British Journal of Nutrition (DOI): https://doi.org/10.1017/S0007114524002757
What the study examined
Oral iron replacement with ferrous salts is the first-line treatment for iron-deficiency anemia (IDA), but roughly one-third to one-half of patients develop gastrointestinal side effects such as nausea, abdominal pain, bloating, and constipation. These symptoms are a leading cause of poor adherence and treatment failure, leaving many patients under-treated.
Koker and colleagues (2024), publishing in the British Journal of Nutrition, ran a prospective randomized controlled trial to test whether co-administering the well-characterized probiotic strain Lactobacillus plantarum 299v (Lp299v, now classified as Lactiplantibacillus plantarum 299v) could improve both tolerability and iron status in patients starting oral iron. The trial enrolled 295 newly diagnosed IDA patients between September 2020 and March 2022, randomizing them to iron replacement therapy alone (IRT-only, n=157) or iron replacement plus probiotic (IRT-Pro, n=138).
This trial is notable because most prior work on Lp299v and iron focused on absorption in healthy volunteers using isotope tracers. Here the endpoint was clinically meaningful: real-world tolerability and iron recovery in patients who actually have anemia.
Methods and intervention
All participants received ferrous sulphate providing 100 mg of elemental iron once daily for three months. The IRT-Pro group additionally took Lactobacillus plantarum 299v at 10 billion colony-forming units (CFU) daily for the first 30 days of treatment. Patients were followed for three months with assessment of gastrointestinal symptoms, treatment discontinuation, and laboratory iron indices including serum iron, transferrin saturation, ferritin, and hemoglobin.
The design was pragmatic and open-label rather than placebo-controlled, which is a limitation to weigh when interpreting the subjective symptom endpoints. Nonetheless, the objective laboratory markers of iron status provide an independent line of evidence that is less susceptible to reporting bias.
Key findings
Gastrointestinal tolerance improved dramatically with the probiotic. Over three months, gastrointestinal intolerance occurred in 13.0% of the IRT-Pro group versus 46.5% of the IRT-only group (P < 0.001). Treatment discontinuation within the first 30 days fell from 15.9% to 3.6% (P < 0.001), corresponding to a number needed to treat of just 3 patients to prevent one case of intolerance.
Iron status also improved. At three months, serum iron was 76.0 vs. 60.0 µg/dl (P < 0.001) and transferrin saturation was 20.1% vs. 14.5% (P < 0.001) favoring the probiotic group. Hemoglobin rose more in the probiotic group, with a mean change from baseline of 0.9 vs. 0.4 g/dl (P < 0.001). The probiotic group also showed significantly lower rates of new-onset nausea, abdominal pain, bloating, and constipation.
Together the results suggest Lp299v does more than mask side effects: better tolerance likely supports adherence, while enhanced iron bioavailability drives faster hematologic recovery.
The mechanism: acidification and DCYTB up-regulation
Non-heme iron is absorbed most efficiently in its reduced ferrous (Fe2+) form. In the duodenal enterocyte, dietary ferric (Fe3+) iron is first reduced by the brush-border ferric reductase DCYTB (duodenal cytochrome b) before being transported into the cell by the divalent metal transporter DMT1. Anything that increases the pool of reducible ferric iron or up-regulates DCYTB can raise absorption.
Lactobacillus plantarum 299v ferments carbohydrates to lactic and other organic acids, lowering luminal pH. A more acidic environment keeps iron soluble and favors reduction of ferric to absorbable ferrous iron. In a mechanistic study using human Caco-2/HT29-MTX intestinal co-cultures, Hoppe and colleagues (Nutrients, 2018) showed that iron supplements containing Lp299v increased ferric iron in digested meals and up-regulated DCYTB, pointing to a direct effect on the enterocyte iron-reduction machinery.
These mechanistic findings are consistent with human absorption data: in a double-isotope crossover study in women of reproductive age, Hoppe and colleagues (British Journal of Nutrition, 2015) found that adding Lp299v to an iron-fortified fruit drink increased iron absorption by nearly 50% (28.8% vs. 19.3% of the dose, P < 0.004). The improved gastrointestinal tolerance seen in IDA patients may in turn reflect a lower required iron burden and the strain's broader effects on gut barrier function and the microbiota.
How it fits the metal-microbiome-disease axis
This body of work is an instructive counterpoint within the metal-microbiome-disease axis. Much of the axis concerns how toxic heavy-metal exposure disrupts the microbiome and drives disease. Iron sits at the center of host-microbe metal competition: the microbiome both shapes and responds to host iron handling, and dysbiosis can impair the metallostasis on which healthy iron absorption depends.
The Lp299v case illustrates the axis running in the beneficial direction. Here a defined microbial intervention improves host metallostasis, remodeling the luminal chemistry and enterocyte transport pathways that govern iron uptake to correct an iron-deficient disease state. It shows that microbiome composition is not merely a downstream casualty of metal dysregulation but an actionable lever over the host metallome.
The same principle underscores why microbiome disruption matters in the harmful direction. If a single probiotic strain can measurably shift luminal pH and ferric-reductase expression to improve iron status, then heavy-metal-driven dysbiosis or loss of acid-producing commensals could plausibly degrade these same iron-handling mechanisms, contributing to the anemia and metabolic disturbances often observed alongside chronic metal exposure. Iron nutrition thus becomes a concrete example of how the microbiome mediates the link between environmental metal chemistry and human disease.
Key findings
- In 295 iron-deficiency anemia patients, adding L. plantarum 299v (10 billion CFU/day for 30 days) to oral ferrous sulphate cut gastrointestinal intolerance from 46.5% to 13.0% (P < 0.001).
- Early treatment discontinuation dropped from 15.9% to 3.6% (P < 0.001); number needed to treat was 3.
- Iron status improved: serum iron 76.0 vs. 60.0 µg/dl, transferrin saturation 20.1% vs. 14.5%, and hemoglobin gain 0.9 vs. 0.4 g/dl (all P < 0.001).
- Mechanistically, Lp299v acidifies the gut lumen and up-regulates the ferric reductase DCYTB, favoring reduction of ferric to absorbable ferrous iron.
- In healthy women, Lp299v raised non-heme iron absorption from an iron drink by nearly 50% (28.8% vs. 19.3% of dose, P < 0.004).
- The findings demonstrate a microbial lever over host iron metallostasis, the beneficial mirror image of the metal-microbiome-disease axis.
Frequently asked questions
Does Lactobacillus plantarum 299v reduce the side effects of oral iron tablets?
Yes. In a randomized trial of 295 iron-deficiency anemia patients, taking L. plantarum 299v (10 billion CFU daily for 30 days) alongside ferrous sulphate reduced gastrointestinal intolerance from 46.5% to 13.0% and cut early treatment dropout from 15.9% to 3.6%, both statistically significant (P < 0.001).
How does L. plantarum 299v improve iron absorption?
The strain ferments carbohydrates into organic acids that lower gut pH, keeping iron soluble and favoring its reduction from ferric (Fe3+) to the readily absorbed ferrous (Fe2+) form. It also up-regulates the intestinal ferric reductase DCYTB, which primes dietary iron for uptake by the DMT1 transporter in the duodenum.
How much can L. plantarum 299v increase iron absorption?
In a double-isotope crossover study in women of reproductive age, adding Lp299v to an iron-fortified fruit drink increased non-heme iron absorption by almost 50% (28.8% versus 19.3% of the administered dose, P < 0.004).
Is L. plantarum 299v a replacement for iron supplements?
No. It is an adjunct, not a substitute. In the trials, the probiotic was given together with standard oral iron (ferrous sulphate). Its role is to improve tolerability and enhance absorption of the iron that is taken, helping more patients complete therapy and recover normal iron status.