Gut Bacterium Prevotella copri Worsens Iron Overload in β-Thalassemia by Activating JAK/STAT Pathway

β-thalassemia is one of the most common inherited blood disorders in the world, and its most troublesome complication is not the anemia itself but the iron that builds up in tissues over a lifetime of transfusions and enhanced gut absorption. A new study from researchers at The First Affiliated Hospital of Guilin Medical University, published in Annals of Hematology, now suggests that a common gut bacterium may be quietly making that iron problem worse. The team found that Prevotella copri, a microbe increasingly recognized as a pro-inflammatory player in the intestine, exacerbates tissue iron retention and chronic inflammation in mice carrying the β-thalassemia mutation, and they traced the effect to a well-known immune signaling cascade: the JAK/STAT pathway.

The researchers began by asking a deceptively simple question: does the gut microbiome of β-thalassemia mice differ from that of healthy animals in ways that could influence disease severity? To find out, they collected fecal samples from wild-type and β-thalassemia mice and subjected them to 16S rRNA sequencing, a technique that reads the genetic barcodes of bacterial communities to map their composition. The analysis revealed that P. copri stood out as a dominant pro-inflammatory bacterium in the β-thalassemia animals, prompting the team to test whether the microbe was merely a bystander or an active contributor to the disorder’s hallmark iron overload and inflammation.

To answer that question, the investigators designed a four-group experiment that separated the effects of the mutation from the effects of the bacterium. They established wild-type mice, wild-type mice given P. copri, β-thalassemia mice, and β-thalassemia mice given P. copri, delivering the bacterium by intragastric gavage, a controlled oral transplantation technique that bypasses uncertainty about natural colonization. This design allowed the researchers to observe what happens when the microbe is introduced into a system already primed by the genetic disease, and to compare it against the same introduction in healthy animals.

The results were striking. Compared with untreated β-thalassemia mice, those that received P. copri showed elevated serum levels of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, alongside a decrease in the anti-inflammatory cytokine interleukin-10. At the same time, serum ferritin, a clinical marker of the body’s iron stores, rose, while ferroportin, the membrane protein responsible for exporting iron from cells into the bloodstream, fell. All of these changes reached statistical significance at p < 0.05, indicating that the bacterium was not simply adding noise to the disease picture but actively pushing the animals toward greater iron retention.

The hematological consequences were equally telling. Hemoglobin levels dropped in the P. copri-treated β-thalassemia mice, while erythropoietin and reticulocyte counts climbed. This pattern suggests that the bacterium worsened the already inefficient erythropoiesis that defines β-thalassemia, forcing the body to compensate with higher erythropoietin output and increased production of immature red blood cells. The authors note that P. copri may further aggravate ineffective erythropoiesis and erythrocyte injury in these animals, compounding the central defect of the disorder rather than merely adding a secondary complication.

To understand the molecular mechanism behind these observations, the team turned to the JAK/STAT signaling pathway, a canonical route by which interleukin-6 and related cytokines transmit inflammatory signals from the cell surface to the nucleus. Using quantitative real-time reverse transcription polymerase chain reaction and Western blotting, they measured the expression of glycoprotein 130, the co-receptor that anchors interleukin-6 signaling, along with Janus kinase 1, signal transducer and activator of transcription 3, and the phosphorylated forms of both kinases. In the β-thalassemia mice given P. copri, the expression levels of GP130, the ratio of phosphorylated to total JAK1, and the ratio of phosphorylated to total STAT3 were all upregulated, indicating that the pathway had been switched into a higher gear by the bacterial intervention.

The tissue-level evidence reinforced the molecular findings. Hematoxylin-eosin staining of colonic tissue revealed mucosal damage accompanied by inflammatory cell infiltration in the P. copri-treated β-thalassemia mice, pointing to direct intestinal injury on top of the systemic inflammation. Prussian blue staining, which highlights iron deposits as blue granules under the microscope, showed markedly aggravated iron accumulation in both the liver and the spleen of the treated animals compared with untreated β-thalassemia controls. Together, these histological observations confirmed that the bacterium’s effects were not confined to blood markers but extended to visible organ pathology.

The authors propose that P. copri exacerbates iron overload by triggering inflammatory responses and upregulating hepcidin, the liver-derived hormone that acts as the master regulator of iron homeostasis. Hepcidin binds to ferroportin and causes it to be internalized and degraded, effectively locking iron inside macrophages, hepatocytes, and enterocytes. By elevating interleukin-6, a potent inducer of hepcidin expression, and subsequently activating the JAK/STAT signaling pathway, P. copri appears to set off a cascade that suppresses iron export and traps the metal in tissues, worsening the iron burden that already plagues β-thalassemia patients.

The study’s implications reach beyond the laboratory. β-thalassemia affects populations across the Mediterranean, the Middle East, and Southeast Asia, and iron overload remains a leading cause of morbidity in these patients despite chelation therapy. If gut microbes can modulate hepcidin and iron distribution through immune signaling, then microbiome-targeted interventions, whether through dietary modification, probiotics, or antibiotics, could theoretically complement existing treatments. The finding also adds to a growing body of evidence that the intestinal microbiota is not a passive passenger in hematological disease but an active participant capable of shaping inflammation, erythropoiesis, and metal metabolism.

As with any animal study, the results require careful interpretation before they can inform clinical practice. The mouse model does not fully recapitulate the human disease, and the specific contribution of P. copri in patients with β-thalassemia remains to be established through human cohort studies. Nevertheless, the mechanistic clarity of the work, linking a specific gut bacterium to a specific signaling pathway and a specific clinical problem, offers a concrete starting point for future investigations. The research was supported by the National Natural Science Foundation of China, the Guangxi Ba Gui Scholars Special Project, and the Guangxi Medical and Health Key Discipline Construction Project, and the full article is available open access in Annals of Hematology.

Subject of Research: The role of Prevotella copri in exacerbating iron overload and chronic inflammation in β-thalassemia mice through JAK/STAT pathway activation.

Article Title: Mechanistic insights into how Prevotella copri exacerbates tissue iron retention and chronic inflammation in β-thalassemia mice via activation of the JAK/STAT signaling pathway

Article References: Li, Y., Huang, T., Chen, G., Liu, Z., Li, J., Ke, Z., Li, Y., Song, J., Mo, L., & Zhu, C. (2026). Mechanistic insights into how Prevotella copri exacerbates tissue iron retention and chronic inflammation in β-thalassemia mice via activation of the JAK/STAT signaling pathway. Annals of Hematology. https://doi.org/10.1007/s00277-026-07320-6

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07320-6

Keywords: Prevotella copri, β-thalassemia, iron overload, JAK/STAT signaling pathway, chronic inflammation, gut microbiome, hepcidin, interleukin-6, ferroportin, ineffective erythropoiesis, Annals of Hematology, Mechanistic