Duodenal dysbiosis is linked to altered ferroportin related transcriptomics programs in iron deficiency anemia

Iron deficiency anemia (IDA) affects over two billion people, yet up to half of patients show inadequate response to oral iron therapy. We hypothesized that IDA is a primary duodenal mucosal disorder where dysbiosis and immune polarization converge to impair enterocyte iron export. This study integrates mucosal-associated microbiome and transcriptomic profiling to elucidate mechanisms underlying impaired iron handling.

Duodenal biopsies from women with IDA (n = 11) and matched controls (n = 9) underwent paired 16S rRNA and RNA-Seq. A Microbial Redox Index (MRI) quantified oxygen-tolerant taxa. Multilayer network modeling linked microbial hubs to epithelial transcriptional remodeling in iron-handling, inflammatory, and barrier-integrity pathways.

IDA subjects demonstrated expected hematological deficits (hemoglobin 10.02 ± 0.82 vs. 12.69 ± 0.67 g/dL; ferritin 10.7 [8.2-35.3] vs. 49.7 [28.4-58.7] ng/mL; P < 0.05). Although the overall ratio of oxygen-tolerant to anaerobic taxa was comparable between groups (P = 0.44), IDA was marked by a collapse of homeostatic ecological control. In controls, Group V a/V b anaerobes showed a strong inverse correlation with Shannon diversity (P = 0.009), indicating a stable, niche-restricting anaerobic core. This relationship was lost in IDA, where both oxygen-tolerant and anaerobic taxa displayed positive correlations with Th17 skewed inflammation (IL17A log2FC = +3.59), hypoxic stress (EGLN3 log2FC = +1.31), and sensitized BMP signaling (BMPR2 log2FC = +0.50). These transcriptomic signatures could reflect a functional ferroportin blockade, as reflected by SLC40A1 mRNA upregulation (log2FC = +1.02) concurrent with a proposed model of post translational ferroportin suppression, despite profound cellular iron starvation (TFRC log2FC = +1.58; SLC11A2 log2FC = +2.2). Together, these features are consistent with a possible enterocyte iron retention phenotype. The lncRNA LOC124902620 emerged as a central regulatory hub linking dysbiosis to iron-handling genes.

IDA is a duodenal mucosal disorder where dysbiosis-driven redox shifts and immune activation could support a model of hepcidin associated ferroportin downregulation. This is consistent with a proposed enterocyte iron retention phenotype. Microbial hubs and the LOC124902620 axis are promising targets for precision interventions to restore mucosal iron export.