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

BACKGROUND & AIMS: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.