The Iron–Gut Microbiome Axis in Adolescent Girls:Global Evidence, Mechanisms, and Therapeutic Strategies to Combat Anemia

Abstract

Background and Aims: Anemia remains one of the most pervasive nutritional disorders worldwide, affecting approxi mately 1.92 billion individuals in 2021 and contributing to nearly 52 million years lived with disability (YLDs) [1]. Among  vulnerable populations, adolescent girls bear a disproportionate burden due to the combined physiological demands of  rapid growth, expanding blood volume, and the onset of menstruation, compounded by chronically inadequate dietary  iron intake in low- and middle-income countries (LMICs). Emerging evidence over the past five years has significantly  advanced our understanding of anemia pathophysiology, positioning the gut microbiome as a critical determinant of  iron homeostasis and absorption. Methods: This narrative evidence synthesis integrates findings from the Global Burden of Disease Study 2021, WHO sur veillance reports (2025), and recent systematic reviews, randomized controlled trials (RCTs), and two-sample Mendelian  randomization (MR) studies published between January 2021 and April 2025. Databases including PubMed, Embase,  Cochrane Library, and Web of Science were systematically explored. Priority was given to studies examining interac tions between iron metabolism, gut microbiota, hepcidin regulation, and adolescent or reproductive-age female popula tions. Evidence from probiotic, prebiotic, and synbiotic interventions, along with dietary iron bioavailability studies, was  appraised using GRADE-informed criteria. Results: Despite a modest decline in global anemia prevalence from 28.2% in 1990 to 24.3% in 2021, the absolute burden  has increased from 1.50 to 1.92 billion cases due to demographic expansion in high-risk regions. Dietary iron deficiency  accounts for 66.2% of anemia-related YLDs, disproportionately affecting women. Mechanistic studies demonstrate that  iron deficiency anemia (IDA) disrupts gut microbial balance by reducing beneficial genera such as Lactobacillus and  Bifidobacterium while promoting pathogenic taxa including Streptococcus and Clostridium. This dysbiosis elevates hepcidin via IL-6/BMP-SMAD signaling, impairing iron absorption and reinforcing a vicious cycle of deficiency. MR analyses  further confirm causal links between specific microbial taxa and IDA risk. Importantly, RCTs indicate that microbi ome-targeted interventions and optimized alternate-day iron dosing significantly improve hematological outcomes. Conclusions: In conclusion, adolescent anemia should be reframed as a gut–iron axis disorder rather than a condition  driven solely by dietary insufficiency. Integrated strategies combining iron supplementation with microbiome modula tion offer a more effective and sustainable approach. Targeting this critical developmental window may yield long-term  benefits for hematological health, reproductive outcomes, and intergenerational nutrition.