Microbiome-derived metabolites in cancer-associated anemia: An underexplored mechanistic link

Abstract

The review by Bangolo et al highlights the role of the gut microbiome in cancer-associated anemia (CAA). However, the impact of microbiome-derived metabolites is underexplored. In this letter, we focus on short-chain fatty acids, tryptophan metabolites, and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis. We also propose a research framework that integrates multi-omics analysis and gnotobiotic models. Finally, we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.

Key Words: Cancer-associated anemia; Gut microbiota; Microbial metabolites; Short-chain fatty acids; Tryptophan; Aryl hydrocarbon receptor

Core Tip: Microbial metabolites—including short-chain fatty acids and tryptophan-derived ligands of the aryl hydrocarbon receptor—modulate erythropoiesis and iron metabolism. This commentary underscores the need to integrate microbial metabolite biology into future research on cancer-associated anemia.

TO THE EDITOR

We read with great interest the recent review by Bangolo et al[1], titled “Exploring the gut microbiome’s influence on cancer-associated anemia: Mechanisms, clinical challenges, and innovative therapies” in the World Journal of Gastrointestinal Pharmacology and Therapeutics. The authors provide an insightful overview of the roles of microbial dysbiosis, inflammation, immune activation, and suppression of erythropoiesis in the development of cancer-associated anemia (CAA). However, we believe one crucial mechanistic dimension—microbiome-derived metabolites—merits further exploration to deepen the understanding of host–microbiome interactions in the pathogenesis and treatment of CAA.

MICROBIAL METABOLITES LINKING DYSBIOSIS TO ANEMIA

Gut microbes generate a broad repertoire of metabolites that actively modulate hematopoiesis and iron homeostasis. Among the most well-characterized are short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate. These molecules regulate hematopoietic stem cell maintenance, promote erythroid progenitor cell survival, and modulate inflammatory cytokines like interleukin (IL)-6 and tumour necrosis factor alpha through mechanisms that include histone deacetylase inhibition[2]. In the inflammatory milieu of CAA, restoring SCFA levels may thus provide dual benefits: Mitigating inflammation and enhancing erythropoietic recovery. Similarly, tryptophan-derived metabolites—such as indole-3-aldehyde, kynurenine, and indole-3-propionic acid—serve as potent ligands for the aryl hydrocarbon receptor (AhR), a key regulator of immune responses and epithelial barrier function[3]. AhR activation has been shown to protect erythroid progenitors under inflammatory stress while suppressing Th17-mediated inflammation, indirectly benefiting iron absorption and red cell production. Polyamines, including putrescine, spermidine, and spermine, further contribute to erythropoiesis by supporting mitochondrial function and chromatin remodeling. Dysbiosis can reduce the abundance of polyamine-producing bacteria, such as Bacteroides fragilis and Escherichia coli[4]. This may lower systemic levels of polyamines, which are essential for erythroid maturation. Reduced polyamine availability impairs mitochondrial function and ribosome biogenesis in erythroid progenitors[5]. It also affects iron metabolism by altering the expression of key regulators like DMT1 and hepcidin[6]. Inflammatory cytokines, such as IL-6, can further suppress polyamine synthesis, amplifying these effects[7]. Together, these changes may lead to both iron sequestration and ineffective erythropoiesis in CAA. Taken together, these microbial metabolites form a mechanistic bridge linking gut ecology to systemic hematologic outcomes.

To better delineate these complex interactions, we suggest a multi-tiered research approach. Integrative analyses of metagenomic, metabolomic, and transcriptomic data from CAA patient cohorts are needed to identify microbial-metabolite signatures associated with anemia severity. Gnotobiotic mouse models colonized with defined microbial communities could help dissect causal relationships and pinpoint protective vs pathogenic strains. Preclinical studies already indicate that supplementation with SCFAs or tryptophan derivatives improves hematologic indices in inflammation-induced anemia models. Clinically, biomarkers such as serum hepcidin and soluble transferrin receptor have been used to distinguish anemia of inflammation from iron-deficiency anemia[8]. Fecal and plasma metabolomic signatures have also been associated with anemia subtypes in chronic diseases[9]. These examples underscore the feasibility of using metabolite-based diagnostics for anemia assessment. In oncology, circulating biomarkers have demonstrated utility in predicting immunotherapy responses in gastric cancer[10]. This supports the broader potential of minimally invasive metabolite profiling across disease contexts. Analogously, profiling of microbial metabolites in blood or stool may aid in stratifying patients at risk for CAA or monitoring treatment response. Personalized microbiome-targeted interventions, guided by individual metabolomic profiles, represent a promising frontier for anemia management in cancer care.

We commend Bangolo et al[1] for their timely and valuable contribution to this topic. We hope that future research will explicitly integrate microbiome-derived metabolite pathways into the broader understanding of CAA. These molecules are not merely bystanders but represent active mediators and therapeutic opportunities deserving focused investigation.

ACKNOWLEDGEMENTS

We express our gratitude to Dr. Tan for assisting in the preparation of the manuscript.