The human gut microbiome is intricately linked to systemic and organ-specific immune responses and is highly responsive to dietary modulation. As metagenomic techniques enable in-depth study of an ever-growing number of gut microbial species, it has become increasingly feasible to decipher the specific functions of the gut microbiome and how they may be modulated by diet. Diet exerts both supportive and selective pressures on the gut microbiome by regulating a multitude of factors, including energy density, macronutrient and micronutrient content, and circadian rhythm. The microbiome, in turn, contributes to local and systemic immune responses by providing colonization resistance against pathogens, shaping immune cell activity and differentiation, and facilitating the production of bioactive metabolites. Emerging research has strengthened the connections between the gut microbiome and cardiometabolic disorders (e.g., cardiovascular disease, obesity, type-2 diabetes), autoimmune conditions (e.g., type-1 diabetes, rheumatoid arthritis, celiac disease), respiratory disease, chronic kidney and liver disease, inflammatory bowel disease, and neurological disorders (e.g., Alzheimer’s, Parkinson’s disease, depressive disorders). Here, we outline ways in which dietary factors impact host response in diseases through alterations of gut microbiome functionality and composition. Consideration of diet-mediated microbial effects within the context of the diseases discussed highlights the potential of microbiome-targeted treatment strategies as alternative or adjunct therapies to improve patient outcomes.

Plasmodium parasites rely on host iron for survival and replication, making host iron availability a critical determinant of malaria pathogenesis. Central to iron homeostasis is the hepcidin–ferroportin regulatory axis, where hepcidin suppresses iron export by inducing ferroportin degradation, thus modulating systemic and cellular iron availability. In the Plasmodium infection model (P. yoelii), we observed a significant downregulation of hepatic hepcidin expression, accompanied by an increase in hepatic ferroportin expression. On the contrary, RBC-ferroportin protein level was notably suppressed upon P. yoelii infection. Given these findings, we aim to investigate the role of a ferroportin inhibitor in Plasmodium infection. In a P. yoelii mouse model, treatment with an oral ferroportin inhibitor, VIT-2763 (Vamifeport) increased parasitemia, accompanied by increased levels of pro-inflammatory cytokines, erythropoietin, and liver injury markers. In P. yoelii infected mice, VIT-2763 treatment suppressed hepcidin expression and increased ferroportin expression in hepatocytes, while reducing ferroportin protein levels in RBCs. VIT-2763 mediated exacerbation of P. yoelii infection reveals the tissue-specific regulation of ferroportin in hepatocytes and RBCs, underscoring the therapeutic potential of modulating the hepcidin–ferroportin axis as an intervention strategy in malaria.