Protein undernutrition alters the colonic bacteriome, disrupts intestinal immune homeostasis, and impairs control of Leishmania infantum infection in a murine model of visceral leishmaniasis

Undernutrition is a significant global health issue that exacerbates susceptibility to infectious diseases, including visceral leishmaniasis (VL), caused by Leishmania infantum. Here, we investigated the interplay between undernutrition, immune responses, and colonic microbiota composition in a murine model of VL. We used BALB/c mice to analyze the effects of a low-protein diet and L. infantum infection on systemic and local immune responses, microbiota composition, and parasite load. Undernutrition significantly downregulated the mRNA expression of cytokines in the colon while increasing the colonic luminal levels of proinflammatory cytokines. The protein-deficient diet also induced dysbiosis, characterized by reduced Bacteroidota and increased Desulfobacterota and Firmicutes, which correlated with histopathological changes and intestinal inflammation. Additionally, secretory IgA levels were markedly elevated in undernourished animals, suggesting a compensatory response to dysbiosis. The parasite load was significantly increased in the spleens of undernourished, infected mice, potentially due to disrupted immune-endocrine communication involving intestinal inflammation and microbial imbalance. These findings highlight the complex interplay between nutritional status, the microbiota, and host immunity in the progression of VL. Undernutrition exacerbates disease severity through local and systemic immune dysregulation and microbial shifts. Our results provide a foundation for exploring therapeutic strategies targeting nutrition and microbiota modulation in VL management.