Host-microbiota-parasite crosstalk: Gut microbiota dysbiosis exacerbates Leishmania infantum pathogenesis through altered immunity and glycerylphosphatide metabolism.

Visceral leishmaniasis, a deadly parasitic disease if untreated, urgently requires novel therapeutic strategies. The gut microbiota can modulate host immunity and disease susceptibility, but its specific impact on visceral leishmaniasis and the underlying molecular mechanisms are unclear. This study examined the interaction between intestinal microbiota and Leishmania infantum infection in a murine model, focusing on parasite load, immune response, and metabolic changes. Mice with induced intestinal dysbiosis were infected with L. infantum and monitored for five weeks. Post-euthanasia, murine liver and spleen were assessed for infection status, plasma was analyzed for antibodies, cytokines, and LC-MS/MS-based metabolomics, liver tissues were sequenced for transcriptomics, and fecal samples were analyzed by 16S rRNA sequencing. Results showed that L. infantum infection disrupted gut microbiota diversity, reducing taxa such as Clostridia_UCG-014 and Lachnospiraceae_NK4A136_group, and inducing dysbiosis-related changes such as decreased Muribaculaceae and increased Bacteroides (P-values from 0.0018 to 0.0472). Dysbiotic mice had higher parasite loads in liver and spleen, more inflammatory lesions, lower serum IgG levels, and elevated Th1- and Th2-type cytokines. Transcriptomic and metabolomic analyses revealed dysregulated lipid metabolism (e.g., cholesterol and fatty acid biosynthesis) and increased glycerophospholipids, potentially supporting parasite membrane synthesis. These findings demonstrate that gut microbiota dysbiosis exacerbates L. infantum pathogenesis by altering host immunity and metabolic pathways, highlighting the potential for microbiota-targeted interventions to combat parasitic infections.