Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity.

is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with . We found that overall bacterial burden and microbiome configurations dominated with spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Quantification of host and bacterial transcripts on human lesions revealed that high lesional transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcomes in -infected mice colonized with , given that its neutralization reduced pathology and inflammation. These results highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences.