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Updated: Aug 4, 2025
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Impavido attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice
C Alicia Traughber1,2,3, Amanda J Iacano3, Kalash Neupane1,2
1Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA.
Abstract:
Impavido (Miltefosine) is an FDA-approved drug for treating leishmaniasis and primary amebic meningoencephalitis. We have shown previously that Miltefosine increased cholesterol release and dampened Nlrp3 inflammasome assembly in macrophages. Here, we show that Miltefosine reduced LPS-induced choline uptake by macrophages, and attenuated Nlrp3 inflammasome assembly in mice. Miltefosine-fed mice showed reduced plasma IL-1β in a polymicrobial cecal slurry model of systemic inflammation. Miltefosine-fed mice showed increased reverse cholesterol transport to the plasma, liver, and feces. Hyperlipidemic apoE-/- mice fed with WTD + Miltefosine showed significantly reduced weight gain and markedly reduced atherosclerotic lesions versus mice fed with WTD. The 16S rDNA sequencing and analysis of gut microbiota showed marked alterations in the microbiota profile of Miltefosine-fed hyperlipidemic apoE-/- versus control, with the most notable changes in Romboutsia and Bacteriodes species. Taken together, these data indicate that Miltefosine causes pleiotropic effects on lipid metabolism, inflammasome activity, atherosclerosis, and the gut microbiota.
Insights
Miltefosine, an FDA-approved drug, reduces inflammation and atherosclerosis by impacting lipid metabolism and gut microbiota. This study reveals its potential beyond infectious diseases, highlighting effects on cholesterol transport and immune response.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Miltefosine (Impavido) is FDA-approved for leishmaniasis and primary amebic meningoencephalitis.
- Previous studies indicated Miltefosine enhances cholesterol release and suppresses Nlrp3 inflammasome in macrophages.
Purpose of the Study:
- To investigate Miltefosine's effects on LPS-induced choline uptake and Nlrp3 inflammasome assembly in macrophages and mice.
- To evaluate Miltefosine's impact on systemic inflammation, reverse cholesterol transport, atherosclerosis, and gut microbiota composition.
Main Methods:
- Assessed LPS-induced choline uptake and Nlrp3 inflammasome assembly in macrophages.
- Administered Miltefosine to mice in polymicrobial sepsis and atherosclerosis models.
- Analyzed plasma IL-1β levels, reverse cholesterol transport, atherosclerotic lesions, and gut microbiota composition via 16S rDNA sequencing.
Main Results:
- Miltefosine reduced LPS-induced choline uptake and attenuated Nlrp3 inflammasome assembly.
- Miltefosine-fed mice exhibited reduced plasma IL-1β and enhanced reverse cholesterol transport.
- In hyperlipidemic mice, Miltefosine decreased weight gain, atherosclerotic lesions, and altered gut microbiota, notably Romboutsia and Bacteroides species.
Conclusions:
- Miltefosine demonstrates pleiotropic effects, influencing lipid metabolism, inflammasome activity, and atherosclerosis.
- The drug significantly modulates the gut microbiota composition.
- These findings suggest potential therapeutic applications for Miltefosine beyond its approved indications.
