Impavido attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice
C. Alicia Traughber,
Amanda J. Iacano,
Kalash Neupane,
Mariam R. Khan,
Emmanuel Opoku,
Tina Nunn,
Ashutosh Prince,
Naseer Sangwan,
Stanley L. Hazen,
Jonathan D. Smith,
Kailash Gulshan
Affiliations
C. Alicia Traughber
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Amanda J. Iacano
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Kalash Neupane
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Mariam R. Khan
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Emmanuel Opoku
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Tina Nunn
Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
Ashutosh Prince
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Naseer Sangwan
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
Stanley L. Hazen
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
Jonathan D. Smith
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Kailash Gulshan
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Corresponding author
Summary: 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.
