Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in Mycobacterium<i> avium</i>-infected female mice

Abstract

Background Disease susceptibility and progression of Mycobacterium avium complex pulmonary disease (MAC -PD) is associated with multiple factors, including low body mass index (BMI). However, the speci fi c impact of low BMI on MAC -PD progression remains poorly understood. This study aims to examine the progression of MAC -PD in the context of low BMI, utilising a disease -resistant mouse model. Methods We employed a MAC infection -resistant female A/J mouse model to compare the progression of MAC -PD under two dietary conditions: one group was fed a standard protein diet, representing protein -energy unrestricted conditions, and the other was fed a low protein diet (LPD), representing protein -energy restriction. Findings Our results reveal that protein -energy restriction signi fi cantly exacerbates MAC -PD progression by disrupting lipid metabolism. Mice fed an LPD showed elevated fatty acid levels and related gene expressions in lung tissues, similar to fi ndings of increased fatty acids in the serum of patients who exhibited the MAC -PD progression. These mice also exhibited increased CD36 expression and lipid accumulation in macrophages upon MAC infection. In vitro experiments emphasised the crucial role of CD36-mediated palmitic acid uptake in bacterial proliferation. Importantly, in vivo studies demonstrated that administering anti-CD36 antibody to LPD-fed A/J mice reduced macrophage lipid accumulation and impeded bacterial growth, resulting in remarkable slowing disease progression. Interpretation Our fi ndings indicate that the metabolic status of host immune cells critically in fl uences MAC -PD progression. This study highlights the potential of adequate nutrient intake in preventing MAC -PD progression, suggesting that targeting CD36-mediated pathways might be a host -directed therapeutic strategy to managing MAC infection. Funding This research was funded by the National Research Foundation of Korea, the Korea Research Institute of Bioscience and Biotechnology, and the Korea National Institute of Health. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).