Mitochondrial homeostasis and severe malnutrition
This is a summary of the following paper: Ling C, Versloot C, Kvissberg M et al. (2023) Rebalancing of mitochondrial homeostasis through an NAD+ -SIRT1 pathway preserves intestinal barrier function in severe malnutrition. eBioMedicine, 96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520344/
Among other symptoms, children with severe malnutrition may develop intestinal dysfunction. This in turn limits nutrient absorption and weakens immunity, resulting in a complicated downward spiral of their condition.
”œA growing body of evidence suggests that impaired mitochondrial function in epithelial cells can disrupt intestinal barrier integrity.” – Ling et al., 2023
This study randomised eight mice to a low protein diet and eight mice to a normal protein diet to simulate severe malnutrition. Another group (n=8) were fed a low protein diet then given oral nicotinamide (water-soluble vitamin B3) supplementation from mid-way through the study. Diets were controlled for vitamin B3 to increase the validity of the study.
Additional experiments were conducted on low protein diet mice using injected resveratrol1 (n=6), injected EX-5272 plus nicotinamide (n=6), placebo injection (n=6), and nicotinamide-only (control) (n=6). Another study investigated normal protein diet mice (control) (n=6), low protein diet mice with injected rapamycin3 (n=8), and low protein diet mice plus placebo injection (n=6). For each mouse, multiple immunological, histological, and broader physiological tests were conducted.
Predictably, the low protein diet led to villus atrophy (reduced gut surface area), nutrient malabsorption, mitochondrial abnormalities, and intestinal barrier dysfunction. In these malnourished mice, nicotinamide supplementation increased mitophagy4 and improved intestinal barrier function. Rapamycin supplementation reduced intestinal barrier dysfunction and nutrient malabsorption.
Oral nicotinamide supplementation may be a more promising treatment for children with severe malnutrition as it is well tolerated and does not affect immune function – severe malnutrition often occurs in high infectious burden areas. By contrast, as an immunosuppressant, rapamycin may be less applicable for this population.
A note from the editors
This paper is highly technical, and the experiment was conducted on mice in a lab setting. The exact findings and methods used are therefore less relevant for practitioners working in the field. Although a full breakdown of pathways, mechanisms, timelines, and treatment protocols is beyond the scope of this summary, these details can be found in the original study. What this paper does highlight is that this specific intervention may offer an additional therapeutic target
1 Resveratrol is a readily available polyphenol supplement, often extracted from the skins of grapes and berries.
2 EX-527 is a selective sirtuin inhibitor drug.
3 Rapamycin is an immunosuppressant drug, commonly used to prevent organ transplant rejection. Recently, many researchers have focused on Rapamycin as a treatment to increase mitochondrial efficiency, which may exhibit numerous benefits for health and disease prevention.
4 Mitophagy is the removal of damaged mitochondria, increasing mitochondrial efficiency.