Caloric Restriction, Friend or Foe: Effects on Metabolic Status in Association with the Intestinal Microbiome and Metabolome.

Abstract

Daily calorie restriction (CR) has shown benefits on weight loss and alleviation of metabolic disorders. We investigated the effects of three CR regimens, i.e., 20% (CR-20), 40% (CR-40), and 60% (CR-60) less than the average daily calorie intake, respectively, on the metabolic parameters, gut microbiome composition, and its related metabolites in healthy mice. Compared with mice fed ad libitum (AL), CR dose-dependently reduced the body weight, and weights of liver and epididymal adipose tissues, and enhanced the insulin sensitivity, glucose tolerance, and lipid homeostasis. Moreover, expression levels of intestinal tight junction proteins (i.e., ZO-1, claudin, and occludin) were significantly promoted by CR than those of AL mice, demonstrating the CR-induced improvement of the intestinal barrier integrity. CR contributed to the enrichment of beneficial microbiota (e.g., Lactobacillus, Bacteroides, and Akkermansia) and increased propionic acid levels. Notably, CR-60 deleteriously caused liver injury, and enhanced hepatic inflammatory cytokines (i.e., IL-1, IL-6, and TNF-α) and lipopolysaccharides, which were accompanied by high levels of trimethylamine (TMA) and trimethylamine oxide (TMAO) in relation to CR-60-altered gut microbiota structure and fecal metabolome. Additionally, we found differential impacts of CR-20, -40, or -60 on amino acid absorption and metabolism. Our findings support the health-promoting benefits of 60-80% daily calorie intake on the metabolic status by regulating the gut microbiota in healthy mice. However, excessive CR caused liver injury and gut microbiota-dependent elevation of TMAO. The differential effects of CR regimens on the intestinal microbiome and fecal metabolome provide novel insights into the dietary pattern-gut microbiome interactions linked with host metabolism.