Longitudinal effects of growth restriction on the murine gut microbiome and metabolome

Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (postweaning week 1) until PN80 (postweaning week 5) for gut microbiome and metabolome analyses. PUN mice exhibited the most alterations in gut microbiome and gut and liver metabolome compared with CON mice. These mice had altered fecal microbial β-diversity (P = 0.001) and exhibited higher proportions of Bifidobacteriales [linear mixed model (LMM) P = 7.1 × 10^-6), Clostridiales (P = 1.459 × 10^-5), Erysipelotrichales (P = 0.0003), and lower Bacteroidales (P = 4.1 × 10^-5)]. PUN liver and fecal metabolome had a reduced total bile acid pool (P < 0.01), as well as lower abundance of riboflavin (P = 0.003), amino acids [i.e., methionine (P = 0.0018), phenylalanine (P = 0.0015), and tyrosine (P = 0.0041)], and higher excreted total peptides (LMM P = 0.0064) compared with CON. Overall, protein restriction during lactation permanently alters the gut microbiome into adulthood. Although the liver bile acids, amino acids, and acyl-carnitines recovered, the fecal peptides and microbiome remained permanently altered into adulthood, indicating that inadequate protein intake in a specific time frame in early life can have an irreversible impact on the microbiome and fecal metabolome.NEW & NOTEWORTHY Undernutrition-induced early-life growth restriction not only leads to increased disease risk but also permanently alters the gut microbiome and gut-liver metabolome during specific windows of early-life development.