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Longitudinal Effects of Growth Restriction on the Murine Gut Microbiome and Metabolome.

Undernutrition induced growth restriction in early life increases the risk of chronic disease in adulthood. While 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 for gut microbiome and metabolome analyses. PUN mice exhibited the most alterations in gut microbiome and gut and liver metabolome compared to CON. These mice had altered fecal microbial Beta-Diversity (p=0.001) and exhibited higher proportions of Bifidobacteriales (Linear Mixed Model (LMM) p=7.158x10-6), Clostridiales (p=1.459x10-5), Erysipelotrichales (p=0.0003) and lower Bacteroidales (p=4.121x10-5). PUN liver and fecal metabolome had a reduced total bile acid pool (p<0.01), as well as lower 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), dipeptides (p=0.001), and tripeptides (p=0.0123) compared to CON. PUN also had abnormally reduced Epiandrosterone (p=0.02) at PN80. PUN liver and fecal metabolome varied in specific acylcarnitines: higher liver oleoyl-L-carnitine (p=0.0038) and palmitoylcarnitine (p=0.0096) vs. CON at PN21, which recovered at PN80. However, PUN also had higher fecal R-ButyrylCarnitine (p=0.0125) through adulthood, despite refeeding. Overall, protein restriction during lactation permanently alters the gut microbiome into adulthood. While the liver bile acids, amino acids, and acylcarnitines 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.