Microbial-Derived Metabolites Reflect an Altered Intestinal Microbiota during Catch-Up Growth in Undernourished Neonatal Mice

Abstract

Background: Protein-energy undernutrition during early development confers a lifelong increased risk of obesity-related metabolic disease. Mechanisms by which metabolic abnormalities persist despite catch-up growth are poorly understood.Objective: We sought to determine whether abnormal metabolomic and intestinal microbiota profiles from undernourished neonatal mice remain altered during catch-up growth.Methods: Male and female CD1 mouse pups were undernourished by timed separation from lactating dams for 4 h at 5 d of age, 8 h at 6 d of age, and 12 h/d from 7 to 15 d of age, then resumed ad libitum nursing, whereas controls fed uninterrupted. Both groups were weaned simultaneously to a standard unpurified diet. At 3 time points (0, 1, and 3 wk after ending feed deprivation), metabolites in urine, plasma, and stool were identified with the use of mass spectrometry, and fecal microbes were identified with the use of 16S metagenomic sequencing.Results: Undernourished mice completely recovered deficits of 36% weight and 9% length by 3 wk of refeeding, at which time they had 1.4-fold higher plasma phenyllactate and 2.0-fold higher urinary p-cresol sulfate concentrations than did controls. Plasma serotonin concentrations in undernourished mice were 25% lower at 0 wk but 1.5-fold higher than in controls at 3 wk. Whereas most urine and plasma metabolites normalized with refeeding, 117 fecal metabolites remained altered at 3 wk, including multiple N-linked glycans. Microbiota profiles from undernourished mice also remained distinct, with lower mean proportions of Bacteroidetes (67% compared with 83%) and higher proportions of Firmicutes (26% compared with 16%). Abundances of the mucolytic organisms Akkermansia muciniphila and Mucispirillum schaedleri were altered at 0 and 1 wk. Whereas microbiota from undernourished mice at 0 wk contained 11% less community diversity (P = 0.015), refed mice at 3 wk harbored 1.2-fold greater diversity (P = 0.0006) than did controls.Conclusion: Microbial-derived metabolites and intestinal microbiota remain altered during catch-up growth in undernourished neonatal mice.