Gut microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) inhibits weight gain and is negatively associated with childhood obesity.

BACKGROUND: Childhood obesity has rapidly increased, becoming a significant global public health concern. Obese children exhibit distinct gut microbiome compositions compared to their normal-weight peers, leading to differences in the metabolic products derived from gut microbiota between the two groups. However, the causal relationship between these microbial-derived metabolites and childhood obesity remains unclear. Therefore, we investigate association between the microbial-derived metabolites and childhood obesity. METHODS: In this study, we conducted an analysis of multiple childhood obesity gut microbiota databases. We utilized curated children's microbiota data at the genus level from the GMrepo database. To investigate metabolic pathways, we used the MetOrigin database to analyze the gut microbiota metabolites. RESULTS: We found that the abundances of Prevotella, Sutterellaceae, Lachnospiraceae, Veillonellaceae, Streptococcaceae, Fusobacteriaceae, and Klebsiella were increased in the gut microbiome of obese children, while Akkermansia, Faecalibacterium, Porphyromonadaceae, Rikenellaceae, Eubacteriaceae, Odoribacter, and Erysipelotrichaceae were decreased compared to their normal-weight counterparts. Furthermore, the gut microbial metabolites acetic acid, propionic acid, and butyric acid were elevated in the feces of obese children, while 4-hydroxyphenylacetic acid (4-HPAA), valeric acid, and lactic acid were decreased in the feces or urine of obese children. Trace analysis and literature review revealed that Eubacteriaceae produces 4-HPAA via the tyrosine metabolism pathway, while Bacteroides generates lactic acid through glycolysis, gluconeogenesis, and pyruvate metabolism pathways. Notably, 4-HPAA treatment reduced weight gain and improved glucose intolerance in mice on a high-fat diet. CONCLUSIONS: Our study analyzed the gut microbiota characteristics of obese children across multiple regions and suggests that the downregulation of 4-HPAA may be associated with the development of obese children.