Multi‐omics reveals different signatures of obesity‐prone and obesity‐resistant mice

Obesity-prone (OP) and obesity-resistant (OR) individuals demonstrate significant metabolic differences, potentially influenced by variations in the gut microbiome. However, the influence of host-microbiota interactions on obesity susceptibility remains unknown. We performed an integrative multi-omics approach to explore microbial, metabolic, and genetic differences in high-fat diet (HFD)-fed OP and OR mice, with additional analyses of gut microbiota variations in humans. In OP mice, the dynamic gut microbiota was characterized by a stable presence of <i>Longibaculum</i>, while <i>Kineothrix</i> predominated in OR mice. We termed both as keystone bacteria. Beyond these, eight dominant bacterial genera were significantly associated with bile acid metabolites and amino acids. Three of these genera were also identified in OR humans and showed positive correlations with genes that may support intestinal barrier function. We identified 22 specific amino acid profiles as potential biomarkers for obesity susceptibility, along with significantly increased levels of ten non-12-OH bile acids in fecal of OR mice. In vivo, mouse experiments demonstrated that ursodeoxycholic and hyodeoxycholic acids could reduce HFD-induced obesity. Additionally, the colon of OP mice displayed a higher presence of inflammatory cells. These findings suggest that host-microbiota interactions may contribute to phenotypic differences between OP and OR. Our study offers insights into crucial intestinal markers associated with obesity, providing a valuable resource for advancing the understanding of obesity-prone and obesity-resistant phenotypes.