Multi-omics Reveals Different Signatures of Obesity-Prone and Obesity-Resistant Mice. Mus musculus musculus

Metabolic phenotypic disparities between obesity-prone (OP) and obesity-resistant (OR) individuals are closely linked to nutrient absorption and utilization. However, the influence of host-microbiota interactions on these metabolic phenotypes remains unknown.We performed an integrative multi-omics analysis in high-fat diet (HFD)-fed OP and OR mice and analyzed gut microbiota variations in humans. Longibaculum and Kineothrix were the keystone bacteria involved in gut microbiota dynamics in OP and OR mice, respectively. Eight, stably present, dominant bacterial genera were significantly associated with bile acid metabolites and amino acids. Three bacterial genera were validated in humans with OR and were positively correlated with genes that maintain intestinal barrier function. Twenty-two specific amino acid profiles could serve as biomarkers for obesity susceptibility. Ten non-12-OH bile acids were highly expressed in OR mice. In vivo mouse experiments demonstrated that ursodeoxycholic and hyodeoxycholic acids reduced HFD-induced obesity by elevating Col6a3 levels. Moreover, OP mice exhibited abnormal intestinal cell adhesion, associated with the proliferation of harmful bacteria, whereas OR mice exhibited eight driver genes protecting intestinal barrier function.These results underscore host-microbiota interactions contributing to phenotypic differences between OP and OR. The driving role of beneficial cornerstone bacteria; the contribution of non-12-OH bile acid metabolites to increased intestinal barrier stability, forming an obesity-resistant phenotype; the community effect of harmful bacteria; and the imbalance of amino acid profiles involved in intestinal mucosal barrier disruption were closely associated with obesity susceptibility. Our findings may help identify crucial intestinal markers associated with obesity, aiding in the development of strategies for obesity treatment and prevention.