Bariatric procedures such as sleeve gastrectomy (SG) induce weight-loss–independent changes in the gut microbiome that are associated with improved metabolic phenotypes. Cecal microbiome transplant (CMT) from post-SG donors confers beneficial effects on adiposity in germ-free (GF) recipients, though the microbial features underlying these effects remain incompletely understood. Here, we investigated whether perturbation of SG-derived microbial communities alters the conservation and mechanism of these phenotypes.
Second-generation GF recipients of SG-derived CMT treated with the macrolide antibiotic tylosin exhibited enhanced improvements in adiposity relative to water-treated controls, indicating that specific antibiotic-selected microbial configurations retain and amplify metabolic benefits. To identify microbial outputs linking community structure to host phenotype, we performed untargeted metabolomic profiling and observed enrichment of microbially associated 3-hydroxy fatty acids (3-OH FAs) in tylosin-treated CMT recipients.
In vitro exposure of 3T3-L1 adipocytes to representative 3-OH FAs reduced lipid droplet accumulation by ~40% without impairing adipocyte differentiation, PPARγ signaling, or cell viability. Transcriptomic analysis revealed early suppression of lipid uptake and storage pathways, followed by gene expression changes consistent with changes in FA uptake, mitochondrial remodeling and altered redox activity. These changes occurred without activation of cell death pathways.
Our findings support a model in which antibiotic-selected post-SG microbiomes enrich microbial lipid metabolites that remodel adipocyte metabolism through non-cytotoxic mitochondrial and cellular reprogramming and suggests a role for microbiome-derived 3-hydroxy fatty acids in mediating reduced adiposity following bariatric surgery.