Mapping the genetic landscape of microbial lipid transformation in the intestinal microbiome

Dietary lipids are a key component in our diet, and fats and their derivatives have been associated with both beneficial as well as adverse effects on host health. However, the contribution of the gut microbiome to lipid metabolism remains understudied. Recognizing the importance of this interplay, we conducted extensive literature reviews to identify key bacterial genes involved in lipid metabolism, and created 88 Hidden Markov Models to allow rapid and accurate identification of these genes in genome and metagenome data. We applied these models to over 1000 metagenomes representative of the small intestine and colon, from both population-based and disease cohorts (LLDeep, MetaCardis and 1000IBD) to determine their lipolytic capacity. We observed that microbiome community types (enterotypes) carry different lipolytic potential. Serum levels of conjugated and sulfonated secondary bile acids were significantly associated with increased abundance of sterol-sulfonation genes (cysC, cysD and BtSULT). Small-intestinal communities were enriched in lipid genes compared to the colonic microbiota, underscoring the importance of microbial lipid metabolism in the small intestine compared to the colon. Overall, we demonstrate the value of our lipid metabolism models for functional microbiome profiling. Additionally, our study suggests that microbial activity in the upper gut might play a direct role in shaping host lipid metabolism, with potential implications for cardiometabolic health.