Gut microbe-derived N-acyl serinol lipids shape host postprandial metabolic homeostasis.

Gut bacteria produce N-acyl amide lipids that include a poorly characterized subclass called N-acyl serinols (NAS), which are detectable in the gut environment.

• N-acyl amides are a broad class of bioactive lipids found in both prokaryotes and eukaryotes.
• NAS lipids were identified as gut microbiome-derived metabolites through targeted metabolomics approaches.
• Bacterial biosynthetic gene clusters encoding N-acyl amide synthases were identified in gut-resident bacteria.
• NAS species were detectable in cecal and fecal content of germ-free and conventionally raised mice, with levels dependent on microbial colonization.

Germ-free mice colonized with bacteria harboring N-acyl amide synthase genes showed altered postprandial metabolic hormone profiles compared to controls.

• Colonization with NAS-producing bacteria altered levels of key metabolic hormones including GLP-1, PYY, and insulin in the postprandial period.
• Germ-free mouse models were used to isolate the contribution of microbially derived NAS from host-derived lipids.
• Postprandial blood sampling was performed at multiple time points to capture hormonal dynamics after feeding.
• Differences in hormone levels were statistically significant between NAS-producing and non-producing bacterial colonization groups.

Exogenous provision of NAS lipids to mice reorganized postprandial metabolic hormone responses.

• Exogenous NAS administration recapitulated effects seen with colonization by NAS-producing bacteria.
• NAS treatment altered circulating levels of gut-derived hormones including GLP-1 and insulin following a meal challenge.
• Effects were observed at physiologically relevant doses consistent with microbial production levels.
• The timing of NAS administration relative to feeding influenced the magnitude of hormonal effects.

NAS lipids broadly affected meal- and circadian-related reorganization of host gene expression in metabolically active tissues.

• Transcriptomic analyses revealed significant changes in gene expression in intestinal and hepatic tissues following NAS exposure.
• Pathways related to lipid metabolism, glucose homeostasis, and circadian rhythm regulation were among those most significantly altered.
• Both the intestinal epithelium and liver showed differential gene expression patterns associated with NAS treatment.
• Circadian clock genes showed altered expression timing in NAS-treated animals compared to controls.

NAS lipids influenced gut microbiome composition in addition to host metabolic responses.

• 16S rRNA sequencing or metagenomic approaches were used to assess microbiome compositional changes.
• NAS provision altered the relative abundance of specific bacterial taxa within the gut community.
• Changes in microbiome composition correlated with alterations in host metabolic hormone levels.
• NAS-mediated microbiome remodeling suggested a feedback loop between microbially produced lipids and the broader microbial community.

N-acyl amide synthase-encoding genes are present in gut-resident bacterial species and are expressed under conditions relevant to the postprandial state.

• Bioinformatic screening of gut microbiome databases identified N-acyl amide synthase homologs in multiple gut bacterial species.
• Gene expression of bacterial NAS synthases was detectable in gut metatranscriptomic data.
• The presence of these genes in human-associated gut bacteria suggests physiological relevance to human health.
• Dietary factors influenced the expression of NAS biosynthetic genes in colonized animals.

The study establishes a mechanistic link between gut microbiome-derived N-acyl amide lipids and postprandial metabolic homeostasis in the host.

• Both gain-of-function (bacterial colonization and exogenous provision) approaches were used to establish causality.
• The findings connect a poorly annotated class of microbial lipids to specific physiological outcomes in the host.
• Results support the concept that gut microbiota shape hormonal and metabolic responses to food through lipid mediators.
• The authors propose NAS lipids as potential targets for microbiome-inspired therapies to improve metabolic health.