In our paper, recently published in Nature Communications, we (my colleagues at the Boyce Thompson Institute and Cornell University) demonstrated that a specific type of bacteria-derived fatty acid – so-called cyclopropane fatty acids, which are also part of the human diet – has a major impact on fat metabolism in the host animal. Using the nematode C. elegans as a model system, we found that dietary bacteria and the host animal contribute to the production of two chemically related signaling molecules that control fat metabolism via the same pathway. We further show that the animal likely acquired the ability to make its own version of this signaling molecule by acquiring a gene from bacteria, essentially mimicking the bacterial biochemistry.
First, we showed that abundant bacterial cyclopropane lipids are precursors to a β-cyclopropyl fatty acid that we named becyp#1. The bacteria-derived becyp#1 activates the nuclear receptor, NHR-49/PPARα, in the host animal, which in turn controls the expression of genes that regulate fatty acid desaturation, highlighting a direct influence of microbiota-derived metabolites on host lipid metabolism.
In parallel to the microbial pathway, we found that the animal itself produces a structurally similar β-methyl fatty acid that we named bemeth#1. Like the bacterial becyp#1, this compound also activates NHR-49/PPARα and regulates the same fatty acid desaturation pathway. Intriguingly, the enzyme that produces bemeth#1, which we named fatty acid C–methyltransferase (fcmt-1), is highly similar to the bacterial cyclopropane-forming enzyme. Through phylogenetic analysis, we posit that fcmt-1 was likely acquired through horizontal gene transfer (HGT), a process in which an organism incorporates genetic material from another organism without being its offspring. While both becyp#1 and bemeth#1 act as agonists of NHR-49, they are metabolized differently by the animal, indicating separate regulatory mechanisms.
This research sheds light on the interplay between host metabolism and the external environment, with a focus on the role of microbiota-derived metabolites in host physiology. The findings provide insights into how gene expression related to fatty acid metabolism is regulated in C. elegans, a popular model organism often used to study human biology. The concept that microbiota-derived molecules can influence host lipid metabolism suggests promising avenues for understanding and potentially treating metabolic disorders in humans. Further research could explore whether similar regulatory mechanisms operate in humans – notably, cyclopropyl lipids are present in the modern human diet.
In summary, this paper provides compelling evidence of the intertwined nature of host and microbiota metabolism, specifically in the context of fat desaturation. The evidence that fcmt-1 was acquired from bacteria via HGT suggests an ancient origin for microbial regulation of nematode fat metabolism. Parallel regulation of a nuclear receptor by both microbiota-derived and endogenously produced β-branched fatty acids highlights the biochemical complexity of metabolic regulation. This study contributes to our understanding of fundamental biological processes and opens avenues for future research into lipid metabolism and its impact on health.