Hundreds of new N-acyl lipids identified, expanding the dictionary of human metabolism

Human metabolism is a complex web of chemical processes and interactions between our cells and the microbes living within us. The more scientists can identify and classify the molecules involved in our metabolism, called metabolites, the more we can learn about human health and disease. Now, researchers at University of California San Diego have made a major advance in our understanding of human metabolism by describing hundreds of new N-acyl lipids, a type of molecule involved in immune and stress responses.

In their study, published in Cell, the researchers identified 851 distinct N-acyl lipids across various tissues and biofluids, 777 of which had never been documented before. Many of these new metabolites may originate from human gut microbes.

“Metabolites are the language that the body uses to communicate with itself and with our microbiome, and studying them can offer significant insight into the role of microbial metabolism in health and disease,” said senior author Pieter Dorrestein, Ph.D., professor at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and Departments of Pharmacology and Pediatrics at UC San Diego School of Medicine. “It’s like we’ve added hundreds of new words to the metabolic dictionary.”

Human metabolism is a delicate system, and imbalances in metabolism have been linked to a wide range of diseases, including diabetes, cancer and neurological disorders. For decades, much of the underlying biochemistry of human metabolism, including the role of the human microbiome, has gone unknown, making it harder to understand and treat diseases related to metabolism.

The hundreds of new compounds help fill this knowledge gap.

“The big surprise here was how diverse this group of compounds actually is,” said first author Helena Mannochio Russo, Ph.D., a postdoctoral researcher in Dorrestein’s lab.

Within the previously unknown molecules, the researchers found that many were found in the digestive tract and contained short-chain fatty acids, a known hallmark of microbial metabolism. The distribution pattern of these molecules also varied based on diet, microbial colonization, and in people with diseases that impact the microbiome, such as diabetes. Together, these findings suggest that the newly-identified metabolites are produced by the human microbiome.

The researchers also found that these microbial metabolites were associated with HIV status and cognitive impairment, suggesting a potential link between the gut microbiome and neurological function in individuals with HIV. However, it will take more research to fully understand the implications of this connection of the gut microbes language and how they affect cognition.

“There’s so much we can learn from existing data, and the more we utilize reverse metabolomics, the more we’ll be able to learn about how the microbiome interacts with us and impacts our health, and the faster we’ll be able to learn from it,” added Mannochio Russo. “This is just the beginning.”