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.
The main findings of the study, published in Cell, were:
- 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.
- The distribution pattern of these molecules varies based on diet, microbial colonization, and in people with diseases that impact the microbiome, such as diabetes.
"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."
Link to full study: https://doi.org/10.1016/j.cell.2025.05.015
Additional co-authors of the study include Vincent Charron-Lamoureux, Martijn van Faassen, Santosh Lamichhane, Wilhan D. Gonçalves Nunes, Victoria Deleray, Adriana V. Ayala, Yuichiro Tanaka, Abubaker Patan, Kyle Vittali, Prajit Rajkumar, Yasin El Abiead, Haoqi Nina Zhao, Paulo Wender Portal Gomes, Ipsita Mohanty, Carlynda Lee, Aidan Sund, Meera Sharma, Yuanhao Liu, David Pattynama, Gregory T. Walker, Grant J. Norton, Lora Khatib, Mohammadsobhan S. Andalibi, Crystal X. Wang, Ronald J. Ellis, David J. Moore, Jennifer E. Iudicello, Donald Franklin, Jr., Scott Letendre, Loryn Chin, Corinn Walker, Simone Renwick, Jasmine Zemlin, Michael J. Meehan, Jane J. Kim, Manuela Raffatellu, Lars Bode, Hiutung Chu, Karsten Zengler, Dionicio Siegel and Rob Knight at UC San Diego, Xinyang Song and Dennis Kasper at Harvard Medical School, Zachary Burcham at University of Tennessee Knoxville, Sejal Kadakia at Children's Hospital of Orange County and Mingxun Wang at UC Riverside.
The study was, in part, supported by the National Institutes of Health (grants R01DK136117, U24DK133658, P30MH062512, F32AT011475, P50HD106463, UL1TR001442, R37AI126277, R37AI126277 and F31AI186410), the National Science Foundation (award 2152526), the National Key R&D Program of China (grants 2022YFA0807300 and 2023YFA1800200, NSF of China (grant 32270945), the Science and Technology Committee of Shanghai Municipality (grants 22ZR1468700, and 22140902400), the Research Counvil of Finland (grant 363417) and a UC San Diego Microbiome Seed Grant.
