By Andrea McBeth, ND

Welcome to our newest blog series: Metabolite of the Month.

Metabolite of the Month: Sphingolipids 

Chemistry has always been a love of mine and it is at the heart of Thaena®’s work. Our journey within the complex world of the human gut microbiome began with the early ponderings of what kind of power lay unknown in the chemistry of a healthy microbiome's metabolism. As time and research has evolved, a diverse array of bacterially derived metabolites, or postbiotics, have been shown to hold fascinating potential. These molecules are at the heart of understanding microbial influences on health, showcasing the intricate chemical dialogues that occur between us and our microbial organ systems. Uncoincidentally, these metabolites also happen to be at the heart of ThaenaBiotic® . 

Through this Metabolite of the Month series, we aim to shed light on the significance of these powerful chemical messengers, exploring one molecule or group at a time. In sharing about these metabolites, our goal is twofold: to marvel at the chemistry of microbial metabolites and to foster a deeper appreciation for their contributions to our health and well-being. If these blogs facilitate a better understanding of the excitement we have here at Thaena® and the potential we see with ThaenaBiotic® – both in the molecules we have identified and those we continue to explore – then we will consider this series a success!

March Molecule Group: Sphingolipids

Our first foray into this series focuses on sphingolipids. Sphingolipids are more than just a fun word to say, they are crucial structural components of cell membranes and vital signaling molecules within immune and metabolic pathways. 

My interest with sphingolipids was kindled by Dr. Elizabeth Johnson at a microbiome conference many years ago. The research she presented reviewed labeled molecules and their dissemination from microbes to host cells in animal models. Her research suggested that the microbiome could be a source of molecules that influence the body far beyond the gut, affecting the liver and metabolism. Her work was just the beginning of several years of research looking at sphingolipids and their role in immunity, metabolism, and disease. 

The human gastrointestinal tract, often dominated by bacteria in the Bacteroidetes phylum such as Bacteroides and Prevotella species, is thought to contain approximately 1 gram of sphingolipids at any given time, based on estimates of cell lipid content. This relatively large amount of sphingolipids highlights a potentially significant reservoir of these specialized and diverse molecules. Sphingolipids are an energetically expensive molecule for our cells to synthesize de novo, a fact that supports the hypothesis that the recycling of sphingolipids from our gut microbiota is a plausible and efficient biological strategy. 

Considering our long history of co-evolution with microbes, it's logical that complex molecules like sphingolipids transcend their roles beyond mere components of lipid membranes. Their structural diversity and peculiar traits, such as odd-chain lengths and branched alkyl chains, set bacterial sphingolipids apart from their mammalian counterparts. This complexity is a testament to the biochemical creativity fostered through our symbiotic relationship with our microbial organ system. It also hints at the sophisticated functions these molecules have assumed as messengers, facilitating a wide array of signals throughout the body. 

Research has illuminated how bacterial sphingolipids impact host lipid metabolism, liver function, and a pivotal role in sustaining immune equilibrium. Such findings underscore their broad systemic influence, extending well beyond the confines of gastrointestinal health, and reflect the intricate ways these evolved molecules contribute to maintaining health and navigating the complexities of disease processes.

Research Summaries

• Bioorthogonal labeling and sphingolipid tracking: A novel approach using bioorthogonal chemistry was employed to trace the transfer of specific bacterial sphingolipids from the gut microbiota to host tissues, including the liver. This method allowed for the detailed mapping of Bacteroides sphingolipid production and its impact on the host.
• Impact on hepatic metabolism: The study found that Bacteroides thetaiotaomicron-derived sphingolipids could ameliorate excess lipid accumulation in the liver, a condition known as hepatic steatosis. This suggests that certain bacterial sphingolipids play a protective role in liver health.
• Transfer of unique sphingolipids: Specifically, a unique bacterial sphingolipid was identified to be transferred from the gut microbiota to the liver, indicating a direct microbial contribution to host hepatic metabolism.
• Improvement of liver cell respiration: The addition of the identified sphingolipid to liver cells improved cellular respiration, suggesting that sphingolipid transfer to the liver could help maintain metabolic health under conditions of dietary stress.
• Modulation of host lipid metabolism: The production of sphingolipids by the gut microbiome was shown to influence host pathways related to lipid metabolism, indicating that bacterial metabolites can have systemic effects on the host's metabolic health.

• Bacteroides sphingolipids and host health: The study demonstrates that sphingolipids produced by Bacteroides species in the gut microbiome are essential for maintaining a symbiotic relationship with the host. A deficiency in these bacterial sphingolipids is associated with increased inflammation and correlates with IBD conditions.
• Impact on inflammatory markers: Patients with IBD showed a decrease in Bacteroides-derived sphingolipids but an increase in host-produced sphingolipids in their intestines. This imbalance suggests a link between the absence of microbial sphingolipids and the exacerbation of inflammatory responses.
• Genetic modification of Bacteroides: The creation of a sphingolipid-deficient Bacteroides strain allowed for direct examination of the role these lipids play in gut health. Colonization of germ-free mice with this modified strain resulted in intestinal inflammation, indicating the protective role of Bacteroides sphingolipids against inflammatory conditions.
• Lipidomic analysis: Through comprehensive lipidomic analysis, the study identified a variety of Bacteroides-derived sphingolipids, including ceramide phosphoinositol and deoxy-sphingolipids. These findings expanded the known repertoire of bacterial sphingolipids and highlighted their complexity and potential functions in the host.
• Correlation with human IBD: An analysis of IBD patient samples revealed lower levels of Bacteroides sphingolipids in those with the disease, negatively correlating with inflammation markers. This suggests that maintaining a healthy balance of microbial sphingolipids in the gut may play a role in managing or preventing IBD.

Conclusion

Our foray into the fascinating world of sphingolipids marks just the beginning Thaena®’s Metabolite of the Month series. We've unveiled just a few of the intricate roles these vital molecules play, bridging the dialogue between our microbiome and overall health, and hinting at the profound systemic influences they exert beyond the gut. The exploration of sphingolipids has opened a window into the complex biochemical networks that underscore our health, illustrating the potential for these microbial metabolites to contribute to our well-being in ways we're only just starting to understand.

As we continue to delve deeper into the molecular intricacies of the gut microbiome, our appreciation for the chemical dialogues between us and our microbial organ system only grows.

Please stay tuned for next month's installment of Metabolite of the Month, where we'll explore a new set of research and intrigue surrounding another group of postbiotics found in healthy human gut microbiomes. The journey ahead promises more revelations and insights into the complex interactions between our bodies and the microscopic worlds that thrive within us. Together, we'll continue to unravel the mysteries of the gut microbiome, each molecule at a time, expanding our horizon of knowledge and fostering a deeper connection to our inner microbial universe.

References

1. Johnson, E. L., Heaver, S. L., Waters, J. L., Kim, B. I., Bretin, A., Goodman, A. L., Gewirtz, A. T., Worgall, T. S., & Ley, R. E. (2020). Sphingolipids produced by gut bacteria enter host metabolic pathways impacting ceramide levels. Nature Communications, 11(1), 2471. https://doi.org/10.1038/s41467-020-16274-w  
2. Rohrhofer, J., Zwirzitz, B., Selberherr, E., & Untersmayr, E. (2021). The Impact of Dietary Sphingolipids on Intestinal Microbiota and Gastrointestinal Immune Homeostasis. Frontiers in Immunology, 12, 635704. https://doi.org/10.3389/fimmu.2021.635704  
3. Bai, X., Ya, R., Tang, X., & Cai, M. (2023). Role and interaction of bacterial sphingolipids in human health. Frontiers in Microbiology, 14, 1289819. https://doi.org/10.3389/fmicb.2023.1289819
4. Le, H. H., Lee, M.-T., Besler, K. R., & Johnson, E. L. (2022). Host hepatic metabolism is modulated by gut microbiota-derived sphingolipids. Cell Host & Microbe, 30(6), 798–808.e7. https://doi.org/10.1016/j.chom.2022.05.002 
5. Brown, E. M., Ke, X., Hitchcock, D., Jeanfavre, S., Avila-Pacheco, J., Nakata, T., Arthur, T. D., Fornelos, N., Heim, C., Franzosa, E. A., Watson, N., Huttenhower, C., Haiser, H. J., Dillow, G., Graham, D. B., Finlay, B. B., Kostic, A. D., Porter, J. A., Vlamakis, H., … Xavier, R. J. (2019). Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis. Cell Host & Microbe, 25(5), 668–680.e7. https://doi.org/10.1016/j.chom.2019.04.002