🧫 Mastering the Microbiome 7/28/25
Bacterial sphingolipids lower intestinal inflammation
Featured Article
Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway [Brown et al., 2025]
🎯 Research Goal
Fat molecules called sphingolipids are important for human health. These sphingolipids are key components of cell membranes - and also serve as signaling molecules. Altered sphingolipid accumulation and metabolism have been linked to a variety of human diseases, from metabolic disorders to Alzheimer’s. Sphingolipids are produced in human cells, but also by bacteria in the gut microbiome (namely Bacteroides species like B. fragilis and B. thetaiotaomicron), and though less well studied, bacterial sphingolipid production appears to have a significant clinical impact. Researchers have shown, for example, that Bacteroides sphingolipid production is lower in people with inflammatory bowel disease (IBD), and that people with relatively higher levels of Bacteroides sphingolipid production tend to experience lower levels of inflammation. How exactly these bacterial sphingolipids are being transported to human cells, and what affects they are having, are still open questions. Their answers could lead to new therapeutic interventions for people with IBD and other inflammatory diseases.
📑 Past Work
In the last half of the 20th century, researchers discovered that bacteria spit out small spherical pockets of their cell membranes called outer-membrane vesicles (OMVs). OMV production has been demonstrated in a variety of different bacterial species (including Bacteroides and other bacteria normally found in the human gut microbiome). We know that these OMVs contain a variety of physiologically relevant molecules - including bacterial DNA, proteins, metabolites, and lipids. In this edition’s featured study, the researchers explored how Bacteroides OMVs deposit sphingolipids inside of host immune cells, and studied the effects of these deposited sphingolipids on the inflammatory response.
🔑 Key Findings
First, the researchers showed that OMVs from the common gut bacterial strain B. thetaiotaomicron (B. theta) contain a variety of sphingolipids molecules - including compounds called ceramides. Altered ceramide levels specifically have been linked to human disease.
Then, they showed that these OMVs can enter host cells and deposit these sphingolipids. Two kinds of cells - a mouse dendritic cell line and a human colon cancer cell line - where treated with OMVs from B. theta. Dendritic cells are particualrly relevant to the inflammatory repsonse - they are immune cells found in the gut that play a key role in detecting pathogens and stimulating other immune cells like T cells.
Host cells already produce a lot of sphingolipids on their own - and therefore the researchers saw that most sphingolipid compounds were not significantly elevated after treatment with OMVs. Levels of certain sphingolipids however, such as the ceramide CerPE, were significantly elevated.
After treatment, the researchers tracked the concentration of bacterial sphingolipids in the cell lines over time and found that many of them remained present after 24 hours at relatively high levels. This suggests that they could have a lasting effect on cell function.
After the cell line experiments, the researchers performed additional studies in mice - showing that CerPE and other Bacteroides sphingolipids were taken up by cells in the colon.
Finally, the researchers investigated how these sphingolipids could impact host cells - treating dendritic cells with B. theta OMVs and analyzing changes in gene expression.
They found that production of the anti-inflammatory cytokine IL-10 was elevated. Cytokines are signaling molecules produced and exchanged between immune cells - allowing one cell to influence the activity of another. This finding suggests that bacterial sphingolipids could play a role in limiting excessive inflammation.
🩺 Clinical Potential
Given the influence of OMVs and sphingolipids on immune cell function, there is interest in using OMVs as therapeutic agents. It might be possible to introduce OMV-producing strains into the gut, or administer OMVs on their own, to achieve a more healthy inflammatory state. The success of these therapeutic efforts depend, however, on further study of the sphingolipid molecules that contribute to the anti-inflammatory effect. The ceramide CerPE appears to play an important role, but this research doesn't discount the possibility that other sphingolipids and non-sphingolipid compounds could influence IL-10 production. There is also the issue of making sure that these therapeutic OMVs are potent enough to have a therapeutic effect. There are a variety of approaches in development to engineer OMV-producing strains or the OMVs themselves to contain desired types of molecules at therapeutic concentrations.
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