Guardians of Your Bodyguard


Breaking down the microbiology world one bite at a time

 Guardians of Your Bodyguard

A Case for Sphingolipids

Your body is guarded by your liver. When you eat a meal, all the stuff in your food, both good and bad, gets absorbed into your blood. Before the blood is transmitted to all the organs in your body, it first passes through the liver. Your liver does the job of patting down your blood to make sure that everything contained within it is safe for your body. It breaks down and balances nutrients obtained from your diet, while detoxifying the medications you take, making it easier for you to absorb all the things you need to keep you running. However, it doesn’t always function so perfectly. In a dentist-like fashion, your liver can get irritated if you eat too much sugar, which leads to a fatty liver. This condition involves a buildup of fat inside your liver, making it hard to perform its routine guardian duties.

However, the liver is not alone in its guardian-like tendencies. Our intestinal friends, our gut microbes, can influence how the liver does its job. But, how? When we eat a meal, we are unintentionally choosing what our microbes eat. This means that depending on our diet, our microbes receive different nutrients, which they can then convert into a variety of different molecules. These molecules can locally influence the gut, as well as enter our bloodstream to influence the rest of our bodies, making them ideal candidates to study how microbes can affect our health. Dr. Elizabeth Johnson, an Assistant Professor at Cornell University, is interested in one such class of molecules, the sphingolipids (SLs).

Figure 1. Structure of sphingolipids. Sphingolipids are made up of a sphingosine backbone attached to a fatty acid group. The R group varies and can be hydrogen, phosphorous or sugar molecules. In this pictorial representation, every point is an atom of carbon (figure made using Adobe Illustrator).

Sphingolipids are a class of lipids that comprise a sphingosine backbone attached to a fatty acid (Figure 1). In our bodies, SLs play roles ranging from regulating how our cells grow, move, and stick to each other, to influencing inflammation. Being such important molecules, they have been implicated in various diseases including neurodegeneration, metabolic disorders, cancers, immune dysfunction, and heart disease. SLs are produced by us, as well as by our gut bacteria, making them a fascinating target to study how the microbiome affects the host. In 2020, Dr. Johnson and her colleagues showed that the production of SLs by gut bacteria can alter SL levels in our livers. This interesting phenomenon warranted further investigation. In a recent paper by the Johnson Lab, the authors asked two questions: (1) Is the change in our liver SL levels caused by the transfer of bacterially produced SLs to our livers? and (2) How do microbiome-derived SLs affect our liver’s health?

A Novel Method Allows Detection

To answer their first question, the authors developed a novel method to measure the transfer of newly produced bacterial SLs from the gut to the liver. This method relies on culturing a bacterial species, Bacteroides thetaiotamicron, colloquially nicknamed B. theta, and allowing it to produce SLs in a test tube. The key to this method is that newly produced SLs are chemically attached to fluorescent molecules. Researchers feed these bacterial cultures to lab mice and measure whether fluorescence transfers into their organs. Fluorescence is thus a proxy for bacterially produced SLs, and its presence in the mouse is indicative of the transfer of these molecules from the gut. Using this method, the scientists identified that B. theta’s SLs indeed make it into the mouse liver! (Figure 2) To confirm that these molecules are SLs and not an artifact, they compared the observed fluorescence transfer to a culture of bacteria mutated such that they can no longer produce SLs. When cultures of this mutated bug were fed to mice, fluorescence detected in the mice was much weaker, indicating that it was in fact, B. theta’s SL production that led to this transfer. Using a range of involved chemical approaches, the authors identified that the specific SL being transferred into mouse livers is derived from homoserine, an amino acid that is not encoded by our DNA!

Figure 2. Transfer Detected. A novel method identifies the transfer of sphingolipids into the mouse liver. B. theta cultured in the lab produce SLs that are attached to fluorescent molecules. When mice are fed these bacteria, scientists can detect fluorescence in their livers (figure made using Bioicons and Adobe Illustrator)

Un-fattening the Fatty Liver

Revealing the identity of this mystery molecule was a big step, but figuring out why we should care about it is an even bigger one. To unravel how the liver is impacted by this molecule, the authors began by studying liver cells in their lab. They used a fatty liver model where liver cells are fed sugar and they consequently accumulate fat. Upon treatment with their favorite SL, the authors noticed that their fatty liver cells began to reverse the energy dysregulation caused by fat accumulation. This suggested that perhaps this bacterial molecule is improving liver metabolism when a sugary diet tries to ruin it. To confirm this observation, the scientists put their mice on a high sucrose diet to induce a fatty liver. Within a month of being on this candy diet, these mice showed fat accumulation in their livers. To determine whether our superhero sphingolipid helps these mice, the authors fed them either normal (“wild-type”) bacteria that produce SLs or mutant bacteria that cannot. Surprisingly, mice fed normal B. theta reversed their fatty livers! They showed a decrease in fat quantity and inflammation, indicating better health compared to their mutant bacteria-fed counterparts (Figure 3). These changes imply that bacterial sphingolipids can enter host livers and improve their metabolism. Even though there is a lot of work to be done to figure out exactly how the SL mediates positive effects on liver metabolism, this research shows one way in which our bacteria may help guard our guardians!

Figure 3. Sphingolipids guard our liver! Mice on a high-sugar diet develop a fatty liver. When fed normal, wild-type B. theta, this fatty liver improves significantly! When fed bacteria that cannot produce sphingolipids, the fatty liver stays the same, indicating that sphingolipid production is key to improving fatty livers (figure made using Bioicons and Adobe Illustrator).

Link to the original post: 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.

Featured image: Created by author using Adobe Illustrator.