Bacteria on a gut membrane releasing signaling lipids that interact directly with cell mitochondria.
Image Credit: Scientific Frontline / AI generated
Scientific Frontline: Extended "At a Glance" Summary: Microbiome-Derived Glycine Lipids
The Core Concept: Microbial glycine lipids are biologically active molecules produced by Bacteroidota species in the human gut and mouth. Contrary to expectations that bacterial lipids provoke inflammation, these specific lipids circulate systemically to improve mitochondrial function and actively mitigate metabolic diseases.
Key Distinction/Mechanism: While many bacterial lipids trigger disease-causing inflammatory responses, specific microbial glycine lipids (such as L654 and L1256) act as therapeutic signals. They are absorbed through the portal vein and lymphatic system, where they enhance mitochondrial respiration, upregulate fat oxidation, and suppress liver inflammation.
Origin/History: In 2022, an interdisciplinary team from the University of Connecticut and the University of Pittsburgh published initial findings that these lipids exhibit immunosuppressive effects against atherosclerosis and liver inflammation, paving the way for recent discoveries regarding their systemic mitochondrial benefits.
Major Frameworks/Components:
- Lipid 1256 (L1256) and Lipid 654 (L654): Specific bacterial lipids that attenuate disease severity in metabolic-dysfunction steatotic liver disease (MASLD).
- Dietary Fiber Modulation: High-fiber interventions (utilizing pea and citrus peel fiber) directly stimulate the microbiome's production of beneficial glycine lipids.
- Mitochondrial Biogenesis: The physiological process enhanced by these lipids in both liver and skeletal muscle tissue to protect against metabolic stress.
- Dual Absorption Pathways: The routes through which microbial lipids travel from the gastrointestinal tract to the rest of the body via portal blood and intestinal lymph.
Branches of Science: Microbiome Therapeutics, Molecular Nutrition, Hepatology, Cellular Metabolism, Molecular Immunology.
Future Application: The development of precise, fiber-based dietary interventions or direct microbial lipid supplements to reverse mitochondrial dysfunction and treat MASLD in human patients.
Why It Matters: Metabolic-dysfunction steatotic liver disease affects approximately 30% of adults and currently has extremely limited therapeutic options. Harnessing microbiome-derived lipids offers a novel, nutrition-based strategy to combat chronic liver disease and systemic metabolic dysfunction.
An interdisciplinary team of researchers from UConn and the University of Pittsburgh is filling knowledge gaps about the surprising roles that our microbiomes play in our health.
The team’s recent studies, published in Gastro Hep Advances and the Journal of Physiology, focus on Bacteroidota species that grow in our guts and mouths, where they produce glycine lipids that interact with our metabolism. The researchers found that microbiome-derived glycine lipids circulate systemically and improve mitochondrial function, which may prevent the progression of metabolic-dysfunction steatotic liver disease (MASLD) and regulate mitochondrial functioning in skeletal muscle tissue.
While lipids produced by bacteria are usually associated with disease-causing processes, in 2022, members of the team—including Dr. Frank Nichols, professor of periodontology in the UConn School of Dental Medicine; Dr. Robert Clark, professor in the Department of Immunology in the UConn School of Medicine; and Christopher Blesso, associate professor in the Department of Nutritional Sciences—published their findings showing that these lipids acted as signals with an immunosuppressive effect on the development of atherosclerosis and liver inflammation.
“Based on previous research, we expected that microbial glycine lipids would be pro-inflammatory and they’d worsen the disease. What we saw was the opposite, and that surprised us,” says Blesso.
To look closer at the impacts on the liver, the researchers focused on the glycine lipids' influence on MASLD. MASLD is an extremely common form of liver disease, impacting around 30% of the adult population, and the treatment options are unfortunately limited.
Using a chronic liver disease mouse model, the researchers induced the progression of MASLD by feeding mice a high-fat, high-sugar diet simulating a typical Western diet. The mice gained weight, accumulated fat in their livers, and developed inflammation, Blesso explains. Then, the researchers administered one of two microbial glycine lipids of interest.
“[In our previous research,] lipid 654 (L654) attenuated some of the liver injury, and then this other lipid is the newest lipid that Frank Nichols has identified, called lipid 1256 (L1256), that is more potent—at least in vitro—than L654,” says Blesso. “The mice were getting one-microgram injections every other day for eight weeks, and then we looked at the disease process.”
Looking at the morphology and histopathology of the liver samples with the help of Neha Mishra, associate professor in the Department of Pathobiology and Veterinary Science, they determined that both L654 and L1256 significantly attenuated disease severity. The researchers also measured gene regulation and found an enhancement of genes that control mitochondria biogenesis and fat oxidation, which helped protect against the progression of MASLD.
“We found that if you deplete the exposure to these microbial glycine lipids, it enhances inflammation,” says Blesso. “If you inject the animals with these lipids, it brings it back down to healthy levels.”
Blesso says that in the 2022 study, they also found that diet was a strong modulator of the levels of glycine lipids produced by the microbiome, and they wanted to understand what causes the changes when the diet is switched from a healthier diet to a Western-type diet. The researchers determined that fiber was an unsurprising key driver of differences in the microbial glycine lipids between the groups.
“We did a combo of pea fiber and citrus peel fiber,” says Blesso. “I thought that would bring those glycine lipid levels back up, or the microbiome production would be rescued.”
The results confirmed Blesso’s hunch, because the high-fiber diet raised microbiome glycine lipid levels, showing a promising nutrition-based approach for reversing liver inflammation and another intervention for the condition, which has few treatment options available. The Blesso lab is exploring whether different types of fiber are more beneficial than others. Blesso says they are also starting a fiber intervention study in humans to examine the effects of fiber supplementation and see if it changes glycine levels.
Next, they wanted to understand how these microbial glycine lipids are absorbed and circulate throughout the body. Blesso explains that these lipids are produced by microbes in the mouth and in the gut. In the gut, there are two potential pathways through which they can travel to the rest of the body. One is through the liver via the portal vein, and another is through the lymphatic system, where they can circulate throughout the body; however, Blesso notes that eventually, most lipids are cleared by the liver.
Ji-Young Lee, former professor in the Department of Nutritional Sciences, and Young-Ki Park, assistant research professor from the NutriPrevention of Obesity, Inflammation, and Liver Disease (NP-OILD) Lab—both now at the University of Maryland—provided samples of portal blood, and University of Pittsburgh researcher Alison Kohan provided samples of intestinal lymph. Using mass spectrometry, Nichols and Anthony Provatas, assistant research professor in the Department of Chemistry and the Center for Environmental Sciences and Engineering (CESE), detected the lipids in both sample types, showing that the microbial glycine lipids are absorbed via both gastrointestinal routes.
Blesso says the NP-OILD also examined liver cell mitochondria function in vitro. Cells that were repeatedly exposed to microbial glycine lipids showed improved mitochondrial functioning overall.
The researchers also looked at human liver tissue samples from the UConn Health Research Biorepository to see if the microbial glycine lipids were present and to determine whether the mouse results could be translatable to humans.
“The lipids are detected in human liver. That shows that there’s likely some relevance to the human disease; we’ll have to look to see if there are differences in diseased patients versus healthy patients,” says Blesso.
An additional aspect of the research, led by Oh Sung Kwon, associate professor in the Department of Kinesiology, examined the effects of microbial glycine lipids on mitochondrial function in skeletal muscle tissue. The researchers studied oxidative phosphorylation, the process by which mitochondria—often called the cell’s powerhouses—produce energy in the tissue. A Western diet can disrupt mitochondrial function and contribute to metabolic stress in muscle tissue. Kwon was interested in whether microbial glycine lipids could support mitochondrial function and influence markers involved in mitochondrial biogenesis and quality control.
“Skeletal muscle plays a major role in how the body uses fat and other fuels,” says Kwon. “We wanted to understand whether these microbial lipids could influence how muscle mitochondria respond to the metabolic stress of a Western diet.”
In male mice fed a Western diet for eight weeks, L1256 accumulated in skeletal muscle and improved mitochondrial respiration supported by fatty acids, a measure of the mitochondria’s capacity to use fat as fuel. It also increased proteins involved in mitochondrial energy production and antioxidant defense and helped preserve muscle fiber size. L654 influenced gene expression and inflammatory signaling, but it did not produce comparable improvements in mitochondrial respiration.
“These findings suggest that the microbiome may influence muscle health through the lipids its bacteria produce,” says Kwon. “L1256 stood out because its effects extended beyond inflammatory signaling to how muscle mitochondria use fuel. The next question is whether similar responses occur in humans.”
Blesso hopes to continue investigating the influences of different types of fiber on the microbiome and on microbial glycine lipid production.
“Previously, we just looked at the immune effects, but now this mitochondrial story is evolving and opens a wide range of models where we can look at different disease states related to mitochondrial dysfunction and see how these microbial lipids affect them,” says Blesso. “Hopefully, we can do some human studies where we give them these different fiber types and see which has the best effect on the glycine lipids. In a nutshell, there’s a lot to the story. It’s evolving. Funding and time are the biggest limitations because there are so many questions that we need to ask.”
Published in journal:
- Journal of Physiology
- Gastro Hep Advances
Title:
- Bacteroidota-derived glycine lipids differentially regulate skeletal muscle mitochondrial adaptation during Western diet feeding in male Ldlr−/− mice
- Fiber-Dependent Microbiome Glycine Lipids Ameliorate Steatotic Liver Disease in Mice via Mitochondrial Enhancement
Authors:
- Siyun Kim, Sung Gi Noh, Minje Ji, Tomas Vence, Lidan Gao, Oliver Otoko, Frank C. Nichols, Christopher N. Blesso, and Oh Sung Kwon
- Liya Anto, Lidan Gao, Jaeeun Lee, Chelsea Garcia, Oliver Otoko, Emma Hickey, Neha Mishra, Siyun Kim, Sung Gi Noh, Mi-Bo Kim, Hyunju Kang, Saki Mihori, Saurav Ranjitkar, Alison B. Kohan, Young-Ki Park, Anthony A. Provatas, Clinton Mathias, Oh Sung Kwon, Robert B. Clark, Ji-Young Lee, Frank C. Nichols, and Christopher N. Blesso
Source/Credit: University of Connecticut | Elaina Hancock
Edited by: Scientific Frontline
Reference Number: mcb110626_02