Bacterial lipids may prove to be potent mediators for difficult to treat metabolic diseases and more
"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." (Adobe illustration)
An interdisciplinary team of researchers from UConn and the University of Pittsburgh are 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, professor in the Department of Immunology in UConn School of Medicine Dr. Robert Clark, and Department of Nutritional Sciences associate professor Christopher Blesso – published their findings where these lipids acted like signals that had an immunosuppressive effect in 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 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 Department of Pathobiology and Veterinary Science associate professor Neha Mishra, they determined that both L654 and L1256 significantly attenuated the 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 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 was switched from the healthier diet to the 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 with few treatment options available. The Blesso lab is exploring if 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 to see if it changes glycine levels.
Next, they wanted to understand how these microbial glycine lipids are absorbed and circulate through the body. Blesso explains that these lipids are produced by microbes in the mouth and in the gut, and in the gut there are two potential pathways where 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, but Blesso says eventually, most lipids are cleared by the liver.
Former Department of Nutritional Sciences professor Ji-Young Lee and assistant research professor Young-Ki Park from the NutriPrevention of Obesity, Inflammation & Liver Disease (NP-OILD) Lab, 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 assistant research professor in the Department of Chemistry and the Center for Environmental Sciences and Engineering (CESE) Anthony Provatas 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 to determine if 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's differences in diseased patients versus healthy patients," says Blesso.
An additional aspect of the research, led by Department of Kinesiology associate professor Oh Sung Kwon, 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 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 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 and 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," says Blesso. "In a nutshell, there's a lot to the story. It's evolving. Funding and time are the biggest limitations because there's so many questions that we need to ask."
