Inflammation is one weapon that the immune system wields to protect the body from foreign pathogens and to heal wounds. Inflammation becomes troublesome when the immune system does not turn off. Combined with certain genetic underpinning, a person can develop a variety of inflammatory diseases, like inflammatory bowel disease, rheumatoid arthritis, type-1 diabetes, and asthma.
The rise in inflammatory-related diseases during the past few decades coincides with a transition in the Western diet. People are now relying more on processed foods that are rich in vegetable oil.
Pressed from a variety of plants and seeds, like soybean, sunflower, and corn, vegetable oil is rich in omega-6 fatty acid, one type of polyunsaturated fatty acid (PUFA). The most common omega-6 fatty acid is linoleic acid, which is an essential PUFA that people must obtain from their diet (Fig.1). The omega-3 fatty acid equivalent is alpha-linolenic acid, which is also an essential PUFA. These two PUFAs are similar in structure except for the number and location of their double bonds. Both interact with receptors that play a critical role in major cellular events, including metabolism, inflammation, cell differentiation, and cell death.
While both PUFAs are considered healthier than saturated fat, Americans are eating much more omega-6 fatty acid because of their reliance on processed foods, and omega-6 fatty acids have a controversial link to inflammation. Several families of enzymes—cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)—metabolize this fatty acid to produce a cascade of lipid mediators that, like a light switch, turn on a pro- or anti-inflammatory response in the human body. The answer to and possibly treatments for the rise in inflammatory-related conditions in recent years may lie in the tangle of lipid mediators.
"With all of these lipid metabolites, the devil is in the detail," said Martin Giera (https://tinyurl.com/334n2ppd), head of the Metabolomics group, Leiden University Medical Center, Netherlands. "Minor structural variations can cause huge biological differences."
SUSPECT NUMBER ONE: 12,13-diHOME
Susan Lynch (https://tinyurl.com/bdhspzet), director of the Benioff Center for Microbiome Medicine and associate director of the Microbiome in Inflammatory Bowel Disease program at the University of California, San Francisco, USA has established a firm link between one chronic pro-inflammatory condition, asthma, and alterations to immune cells. Her work found that specific bacteria in the gut microbiome were the culprit that provoked the production of a specific lipid mediator that left a person vulnerable to asthma and allergies.
- In the last half-century, the Western diet has incorporated more processed foods rich in vegetable oils.
- A controversial link between some varieties of vegetable oil and inflammation may explain a rise in inflammatory-related diseases during this timeframe.
- Fatty acids are broken down by various enzymes and oxidation processes to yield a constellation of lipid mediators that can instigate or mitigate inflammation in the human body.
- New research points to a specific lipid mediator, 12,13-dihydroxy-9Zoctadecenoic acid (12,13-diHOME)—and the microbes that produce it in the gut microbiome—as a cause of increased risk for asthma in young children.
Her research was built on epidemiological studies that pointed to early life decisions, like Cesarian section, antibiotics, and formula feeding, that increase the risk of allergies and asthma in childhood. Asthma is a chronic condition where the airways in the lungs narrow and produce excess mucous. Her work focused on infants (one-month old), at a higher risk for asthma and allergies. She observed that they had a higher concentration of one particular lipid mediator, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), in their feces.
Lynch’s investigation then turned to identifying the culprit. Who was responsible for creating this small compound? In this search, she homed in on the gut microbiome.
DEVELOPMENT OF THE MICROBIOME
The importance of the gut microbiome in our health and well-being has come into sharp focus in the past two decades. It consists of the full complement of microbes—bacteria, protozoa, fungi, and viruses—that maintain a mutually beneficial relationship with humans. The organisms inhabit the length of the gastrointestinal system, but primarily take up residence in the last length of the large intestine.
Colonization (https://doi.org/10.1084/jem.20180448) of the gut by these microbes begins in utero, and the biome becomes fully established during the first three years of life. The microbiome provides an auxiliary microgenome that humans maintain throughout their lives that enhances our ability to metabolize food and drugs.
The benefit of these microbes is centered on a conversation. In any setting, these microbes ‘talk’ to one another by producing small molecules. They follow the same process with human cells, influencing a change in cells throughout the body. Unfortunately, a dysfunctional microbiome can place a person on the path toward inflammatory-related ailments.
Lynch’s team identified three bacterial enzymes encoded by three microbes in the gut microbiome—Enterococcus faecalis NP_814872, Bifidobacterium bifidum YP_003971091, and B. bifidum YP_003971333D—that were capable of producing the 12,13-diHOME in infants exposed to risk factors associated with allergies and asthma (https://doi.org/10.1038/s41564-019-0498-2). She and her team then sought to understand how this lipid interacts with the immune system. They found that in the molecular lexicon this particular lipid mediator slows the production of T-regulatory cells, immune cells that prevent allergic inflammation. A reduction in these protective cells increases the vulnerability to an inflammatory response. This lipid mediator has also been found in the airways of asthmatic adults after a challenge with an allergen.
12,13-diHOME SYNTHESIS IN THE GUT
12,13-diHOME is a metabolite of linoleic acid. The path to 12,13-diHOME production is not a straight line. First, linoleic acid is converted by cytochrome P450 to produce two epoxy-octadecenoic acids ((EpOMEs): 9,10-EpOME or its regioisomer 12,13-EpOME). In the next step, soluble epoxide hydrolase (sEH) hydrolyzes the epoxide into one of two dihydroxy-octadecenoic acids (DiHOMEs). In this case to diols, 9,10 EpOME is converted to 9,10-DiHOME and 12,13EpOME is converted to 12,13-DiHOME.
Lynch and her team compared the feces of infants with healthy and dysfunctional gut microbiomes. Infants in both groups were processing linoleic acid, but the infants with the dysfunctional microbiome produced more 12,13-diHOME while the infants with the healthy gut microbiome produced more anti-inflammatory precursors, like gamma-linoleic acid. The results illustrate one example of the complex microbe-immune interaction that can result in an inflammatory-related disease (Fig.2). But this is just one molecule in relation to one disease.
"We are looking under a street light, but there is a massive diversity of lipid molecules produced by gut microbiome that are bioactive," said Lynch. "There are a whole range of lipids that can affect cellular and immune function."
Finding a needle in a haystack
The link between food and inflammation is complex. New technologies could shed light on this nutritional drama, but the concentration of these compounds are miniscule in bodily fluids and fall below the level of detection for most analytical instruments.
In addition, fatty acid oxidation uses a range of different enzymes that produce dozens of lipid mediators. Zooming out and looking at the big picture, a researcher is faced with hundreds of lipid mediator options to evaluate. The task becomes even more convoluted when one takes into consideration that these lipid mediators can be converted directly from the fatty acids in the food we eat or by the unidentified population of bacteria in the gut microbiome. In the latter case, researchers must then identify the microbe responsible for over or underproduction of a lipid.
"It is impossible to look at a molecule in blood and figure out what made it," says Wheelock.
This means more intensive, investigational studies like the one Lynch’s team carried out with asthma. For his part, Wheelock and his team are developing new analytical techniques (https://doi.org/10.1021/acs.analchem.2c02601) to discriminate and quantify the different chiral species of lipid mediators formed along the lipid mediator pathway. This information will inform the lipid sleuths about the synthetic route the lipid mediator followed and how it may function in the human body. Through these new approaches, Wheelock aims to distinguish enzymatic and autoxidative formation pathways.
His work is currently concentrated on 18-carbon, unsaturated fatty acids known as the octadecanoids, which include the essential linoleic and alpha-linolenic acid pathways described above. This approach enables Wheelock and his team to determine the full pathway of lipid mediators produced from these important dietary lipids. He hopes that improving our understanding of the biosynthesis of these compounds will clarify their role in establishing and propagating a host of diseases.
"We still do not really know how the lipid mediators are initiating an immune response," said Wheelock. "This work will provide unprecedented insight into the octadecanoid lipid mediator pathways, enabling us to link dietary fat consumption, the microbiome, and ultimately health."
CALMING A CYTOKINE STORM
The impact of lipid mediators also took center stage as the COVID-19 pandemic progressed. Severe infection with the SARS-CoV-2 virus instigated a cytokine storm. This unusual immune response led to the dysregulation of pro- and anti-inflammatory lipid mediators. As a result, 15% of severe COVID-19 cases (https://doi.org/10.1186/s12985-022-01814-1) developed Acute Respiratory Distress Syndrome (https://tinyurl.com/yy6ta8vu), a condition where fluid engulfs the tiny, elastic air sacs in the lungs preventing oxygen from reaching the bloodstream. For many people who survived the illness, long-term symptoms persist, often called ‘long-haul COVID.’
The cytokine storm piqued the interest of cancer researchers, who have been exploring the role of specializing pro-resolving mediators (SPMs), like lipoxins, resolvins, protectins, and maresins, in slowing cancerous tumor progression. They found the very treatments used to stop cancer—radiation, chemotherapy, and surgery—promoted inflammation that initiated a similar cytokine storm. The remaining cancer cells used the flurry of immune cells along with the cellular debris left over from cancer treatment to regroup and grow. The researchers found that SPMs reduced inflammation and prompted macrophages into action to remove the cellular debris. These two factors slowed tumor growth and disease progression.
During the 2021 AOCS annual meeting, the session COVID 19 Infections and Lipid Mediators: A Clinical Perspective (https://www.youtube.com/watch?v=v-8GADodXls) brought together researchers who discussed what they have learned during the pandemic. Dipak Panigraphy (https://tinyurl.com/sbf3nd83), assistant professor of pathology, Beth Israel Deaconess Medical Center, shared his experience with cancer research and the overlap with severe COVID-19 infection (https://www.youtube.com/watch?v=ZyGj8ms5H5g).
Many of the cytokines stirred up during cancer treatment were the same ones instigated during severe COVID-19 infections. Their team’s research has shown that intervention with SPMs is an effective treatment during a COVID-19 infection. In particular, resolvins, a group of molecules derived from omega-3 fatty acids, have potential to speed the time to recovery and lessen the symptoms experienced. These compounds may also provide relief to COVID-19 survivors who continue to experience long-term symptoms, like fatigue, joint pain, chest pain, cough, difficulty breathing, and loss of taste and smell.
SO ARE VEGETABLE OILS GOOD FOR YOU OR NOT?
The on-going debate regarding the health benefits of omega-6 fatty acids continues to produce ambiguous and confusing results in the scientific literature. Some research points to the harmful effects of consuming omega-6 fatty acids, while other studies point to health benefits. According to Craig Wheelock, asking whether to eat foods enriched with either omega-3 or omega-6 fatty acid is the wrong question.
"For decades, we have been looking at the association between the parent fatty acid and clinical outcomes," says Wheelock (https://tinyurl.com/253mcknv), principal researcher and leader of the Integrative Molecular Phenotyping laboratory at the Karolinska Institute in Sweden. (see sidebar on pg. 13) "What we need to be focused on is the downstream lipid mediators that are exerting the biological function."
According to Wheelock, the answers lie not in the omega-6 and omega-3 debate but a better understanding of the relationship between dietary fat consumption, the gut microbiome, and the lipid mediators that result. Lynch advocates for a better understanding of the molecular composition of food and how it affects the substrates that are available to microbes in the gut. Other research questions to tackle include: how these substrates move through the gastro-intestinal track, where the molecules are absorbed and metabolized, and how these compounds dictate the fate of lipid productivity substrates.
"We need to understand the biological activities of all of these lipids and their derivatives," said Lynch. "This is really complex and difficult and will take years to untangle."
While this approach is still in its infancy and researchers will have to navigate some tricky analytics, the future is written in the dozens of lipid mediators yet to be studied. As tools and techniques improve, opportunities abound to find new approaches to realign a perturbed gut microbiome to prevent disease and find new therapies to treat a host of chronic, inflammatory diseases.
About the Author
Stacy Kish is a science writer for INFORM and other media outlets. She can be contacted at firstname.lastname@example.org