Specialized Pro-resolving Mediators: Getting Rid of Chronic Inflammation

In the US, 60% of adults are diagnosed with a chronic disease, and 40% have two or more conditions.[ref] Let that sink in for a second. For all of our advances in medicine, technology, and modern advantages, overall as a population, we really aren’t healthy.

What if I told you that most modern medicine has it all wrong when it comes to chronic disease? Some of you are likely nodding in agreement, and others are raising a skeptical eyebrow right now.

Recent research has created a paradigm shift in understanding the root cause of most chronic diseases. And mainstream medicine hasn’t made the shift – yet.

This article applies to almost everyone with a chronic disease: heart disease, diabetes, gum disease, neurodegeneration, neuropathy, arthritis, chronic pancreatitis, etc. Healthy and young? This article holds the keys to staying that way.

Content warning: This turned out to be really long article. I think it is an important topic and encourage you to keep reading to the end.

What causes chronic diseases?

Most chronic diseases have constant, low-level inflammation as an underlying cause. (No, this isn’t the new, paradigm-shifting research – pretty much everyone accepts this.)

Diseases that have chronic inflammation at their root include, well, pretty much every chronic condition: heart disease, Alzheimer’s, rheumatoid arthritis, diabetes, neuropathic pain, mood disorders, IBD, obesity, fatty liver disease, MS, chronic kidney disease, arthritis, cancer, obesity, asthma, autoimmune diseases, and more.[ref][ref] You name the ‘co-morbidity’ and there is likely a connection to low-levels of continuing inflammation.

The more I’ve learned about genetics and health, the clearer it has become that inflammation is a component of most diseases. The genetic variants that increase inflammatory cytokines connect to pretty much every disease – autoimmune, metabolic health, pain syndromes, depression, aging, CVD, neurodegeneration, etc. To be honest, I’m kind of sick of writing about TNF-alpha variants and other inflammatory genes.

But… inflammation turns out to be only half the story. I had missed the boat on the recent research on the resolution of inflammation. Importantly, many doctors and healthcare practitioners are also missing the boat here, too.

Over the past decade or so, researchers have been teasing out the mechanisms through which inflammation is resolved. This recent paradigm-shifting research comes down to…

the resolution of inflammation is an active process.

Inflammatory cytokines and the processes that ramp up inflammation don’t just fade away, like doctors and researchers used to think. Instead, resolution of inflammation is an active process.

A whole slew of molecules are produced to both halt the inflammatory processes and initiate a bunch of processes to clean up and return the tissue to homeostasis. These molecules are called specialized pro-resolving mediators (SPMs). They are lipids (fatty acids) that signal for the resolution of inflammation.

To be clear, this is different than anti-inflammatory drugs or supplements that block inflammation. It is also different from antioxidants from foods or supplements. While antioxidants and anti-inflammatory supplements can be helpful, they only address half the problem.

Before we get into the pro-resolving mediators, let’s take a quick trip through the basics of inflammation and talk about a couple of important players here.

Inflammation: Quick Overview

The immune system is ready to react when you get a cut, are infected by bad bacteria, or break a bone. When an insult happens – a cut, pathogen, or injury – a cascade of inflammatory events is started.

White blood cells, also called leukocytes, are a type of immune cell that protects the body against invaders. White blood cells begin in the bone marrow, derived from hematopoietic stem cells. Leukocyte (white blood cell) is a general term. There are specific subtypes of white blood cells, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes (which become macrophages). They all have a role in inflammation and protecting your body from infection.

Inflammation is classically characterized by warmth, swelling, redness, and pain. (Calor, Dolor, Rubor, and Tumor, if you like it in Latin)[ref] These signs of inflammation are due to increased blood flow, capillary dilation (swelling), leukocyte (WBC) infiltration, and the production of inflammatory cytokines.

Example time: You get a sliver of wood in your finger. It may swell up, be painful, and turn red. Pus (which contains a lot of white blood cells) may gather at the site of the sliver. You finally get that tiny piece of wood out of your finger, and by the next day, your finger is back to normal – no more redness, swelling, or pain.

What happened was the foreign object (the sliver) and bacteria were detected. Neutrophils, which are one type of white blood cell, rushed in. Inflammatory cytokines were released, causing vasodilation and fluid rushing into the area; more inflammatory cytokines were recruited; mast cells released their mediators; macrophages engulfed the bacteria on the splinter; ROS (reactive oxygen species) produced to kill the bacteria, and then… resolution. Back to normal.

Until recently, scientists didn’t realize that the resolution of inflammation is waaay more than just the cytokines slipping away and immune system cells retreating.

Concurrent with acute inflammation is the onset of resolution of inflammation.

Pro-resolving mediators are produced by immune system cells to actively cause the resolution of inflammation and healing back to normal. It happens at the same time as inflammatory processes.

Chronic inflammation is due to lack of resolution

Currently, if you go to the doctor with a disease that is caused by chronic inflammation, you will often be prescribed an anti-inflammatory medication. Something to block the formation of inflammatory cytokines, such as NSAIDs or leukotriene inhibitors.

For example, TNF-alpha is an inflammatory cytokine that elevates in rheumatoid arthritis. Medications that block TNF, such as anti-TNF antibodies, are used to decrease the symptoms in RA. But the side effects include a suppressed immune system that makes patients more susceptible to pathogens.

But why does TNF-alpha stay elevated in RA? One big part of the picture seems to be an inadequate or insufficient resolution of the inflammation.

As one research study puts it: “While it was previously thought that passive disappearance of proinflammatory factors was sufficient for the cessation of inflammation, it is now known that the resolution of acute inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by a panoply of endogenous factors that include SPMs, protein/peptide mediators such as annexin A1 and interleukin 10, gases such as carbon monoxide and hydrogen sulfide, and nucleotides such as adenosine and inosine.”[ref]. (We are sticking to just talking about SPMs here, but keep in mind that as in-depth as SPMs are, there is still more to the topic.)

SPMs (specialized pro-resolving mediators) are not only important in halting the inflammatory response, but they also “orchestrate the clearance of tissue pathogens, dying cells, and debris from the battlefield of infectious inflammation.”[ref]

In addition to promoting the resolution of inflammation in chronic diseases, these SPMs are also important in turning off the immune response and returning the body to normal after a bacterial, viral, or fungal infection. The lack of pro-resolving mediators is thought to be a cause of severe COVID-19 symptoms such as acute respiratory distress syndrome.

Macrophages are an important player in inflammation. They are a specialized type of leukocyte (white blood cell) that can differentiate into two different forms.

  • The M1 form of macrophages is proinflammatory, producing high levels of cytokines such as TNF-α, IL-1ß, IL-6, IL-12.
  • The M2 form of macrophages is anti-inflammatory – and a big part of the resolution of inflammation.

The M2 form of macrophages is programed by the SPMs and cleans up the inflammation – engulfing and removing the leftover inflammatory debris.[ref]

In all, the resolution of inflammation by SPMs includes:[ref]

  1. removal of microbes, dead cells, and debris
  2. restoration of the integrity of blood vessels
  3. regeneration of tissues
  4. remission of fever
  5. relief of pain

Final point to drive home here: people with chronic inflammatory diseases have lower levels of the SPMs (pro-resolving mediators) that are specific to the resolution of their chronic condition.[ref]

It isn’t just the low levels of continuing inflammation; it is also the lack of clean-up and restoration. The house burned down (acute inflammation), and not only did the remains still smolder, but there also was no clean-up crew to remove the mess and rebuild.

Here is a screenshot from a great Frontiers in Immunology article that sums up the process of resolution of inflammation:

 

Let’s dig into the details on what is currently known about the resolution of inflammation. Keep in mind that much of this is fairly recent research, so there are likely more discoveries yet to be made in this area.

Lipid mediators: What does this mean?

We often think of the fats that we eat as just something that produces energy (or makes you fat). Energy production or fat storage are just two of the many functions of fat in the body. For example, lipids (fats) also make up the cell membrane surrounding the trillions of cells in your body, and lipids are also essential for creating certain hormones.

Lipid is a general term for fats, including the fatty acids that we are familiar with eating (saturated, unsaturated, long chains and short). Basically, fatty acids are chains of hydrogens and carbons. We categorize them by the bonds, such as all saturated bonds or with an unsaturated bond at a certain spot (e.g. omega-6 or omega-3  polyunsaturated fatty acids).

In addition to being used for creating cellular energy, certain lipids act as signaling molecules, which means that they can bind with a receptor and cause something to happen in a cell.

Specialized pro-resolving mediators (SPMs) are lipids derived from polyunsaturated fatty acids. These lipid mediators are categorized and named:

  1. Lipoxins
  2. Resolvins
  3. Protectins
  4. Maresins
  5. Cysteinyl SPMs

I’m going to explain each of these lipid mediators briefly and then cover the genes/enzymes involved in the biosynthesis of the SPMs.

Creation of the specialized pro-resolving mediators

The SPMs are produced using polyunsaturated fatty acids (PUFAs) as the base molecules. Specifically, DHA and EPA are the precursors for many SPMs, and arachidonic acid (AA) is also a precursor. DHA and EPA are omega-3 PUFAs found in fish oil. Arachidonic acid is an omega-6 fatty acid found in meat and plant oils.

These precursors come from eating foods that contain the needed omega-3 and omega-6s. The precursor fatty acids are then converted by specific enzymes produced by certain cell types when triggered by acute inflammation.[ref]

Overview of creation of pro-resolving mediators. Screenshot of PMC4315926

1) Lipoxins

Lipoxins are derived from arachidonic acid (omega-6 fatty acid) and are created at the onset of inflammation. The pro-resolution processes start almost as soon as acute inflammation begins.

While the majority of specialized pro-resolving mediators are derived from omega-3 fatty acids (DHA and EPA), lipoxin is the outlier and formed from the conversion of an omega-6 fatty acid, arachidonic acid (AA). There are several lipoxins types, named lipoxin A4 and lipoxin B4.

Here are a few examples of what lipoxins do:

  • Lipoxins are important in preventing heart disease via the resolution of inflammation in atherosclerosis.[ref] (Let that sink in for a minute – heart disease is the number 1 cause of death, and lipoxins may hold the key to prevention.)
  • Lipoxins are important in protecting the brain in neurodegeneration and glaucoma.[ref]
  • After a stroke, lipoxins are important in resolving inflammation.[ref]

2) Resolvins

Resolvins derived from EPA are named RvE1 through RvE4 (resolvin E1, etc). Resolvins derived from DHA are called the D-series. They are named RvD1 through RvD6.[ref] Resolvins derived from DPA, another omega-3 fatty acid, include RvD1, RvD2, RvD5, RvT1, RvT2, RvT3, RvT4. The details aren’t important here – I’m just wanting to drive home the point that there are multiple resolvins derived from omega-3 fatty acids.

What do resolvins do?

  • After a stroke, RevD1 is important in resolving inflammation.[ref]
  • Resolvin E1 is important in protecting against atherosclerosis, carotid artery disease, and clearance of tumor cell debris. Resolvin D5 is important in clearing out bacterial pathogens.[ref][ref]
  • Animal studies show the potential of resolvin E1 and D1 in neurodegenerative diseases.[ref]
  • Resolvin D2 is important in periodontal disease in preventing bone loss.[ref]

3) Protectins

Protectin D1 is derived from DHA, and from DPA (another omega-3 fatty acid) we get protectin P2.[ref] Protectins are important in switching macrophages from the proinflammatory to the anti-inflammatory type.[ref] Macrophages can increase inflammation (M1 type), or they can clean up and stop inflammation (M2 type)

  • In animal studies, protectin D1 is important in reducing the amyloid-beta plaque, which causes Alzheimer’s disease.[ref]
  • Protectin D1 is important in the cornea to protect from injury and in the retina.
  • Protectins are also important in resolving inflammation in adipose (fat) tissue. Chronic inflammation goes hand-in-hand with obesity, and protectins have reversed the inflammation.[ref]
  • Protectin D1 also dampens hyperactivity in the airways. People with asthma have lower levels of protectin D1.[ref]

4) Maresins (derived from DHA)

Maresins are also derived from DHA and abbreviated MaR1, MaR2, and eMaR. Maresins are important for:

  • Tissue regeneration and bacterial infections.[ref]
  • Pain sensitivity and bone regeneration.[ref]
  • Maresin 1 pretreatment (animal study) shows that it stops UVB damage.[ref]

5) Cysteinyl SPMs

Discovered within the past couple of years, cysteinyl SPMs are also derived from DHA and are peptides conjugated with the other lipid mediators. The family of cysteinyl SPMs includes MCTR1, MCTR2, MCTR3, PCTR1, PCTR2, PCTR3, RCTR1, RCTR2, RCTR3. They are involved in tissue regeneration and cardiovascular protection.[ref]

Conversion enzymes: Biosynthesis of SPMs

The precursor molecules for the lipid mediators are pretty straightforward and easy to understand: DHA and EPA, which are omega-3 polyunsaturated fatty acids found in fish oil, and Arachidonic Acid (AA), which is an omega-6 polyunsaturated fatty acid.

You need enough of the precursor fatty acids to make the lipid mediators. If you never get any DHA/EPA in your diet, you are likely behind the 8-ball when it comes to producing pro-resolving lipid mediators. But what if you are eating fish daily. Getting enough arachidonic acid… Doing it right for the precursors?

The precursor fatty acids still need to be converted into the SPMs via enzymatic processes, and then they need the receptors available to bind to and complete their pro-resolution actions.

The enzymes that convert DHA, EPA, and DPA into the SPMs include 5-LOX, 12-LOX, and 15-LOX.

  • The ALOX12 and ALOX15 genes encode 12-LOX and 15-LOX, which convert DHA and DPA into the D-series resolvins, protectins, and maresins.[ref]
  • The ALOX5 gene encodes the 5-LOX enzyme that is also needed in the conversion of the D-series resolvins, as well as the E-series resolvins and DPA-derived resolvins.

Cell studies show that when lower amounts of these enzymes are produced, there is more chronic inflammation. One study looked at the role of SPMs in tendonitis, which is common in people with diabetes. The diabetic tendon samples showed chronic inflammation plus low levels of the enzymes needed to produce the pro-resolution lipid mediators.[ref]

These enzymes, though, are not specific just to forming the pro-resolving lipid mediators. In fact, they also act as enzymes in reactions that create inflammatory molecules, such as inflammatory lipids from AA. Thus, what type of fat you eat (omega-6 oils vs. omega-3) interacts with your ability to convert the lipids into either proinflammatory or pro-resolving lipid mediators.

Aspirin in the conversion of SPMs

Willowbark, which contains salicylic acid (the active ingredient in aspirin), has been used to stop inflammation since at least 4,000 BCE.[ref] It turns out that aspirin, though, doesn’t just stop inflammation by blocking the formation of prostanoids. It also helps to form pro-resolving mediators.

In addition to the enzymes above, the COX2 enzyme is involved in converting the resolvins and lipoxin in a special way that involves aspirin.

Aspirin is a COX1 inhibitor at lower levels, and at higher levels, it also changes the enzyme function of COX-2 via acetylation.[ref]

Aspirin is unique among NSAIDs in that it acetylates COX2, which then triggers the formation of ‘aspirin-triggered specialized pro-resolving mediators‘ or AT-SPMs. These aspirin-triggered SPMs include AT-lipoxin A4, AT-resolvin D1, and AT-resolvin D3.[ref][ref]

Aspirin-triggered SPMs are unique in that they have a prolonged half-life and act to resolve inflammation for longer.[ref] It is likely why only aspirin, and not other NSAIDs, helps to prevent heart disease and reduces the risk of colon cancer (for some people).

You’re likely thinking – as I was – that there has to be another way that the body can produce these SPMs without aspirin. Very recently, researchers have discovered that an endogenous compound can also act to form the so-called aspirin-induced SPMs. “In addition to aspirin, N-acetyl sphingosine (N-AS), generated from acetyl-CoA and sphingosine via sphingosine kinase1 (SphK1), also acetylates COX2 and increases RvE1 and 17R-RvD1.”[ref]

Receptors for SPMs:

The specialized pro-resolving mediators resolve inflammation by binding to a cellular receptor and thus producing an action. Some of the actions triggered include blocking inflammatory cytokines, converting macrophages to anti-inflammatory, promoting stem cells for tissue regeneration, and cleaning up cellular debris.

Here are some of the receptors for SPMs:[ref]

  • ALX (encoded by the FPR2 gene) is a RvD1 receptor. In mice, a lack of this receptor causes endothelial dysfunction, cardiomyopathy, and obesity.
  • Protectin D1 activates GPR37 “Mice lacking Gpr37 display defects in macrophage phagocytic activity and delayed resolution of inflammatory pain”
  • RvD5n-3 DPA was shown to bind to an orphan receptor GPR101 with high selectivity and stereospecificity.
  • ERV1/ChemR23 is the receptor for several SPMs
  • DRV1/GPR32
  • DRV2/GPR18

The cell types receiving the SPM pro-resolution signals via these receptors include platelets, macrophages, eosinophils, dendritic cells, epithelial cells (skin, intestinal cells), regulatory T cells, neutrophils, mast cells, and endothelial cells (lining of blood vessels).

The different SPMs bind with receptors on the cells to inhibit inflammation, stimulate the clearance of cellular debris, or promote tissue regeneration.

Let me give you some examples to illustrate how the different SPMs binding to receptors can cause a plethora of reactions that resolve inflammation as well as promote healing.

  • Protectin D1 binds to receptors on neutrophils, inhibiting the release of  TNF-alpha and interferon-gamma.[ref]
  • Resolvin D2 binds to receptors on muscle stem cells and promotes the increase in muscle cell creation (important in muscular dystrophy).[ref]
  • Pain is part of inflammation, and SPMs specifically target and reverse pain. Through inhibiting TRPV1, maresin R1 blocks neuropathic pain. Resolvin E1, resolvin D1, and aspirin-triggered resolvins reduce pain by knocking down TRPV3.[ref]
  • The interaction of resolvin D1 with the FPR2 receptor causes an increase in PPARγ, which stops the migration of NF-ᴋB into the nucleus.[ref]
  • In type 2 diabetes, it has been shown that upregulating the SPM receptors – especially the receptor for resolvin E1, potently regulates blood glucose levels.[ref]
  • Resolvin D1 and D2 counteract histamine when it comes to watery-eyes in allergic reactions. Resolvin D1 blocks histamine action via the H1 receptor (acted on by β adrenergic receptor kinase 1 and protein kinase C phosphorylation).[ref]
  • Resolvin D1, D2, and E1 prevent histamine-induced TRPV1 sensitisation. It may be important for stopping gut irritability in IBS.[ref]
  • In periodontal disease, maresin R1 and resolvin E1 increase periodontal ligament stem cells, which regenerate lost tissue in gum disease.[ref]

Receptor agonist drugs: In addition to natural SPMs binding to the receptors, synthetic drugs are being investigated to promote these same pathways of the resolution of inflammation.[ref][ref][ref] Phase I clinical trials are underway.[ref]

Chronic diseases and resolution of inflammation:

I wanted to circle back around here and explain how the resolution of inflammation as an active process is important in stopping chronic diseases using specific examples.

Keep in mind that the process should go:

pathogen/wound/toxin –> inflammation –> resolution

While many of these chronic diseases have different initiating factors (toxicants, bacteria, etc), the process of inflammation alongside the lack of resolution underlies their pathology.

Cardiovascular Disease (CVD) – In cardiovascular disease, ALOX5 was identified in an early genetics study. This gene encodes one of the enzymes needed for converting EPA into a pro-resolving mediator. Additionally, the enzyme is involved in increasing inflammatory lipid mediators. The discovery that the gene was linked to CVD was the first signal that there was something wrong with resolving inflammation in heart disease. Currently, researchers point the finger squarely at the lack of resolution of inflammation as causal in heart disease. One recent study explains:

“Atherosclerosis is a major human killer and non-resolving inflammation is a prime suspect” [ref]

Chronic Obstructive Pulmonary Disease  – COPD is a general term that includes inflammatory lung diseases such as emphysema and chronic bronchitis. The anti-inflammatory and resolution effects of lipoxin are very important in the lungs. In the lungs, lipoxin A4 triggers the migration of epithelial cells to repair injured bronchial tissue. Lipoxin B4 inhibits the migration of excess neutrophils into the area. Aspirin-triggered lipoxins also play a role in resolving inflammation in the lungs. Resolvin D1 is also important in lung immune system modulation and in the response to cigarette smoke.

COPD patients generally have both lower levels of lipoxins and lower levels of the receptors for lipoxin in the lungs. It could cause the persistence of inflammation in the lungs via the lack of resolution.[ref]

Chronic back pain: Lower back pain, which affects a fairly large portion of the population at various times in life, is due to neuroinflammation. Animal models of herniated lumbar disc pain show that protectin D1 (from DHA) decreases inflammatory cytokines (IL-1β and IL6), facilitates healing, and attenuates the pain.[ref]

Arthritis affects millions of people worldwide. From RA to osteoarthritis to gouty arthritis, inflammation is at the heart of this painful condition. Patients with arthritis have lower levels of some SPMs, depending on the type and aggressiveness of the disease. In arthritis studies, treatment with resolvin D1 or MaresinR1 acts as an analgesic for days to weeks. Supplementation with DHA and EPA also has some effectiveness in helping reduce inflammation in arthritis.[ref]

Multiple sclerosis: SPM biosynthesis is impaired in people with multiple sclerosis, and low levels of SPMs correlate with disease progression in MS.[ref] This may be a key to the chronic inflammation involved in MS, which eventually causes demyelination of the neurons.

IBD: Inflammatory bowel disease (Crohn’s or ulcerative colitis) is caused by chronic intestinal inflammation. The lack of resolution of inflammation is thought to be a strong contributing factor: “…defective expression of pro-resolution mediators may contribute to the chronic inflammatory response associated with IBD. Notably, colonic mucosa from UC patients demonstrates defective LXA4 [lipoxin A4] biosynthesis, which may contribute to the inability of these patients to resolve persistent colonic inflammation.”[ref]

Diabetes: In type 2 diabetes, there is inflammatory dysregulation. Research shows that the BLT1 receptor for resolvin E1 doesn’t signal as well as it does in people without diabetes. Interestingly, higher levels of resolvin E1 were able to overcome some of the inflammatory dysregulations.[ref]

Neuropathic pain comes from damage to the central nervous system. It can take the form of peripheral neuropathy, mechanical allodynia, MS, or other pain syndromes. While it makes sense that the resolution of inflammation would stop pain, researchers have discovered that the role of the SPMs may be more in-depth when it comes to neuropathic pain. Research points to a role of SPMs in both opioid receptors and TRP channels, which may signal to stop pain through the central nervous system.

Research on neuropathic pain and supplemental SPMs shows an array of positive results (mostly in animal studies). Lipoxin A4 reduces inflammatory hyperalgesia, inhibits NF-kB, reduces IL-1B, TNF-a, and IL6. Resolvins blunt pain perception, down-regulates NF-kB in the lower back, prevents inflammatory hypersensitivity and acts as analgesics.

Getting a little more specific: Resolvin D1 and resolvin D2 can directly inhibit TRP channels on the surface of sensory neurons. TRPV1, TRPV3, and TRPV4 and TRPA1 are inhibited by these resolvins, and this reduces sensitivity to heat-induced pain as well as agonist-induced pain. Additionally, maresin R1 acts on the TRPV receptors. These receptors are also activated by capsaicin in hot chili peppers.[ref]

Related article: TRPV1 receptor variants

Infections: Sepsis is an out-of-control inflammatory reaction, usually in response to a bacterial infection. SPMs, in addition to all their anti-inflammatory and pro-resolving properties, also enhance the clearance of bacterial and viral pathogens while at the same time limiting collateral tissue damage.[ref]

Specialized pro-resolving mediators also play a role in host defense against viruses such as influenza A, RSV, and HIV. Clearance of bacterial pathogens also involves SPMs. For example, animal studies show that the absence of lipoxins in Lyme disease causes chronic disease symptoms such as joint pain.[ref]

Atrial Fibrillation: A-fib persistence increases inflammation through excessive ROS production in the endothelium. Researchers now think that resolvin D1 may inhibit the increase in inflammation.[ref]

Cancer: Inflammation and SPMs

A lot of research is currently focused on the role of SPMs in cancer.

Cancer can, in some ways, be viewed as a wound that doesn’t heal. With chemotherapy, surgery, or radiation, a tumor can be reduced in size, but whether or not the cancer is ‘cured’ is conditional upon the clearance of debris.

Essentially, dead cancer cells trigger a proinflammatory immune response which paradoxically stimulates tumor growth. Traditionally, the focus has been on anti-inflammatory drugs, which have so far yielded only a transient effect on stopping tumor activity. Therefore, pro-resolution mediators are of great interest in cancer research.[ref]

  • Researchers are looking at the use of resolvins prior to surgery or chemotherapy to prevent metastasis from occurring due to micro-metastases escape.[ref]
  • Other research points to positive outcomes using pro-resolving factors along with cancer treatment to prevent cancer cells from being available to move through the bloodstream or lymphatic system.[ref]

Increasing DHA/EPA in the diet, along with decreasing omega-6 fatty acids, reduces the viability of breast cancer cells in cell studies. The current Western diet averages a ratio of up to 20:1 for omega-6:omega-3 intake, which is many-fold higher than the ratio was historically. Changing that ratio in breast cancer cell lines to 1:1 omega-6:EPA/DHA stopped cancer growth.[ref] Keep in mind, this is a cell study that gives us a mechanism of action, rather than a cancer cure-all.

Resolvin D1 and D2 have been shown in cell studies to inhibit the proliferation of prostate cancer.[ref]

As I mentioned above, aspirin-triggered pro-resolving mediators have a longer half-life than their non-aspirin triggered counterparts. Additionally, low-dose aspirin along with EPA increases levels of resolvin.[ref] Regularly taking aspirin intake is associated with a decreased colon cancer risk in some people. New research points to aspirin-triggered resolvin D1 as a big reason aspirin has anticancer activity. Researchers used animal models of cancer to figure out that blocking the receptor for AT-resolvin D1 blocks the antitumor action of aspirin. Thus, the pro-resolving mediators created by the interaction of aspirin, COX, and EPA are likely the key to cancer prevention by aspirin.[ref]

Circadian rhythm and the production of SPMs

Your circadian rhythm – the 24-hour built-in clock – controls the rhythmic production of hormones, enzymes, proteins, and more. Your body prioritizes the processes needed when you are awake and active and then switches to cellular repair and restoration processes while you sleep.

Circadian rhythm is important in healing for a lot of reasons — one of which was recently discovered with research into SPMs. It turns out that there is a circadian rhythm to SPM production. And the highs and lows of the rhythm are important. SPM concentrations from healthy volunteers rise high and then fall over the course of the day, but in people with heart disease, the rhythm is flat.[ref]

Without the production of SPMs to stop the chronic inflammatory processes going on in heart disease, the inflammation continues unchecked and atherosclerosis builds in the blood vessels. Researchers found that in mice, the core circadian clock gene BMAL1 controls the concentration of pro-resolving mediators. As BMAL1 rises and falls, so do these important healing compounds, but without the core circadian clock, SPM levels remained low and flat.[ref]


Genetic Variants Impacting SPMs

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Omega-3 Fatty Acid conversion:

The precursor molecules for specialized pro-resolving mediators are EPA, DPA, DHA, and AA. DHA and EPA are obtained directly in the diet through eating oily fish or taking fish or krill oil supplements.

Plant-based omega-3s include flaxseed and chia seeds. They have high amounts of alpha-linolenic acid, which can be converted to the longer-chain EPA, DPA, and then DHA fatty acids. They are converted using the enzymes encoded by the FADS2, FADS1, and ELOVL genes.

People with variants in the FADS1/2 enzymes convert very little plant-based omega-3 fatty acids into DHA/EPA.

My simplified overview of the genes involved in PUFA conversion.

FADS1 gene: The FADS1 enzyme converts flaxseed oil and chia seed oil into DHA and EPA. Multiple FADS1 variants are inherited together such that if you inherit one, you should inherit all the variants. Below, I’ve only included one variant, rs174546 (T is the risk allele)– which is almost always inherited together with rs174547 (C allele), 174537 (T allele), rs174550 (C allele), and rs174548 (G allele).[ref]

Check your genetic data for rs174546 (23andMe v4, v5;  AncestryDNA)

  • T/T: low FADS1 enzyme activity; benefits more from direct EPA/DHA intake[ref][ref][ref][ref] Arachidonic acid is also reduced[ref]
  • C/T: lower FADS1 enzyme activity, benefit more from direct EPA/DHA intake
  • C/C: typical FADS1 activity

Members: Your genotype for rs174546 is .

FADS2 gene: The FADS2 variant is inherited together with the FAD1 variant for many people. It is also important in converting omega-3 oils into DHA/EPA.

Check your genetic data for rs1535 (23andMe v4, v5; AncestryDNA):

  • G/G: low FADS2 enzyme activity, decreased ALA to EPA conversion [ref] benefits the most from fish oil supplement post-heart attack[ref] high intake of EPA/DHA decreases asthma risk in kids[ref]
  • A/G: somewhat decreased FADS2 enzyme activity
  • A/A: typical FADS2

Members: Your genotype for rs1535 is .

ELOVL2 gene encodes an enzyme also needed to transform fatty acids to longer-chain fats.

Check your genetic data for rs3734398 (23andMe v5; AncestryDNA):

  • C/C: associated with higher levels of EPA and DPA, lower levels of DHA (e.g., decreased conversion of EPA to DHA)[ref]
  • C/T: associated with higher levels of EPA and DPA, lower levels of DHA (e.g., decreased conversion of EPA to DHA)
  • T/T: typical

Members: Your genotype for rs3734398 is .

Enzymes that produce SPM

The research here is fairly new, and I’m sure there will be more to come on the way genetic variants interact with diet in the formation of pro-resolving mediators. So take this information as more of an introduction with (hopefully) more to come.

ALOX5 gene: encodes the enzyme responsible for converting EPA and DHA into resolvins, maresins, and protectins. But this enzyme is also used to convert AA from omega-6 oils into inflammatory leukotrienes. Thus, higher enzyme production may be associated with higher inflammation in people eating a lot of omega-6 fatty acids, but the enzyme is also needed to produce SPMs from EPA/DHA. Thus, the influence of the omega-6 to omega-3 ratio in the diet is likely important and is also likely not considered in the studies.

Check your genetic data for rs4987105 (23andMe v4; AncestryDNA):

  • C/C: most common genotype (higher levels of type 2 diabetes, higher levels of C-reactive protein – a study done in the EU)[ref]
  • C/T: decreased risk of type 2 diabetes, lower levels of C-reactive protein (a marker of inflammation)
  • T/T: decreased risk of type 2 diabetes, lower levels of C-reactive protein (a marker of inflammation)

Members: Your genotype for rs4987105 is .

ALOX5AP gene: encodes an enzyme needed for ALOX5 activation. This enzyme is involved in increased inflammation from inflammatory lipids produced from AA – as well as pro-resolving mediators produced from DHA/EPA. Similar to ALOX5 research, I think the diet of the study group likely influences whether the variant has a positive or negative effect. So keep in mind that the average diet includes a lot of omega-6 oils and not a lot of DHA/EPA these days.

Check your genetic data for rs17216473 (AncestryDNA):

  • A/A: increased risk of heart attacks[ref]
  • A/G: increased risk of heart attacks
  • G/G: decreased risk of heart attacks[ref]

Members: Your genotype for rs17216473 is .

Check your genetic data for rs10507391 (AncestryDNA):

ALOX12 gene: encodes the enzyme needed to convert EPA/DHA into SPMs. This enzyme, though, is also used in turning AA from omega-6 oils into inflammatory mediators such as 12-HETE. Thus, like the ALOX5 genetic variants, the research results are likely dependent on the amount of omega-6 vs. DHA/EPA that the study participants eat. High levels of the inflammatory mediators from ALOX12 are linked to increased cancer risk and heart disease.

Check your genetic data for rs1126667 R261Q(23andMe v4, v5; AncestryDNA):

  • A/A: decreased risk of breast cancer in White women (study done in the US)[ref], lower blood pressure, and decreased enzyme function (study done in the EU)[ref]
  • A/G: slightly decreased risk of breast cancer, lower blood pressure, and decreased enzyme function
  • G/G: typical

Members: Your genotype for rs1126667 is .

COX2 gene: encodes the enzyme that converts arachidonic acid into proinflammatory mediators. Acetylation of COX2 by aspirin interacts with SPMs to create aspirin-triggered pro-resolving mediators.

Check your genetic data for rs4648310 (AncestryDNA):

  • T/T: typical
  • C/T: low DHA/EPA intake associated with a significantly increased risk of prostate cancer, but high DHA/EPA ameliorates the increased risk
  • C/C: low DHA/EPA intake associated with a significantly increased risk of prostate cancer, but high DHA/EPA ameliorates the increased risk[ref]

Members: Your genotype for rs4648310 is .

Check your genetic data for rs5275 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: increasing the intake of EPA/DHA (eating salmon once a week) reduced prostate cancer risk by 70%
  • G/G: increasing the intake of EPA/DHA (eating salmon week) reduced prostate cancer risk by 70%[ref]

Members: Your genotype for rs5275 is .

Receptors for the SPMs:

Several of the genes that encode receptors for various pro-resolving mediators were classified up until recently as ‘orphan receptors’. Researchers knew the gene existed, but they weren’t really sure what activated the receptor.

A variant in the FPR2 gene (not covered in Ancestry or 23andMe data), rs11666254  causes downregulation and is linked to increased risk of sepsis, which shows the importance of this receptor in the resolution of inflammation due to bacterial pathogens.[ref]

GPR18 gene: encodes the receptor for resolvin D2.

Check your genetic data for rs3742130 (23andMe v4):

  • A/A: identified in a large genetic study as altering the risk of IBD[ref]
  • A/G: identified in a large genetic study as altering the risk of IBD
  • G/G: typical

Members: Your genotype for rs3742130 is .

CMKLR1 gene encodes the ERV1/ChemR23 receptor for both resolvin E1 and chemerin1 (an adipokine). Animal studies show that this receptor is important in preventing hyperglycemia and hyperinsulinemia, and the results seem to hold true in people who are overweight. Higher EPA intake coupled with the ERV1 receptor prevents hyperinsulinemia.[ref]

Check your genetic data for rs1878022 (23andMe v4, AncestryDNA):

  • C/C: increased receptor expression, reduced inflammation in obesity[ref]
  • C/T: increased receptor expression, reduced inflammation in obesity
  • T/T: typical

Members: Your genotype for rs1878022 is .

GPR37/PaelR encodes the receptor for protectin D1, which is important in resolving inflammation in the brain.[ref] Variants are related to Parkinson’s and autism.

Check your genetic data for rs149031046 (23andMe v5):

  • G/G: typical
  • A/G: possibly important for autism [ref][ref]
  • A/A: possibly related to autism(rare)

Members: Your genotype for rs149031046 is .

 


Lifehacks:

You’ve made it to the application part of this article! Thanks for hanging in this far.

Is the cure for all chronic diseases to take a couple of fish oil pills?

I don’t think it is that simple. Instead, there is a lot of nuance of how much EPA, DHA, and DPA is needed – as well as avoiding inhibitors of the production of SPMs. There are also questions surrounding the oxidation of fish oil supplements, especially the cheap stuff that you get at the grocery store, and whether oxidized fish oil has a negative impact instead of a positive benefit.

Start by knowing your current DHA/EPA consumption:
Cronometer.com is a free web app where you can track what you eat. It breaks down your nutrient intake, including omega-3 and omega-6 fats, and it’s fairly detailed in its list of foods. For example, you can differentiate between regular eggs vs. omega-3-enhanced eggs and grass-fed beef vs. regular beef. It doesn’t break out DHA/EPA vs. other omega-3 fats, though.

Increasing fish consumption or supplemental marine oils:

The pro-resolving lipid mediators are derived from EPA and DHA, found in salt-water fish oil, as well as arachidonic acid, found in meat. If you aren’t eating much fish or getting much DHA or EPA in your diet, then you may want to consider supplemental marine oil.

Talk to your doctor if you have any questions on whether supplements are right for you and at which doses. High doses of fish oil may interact negatively with certain medications.

Clinical trials show that omega-3 fatty acid supplements are not miracle drugs, when it comes to the resolution of inflammation.[ref] Some studies show great results, but other studies don’t show much benefit. Many use lower doses of supplements, include other types of omega-3s (such as flax seed), or only look at a very short-term impact.

Is more better? A recently concluded trial using vitamin D and/or fish oil (compared with placebo) showed that 1,000 mg of fish oil didn’t reduce the risk of cardiovascular disease in people who normally eat fish. But supplemental fish oil did reduce CVD risk (e.g. heart attacks) in people with below-average fish intake.[ref]

Prescription DHA/EPA: One hypothesis why clinical trials on fish oil have mixed results is that the doses used aren’t high enough and/or the quality of the product isn’t pure enough. Pharmaceutical companies have seen this as a market for prescription products. High-dose, pharmaceutical-grade DHA and EPA pills, such as Lovaza, have been shown in clinical trials to increase several specific SPMs.[ref] Lovaza is prescribed for reducing triglycerides.[ref]

Clinical trials of high doses of DHA/EPA:

Clinical trials using high doses of DHA/EPA and also measuring specialized pro-resolving mediators (SPMs) show:[ref]

  • In chronic kidney disease, 4g/day of an omega-3 supplement for eight weeks increased resolvins (RvE1, RvE2, RvE3, RvD5).
  • In overweight major depressive disorder patients, supplementing with between 1 and 4 g/day of EPA was investigated. The results showed that all of the supplemental doses increased EPA, DPA, and subsequent SPM levels in a dose-dependent fashion.[ref] (Note that this clinical trial didn’t find that EPA was better than placebo at reducing depressive symptoms – everyone improved, even the placebo group.)[ref]
  • In pregnancy, 3.7 g of supplemental DHA/EPA increased SPMs in offspring.
  • In peripheral artery disease, a 4.4g supplement of DHA/EPA for 3 months increased resolvin E3.
  • Another study of peripheral artery disease found that a marine oil supplement of 4.5g (DHA/EPA/DPA) increased maresins.
  • A marine oil supplement in healthy people increased several different SPMs.
  • In people with arthritis, a microalgae oil supplement containing 2.1g DHA/day for ten weeks increased SPMs.

Oxidation in fish oil supplements:
A real concern with taking fish oil supplements is that many are oxidized, possibly leading to negative effects from the supplement rather than increased SPMs. Exposure to air or to higher temperatures accelerates the oxidation of fish oil supplements. You’ll want to check the expiration dates on fish oil supplements. Some people suggest keeping them in the refrigerator, especially if you live in a warm locale.[ref]

What about arachidonic acid?
Arachidonic acid is the omega-6 precursor to lipoxins. Most people get plenty of AA in their diets. Foods high in arachidonic acid include chicken, eggs, pork, beef, milk, and salmon. The only significant plant sources of arachidonic acid for vegans are red and brown seaweed. Keep in mind that arachidonic acid can be converted into the lipoxin SPMs, but also converted into proinflammatory molecules also. Going overboard with AA is likely not needed. Note that the body can also convert linoleic acid into arachidonic acid. Linoleic acid is found in vegetable oils, nuts, and seeds – abundant in the modern diet.

Medications that block the formation of SPMs

A study examining how muscles rebound from unaccustomed hard exercise showed that ibuprofen (Advil) blocks the formation of proinflammatory mediators, which was expected. But, the researchers also detected that ibuprofen blocked the formation of SPMs (lipoxins, resolvins, and protectins).[ref]

Zileuton, a leukotriene synthesis inhibitor, also blocks the formation of SPMs.[ref]

Medications that increase the formation of SPMs.

Traumeel, a herbal pain relief product offered as an injection or cream, has been shown to increase the production of resolvin D2, resolvin D5, and lipoxin A4 after 24 hours (animal study, injections).[ref]


Members Blueprint:

This section includes information for members on research on increasing the formation of SPMs via supplement stacks and dietary changes. I go into details on omega-3 vs omega-6 sources, and I’ll explain the differences in SPMs, krill oil, fish oil, and algae oil. Plus, I’ll cover the timing of supplements and ways to change your omega 6: omega 3 ratio.  Consider joining today to see the rest of this article. It is worth the monthly membership fee.

Specialized Pro-resolving Mediator Supplements and Stacks:

Natural substances that increase the formation of SPMs

This section of the article is only available to Genetic Lifehacks members.

Not a member? Join Now.


Member Benefits:

Read this Member's Only section.

See your genotype in each article.

Print out topic summary reports.


Conclusion:

Targeting the resolution of inflammation rather than just blocking the formation of proinflammatory cytokines is likely to help prevent and reverse chronic diseases.

While this whole article has focused on the resolution of inflammation, the other half of the picture is to stop the source of inflammation.

Modern sources of inflammation include cigarette smoke, air pollution exposure, a crappy diet, poor sleep, chronic infections (e.g., gum disease), or stress.

Your source of chronic inflammation is likely not the same as mine.

Not everyone reacts to inflammatory substances in the same way. One person may be able to eliminate a little arsenic with no problem, but they may not be able to handle organophosphate pesticides.

Start by looking at your genetic variants that increase inflammatory cytokines. Also, look at your detoxification genetic variants. If you see a lot of risk alleles highlighted, go and read the article. For example, some people should be careful to avoid BPA or phthalates, while others should focus on certain pesticides. Arsenic in your well water may be a problem when combined with certain genetic variants. If air quality is poor in your area, an indoor air filtration system may be a good investment.

Consider ways to limit inflammatory conditions in the body, and then couple that with ways to boost the resolution of inflammation.


Related Articles and Topics:

TNF-alpha: Inflammation and Your Genes
Do you feel like you are always dealing with inflammation? Joint pain, food sensitivity, etc? Perhaps you are genetically geared towards a higher inflammatory response. Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system.

L-theanine for anxiety: genetics and nature’s chill pill
L-theanine is known for reducing anxiety and promoting sleep. Discover the many benefits of l-theanine and how supplementation might work for you.

Quercetin: Scientific studies + genetic connections
Quercetin is a natural flavonoid acting as both an antioxidant and anti-inflammatory. This article focuses on the results of clinical trials involving quercetin as well as linking to specific genetic topics. By using your genetic data, you can make a more informed decision on whether quercetin is worth trying.

Depression Causes: Genetic Overview
Depression can have multiple physiological causes. This article ties together 9 separate articles on depression to simply your genetic search.

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https://academic.oup.com/HTTPHandlers/Sigma/LoginHandler.ashx?error=login_required&state=178926e4-6e35-4c5a-8944-5566db5f3171redirecturl%3Dhttpszazjzjacademiczwoupzwcomzjjnzjarticlezj141zj7zj1247zj4743365. Accessed 2 Mar. 2022.

 


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.