Specialised pro-resolving mediators (SPMs) are bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs). They are naturally produced endogenously but can also be supplemented as an SPM-enriched fish oil. SPMs include lipoxins, which are derived from omega-6 arachidonic acid, and resolvins, protectins and maresins, which are derived from omega-3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA).¹

Figure 1. Pro-Inflammatory and Pro-Resolving Lipid Mediators²

The most important distinction to make between the action of SPMs and their PUFA precursors is that ‘immunoresolvent’³ properties are unique to SPMs. The therapeutic effects of EPA and DHA have been attributed to their ability to reduce inflammation. SPMs take this one step further. They facilitate the resolution of inflammation by counter-regulating pro-inflammatory chemical mediators.⁴

Resolution is an active, programmed and highly regulated process.^5,6 Lipoxins carry the ‘stop’ signal for neutrophil infiltration/inflammation and counter-regulate leukotriene (LT)-stimulated neutrophil responses. Lipoxins direct the transition from the production of pro-inflammatory eicosanoids to pro-resolving lipids mediators, a process known as lipid mediator class switching. Following on from this, resolvins and protectins orchestrate the clearance of apoptotic neutrophils and cellular debris from the site of inflammation via resolving macrophages. In this way, SPMs are collectively responsible for reducing the magnitude and duration of inflammation, promoting return to homeostasis, blocking chronic inflammation, reducing fibrosis, and enhancing wound healing and tissue regeneration.^4,7,8

Lipoxin biosynthesis occurs naturally over the course of self-limiting inflammation,^4,9 however, impairment of this process occurs due to insufficient concentrations of pro-resolving lipid mediators. This leads to chronic inflammation and excessive tissue damage.¹⁰ Observational studies show that concentrations of SPMs are disordered in inflammatory conditions such as Alzheimer’s disease, cardiovascular disease, infectious diseases including periodontitis, obesity and diabetes, autoimmune diseases (e.g. rheumatoid arthritis,² multiple sclerosis¹¹ and lupus),¹² severe asthma,¹³ endometriosis,¹⁴ post-stroke,¹⁵ and immediately post-surgery.¹⁶ Supplementing with SPMs may be beneficial in these conditions, where the body does not produce enough SPMs to terminate inflammation.

Clinical Trials Support SPM Supplementation

Chronic Pain

Four weeks of oral supplementation with an SPM-enriched marine lipid fraction has shown promising effects in chronic pain. In this open-label clinical trial (n=45), significant positive change was found for measures of pain intensity and pain interference. Significant improvements were also reported across subdomains of fatigue, sleep disturbance, physical and social functioning, depression, and anxiety, indicative of improvements in quality of life from a biopsychosocial perspective. The SPM-enriched marine oil was standardised to 17-hydroxy-docosahexaenoic acid (17-HDHA) and 18-hydroxy-eicosapentaenoic acid (18-HEPE), the precursors of D series resolvins and E-series resolvins, respectively. A total of 1500 mg/day of the marine lipid fraction was administered each day, though the dose was lowered to 1000 mg/day in those whose pain intensity decreased substantially after two weeks.¹⁷

Symptomatic Knee Osteoarthritis (OA)

The GAUDI study, a randomised, double-blind, placebo-controlled pilot study (n=51), revealed that 12-weeks of SPM consumption reduced pain and improved quality of life in osteoarthritis (OA) patients. Participants took 2000 mg/day of SPM-enriched oil for the first six weeks, and 1000 mg/day for the remaining six weeks of the treatment period. While SPMs were able to promote larger changes in total pain over 12 weeks of supplementation, they did not produce long-lasting residual effects. Twelve weeks after supplementation ceased, pain scores were similar between the SPM and placebo groups, suggesting that continuous supplementation is required to maintain clinical benefits. However, this study was confounded by the use of olive oil as the placebo, which led to a pattern of improvement in OA patients.¹⁸

Peripheral Artery Disease (PAD)

Short-term use of SPM-enriched marine oil may also be effective for patients with peripheral artery disease (PAD), an advanced from of atherosclerosis characterised by chronic inflammation. In an open-label pilot study, the effects of SPMs were assessed in 10 healthy volunteers and 10 patients with PAD. Doses escalated from 1500 mg, 3000 mg and 6000 mg of SPM-enriched marine oil per day. Each treatment period lasted for five days and was separated by a nine-day washout period. Overall, supplementation induced a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophage (MDM), as indicated by several cellular biomarkers and biochemical measures. Among these were a dose-dependent effect on omega-3 index, a downward trend in high-sensitivity C-reactive protein (hs-CRP) levels, changes in MDM gene expression, and a significant increase in the plasma SPM-to-prostaglandin ratio in the PAD cohort.¹⁹

Co-supplementation with Curcumin for Inflammation-Associated Discomfort

Another open-label pilot study (n=29) observed the effects of a combination of an SPM-enriched marine oil and a highly bioavailable curcumin supplement taken for 60 days. Within 30 days, treatment improved pain and discomfort in generally healthy individuals with mild to moderate pain. The SPM supplement provided 500 mg of marine lipid concentrate and 300 μg of SPM precursors including 14-HDHA, 17-HDHA and 18-HEPE. The curcumin supplement contained 200 mg of curcuminoids and 150 mg galactomannans (from Fenugreek seed).²⁰

Preclinical Research – A Wellspring of Potential Uses

An abundance of preclinical evidence signposts other uses for SPMs. Controlling tissue damage from infectious diseases; promoting colonic mucosal wound repair, relevant for inflammatory bowel disease (IBD); and reducing neuroinflammation, significant for Alzheimer’s disease, Parkinson’s disease, and depression,²¹ are some of conditions in which in vivo evidence has suggested potential benefit from increased SPM supply. Clinical evidence is yet to confirm these indications.

Resolving Inflammation With SPMs

SPMs present a valuable treatment option in conditions characterised by unresolved/chronic inflammation. Use of SPMs may be enhanced by co-supplementation with anti-inflammatory agents such as curcumin, offering a potentially synergistic approach to the treatment of inflammatory pain. In time, future studies may reveal the extent to which SPM supplementation can lead to clinical improvements in cardiometabolic health, neuroinflammatory diseases and autoimmune conditions.

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