Fats Against Inflammation: How Omega-3 and the N-6/N-3 Balance Affect Chronic Disease

Nutrients has published an editorial that “collects under one cover” six papers on how dietary polyunsaturated fatty acids (PUFAs) manage inflammation and affect the risk and course of chronic diseases. The authors explain why the omega-6/omega-3 balance, membrane composition, and PUFA derivatives - specialized pro-resolving mediators (SPMs) - can change the rules of the game: from metabolic disorders and liver disease to pain and response to chemotherapy.

Background

Chronic, “smoldering” inflammation is a common denominator for most non-communicable diseases: metabolic disorders, fatty liver disease, cardiovascular disease, oncology, and chronic pain. Against this background, interest in fat in the diet has gone far beyond calorie counting: the type of polyunsaturated fatty acids (PUFA), their balance, and how they are integrated into cell membranes directly determine which inflammation mediators the body will synthesize and how quickly the immune response can “self-terminate” without entering the chronic phase.

Dietary PUFAs are not just fuel. Omega-6 provides a substrate for eicosanoids, many of which support the inflammatory cascade, while omega-3 (EPA/DHA) is the raw material for specialized pro-resolving mediators (resolvins, protectins, maresins), which do not “silence” the immune system, but switch it from attack mode to recovery mode. At the same time, the proportion of EPA/DHA in membranes changes the “settings” of receptors and signaling platforms on the cell surface, affecting tissue sensitivity to cytokines, stress, and even antitumor drugs. This is why a shift in diet towards excess omega-6 and deficiency of omega-3 is considered one of the key dietary drivers of systemic inflammation.

The clinical picture is far from black and white. Randomized omega-3 trials often yield mixed results: the effect depends on the dose and form (ethyl esters, triglycerides, phospholipids), duration (months are needed to rebuild membranes), initial nutrition, and which endpoints are chosen (biomarkers vs. clinical outcomes). Tissue specificity is added: where inflammation is “tied” to lipotoxicity (liver), to a resolution deficit (periodontium, some pain syndromes), or where the lipid signature of membranes is important (oncology), omega-3 and their derivatives may work significantly more effectively.

The scientific agenda is therefore shifting from talk of “good” and “bad” fats to precise biology: which PUFAs, in what form, and for how long are needed to change membrane composition and mediator profiles; in which disease phenotypes does this provide clinical benefit; how to combine nutrition and nutraceuticals with standard therapy to enhance response and reduce toxicity. The special editorial issue of Nutrients, to which this article belongs, is gathering precisely such mechanistic, clinical, and interdisciplinary work – from microbiota and short-chain acids to tumor sensitivity to chemotherapy – to move beyond the abstract “fat is good/bad” to a manageable, evidence-based anti-inflammatory strategy on the plate.

The main thing in a nutshell

• The Western diet, which is rich in omega-6 and deficient in omega-3, has shifted the n-6/n-3 ratio to levels that are about 20 times higher than they were a century ago; this is associated with decreased immune function and increased inflammatory conditions.
• The Mediterranean approach (high in plant fiber, less red meat, olive oil as the main fat) is consistently associated with better outcomes compared with the "Western" diet.
• Omega-3s (EPA/DHA) are generally pro-resolving: in RCTs they reduced levels of pro-inflammatory mediators; however, the effect often disappears after discontinuation of supplementation, and clinical data are mixed.
• To date, only three prescription omega-3 drugs (Lovaza, Omtryg, Vascepa) have been approved in the United States, showing how demanding the clinical evidence base is for fat supplements.

The special issue does one important thing: it does not argue about “fats in general,” but examines specific scenarios and mechanisms – where PUFAs help, where they interfere, and how to integrate them into clinical logic.

What's Included in the Issue (and Why It's Important)

• Reviews:
  • PUFAs and oral health - how omega-3s shift immune responses in cervical tissues and periodontitis.
  • Microbiota → SCFAs → heart failure: why fiber fermentation by gut bacteria may influence systemic inflammation and hemodynamics.
• Original research:
  • Oral fat alters adipose tissue hormones: after a single lipid intake, people showed changes in the level of the antimicrobial peptide CAMP, demonstrating a direct effect of “what we eat” → “what adipose tissue secretes.”
  • Liver lipotoxicity: the CCN1/integrin α5β1 axis triggers NLRP3-dependent pyroptosis, a mechanism through which excess lipids damage the liver and increase inflammation.
  • Oncology and membranes: enrichment of membranes with DHA increases the sensitivity of tumor cells to doxorubicin, an example of how lipid composition alters the effect of chemotherapy.
  • Pain and “pro-resolution” deficiency: arachidonic acid “primes” vulvar fibroblasts to the inflammatory response; in parallel, a deficiency of SPM was recorded, a possible explanation for chronic pain in vulvodynia and a target for therapy.

How does this fit into the bigger picture of inflammation?

Chronic inflammation is the common denominator of metabolic diseases, non-alcoholic fatty liver disease, coronary heart disease and "pain diseases". PUFAs work at several levels:

• Membrane material: the more DHA/EPA in phospholipids, the different the “settings” of receptors and signaling platforms on the cell surface - this can enhance antitumor and anti-inflammatory responses and even enhance the effect of chemotherapy.
• Raw materials for mediators: SPM (resolvins, protectins, maresins) are synthesized from omega-3, which suppresses inflammation not with a rough block, but with a “smart completion” of the response.
• n-6/n-3 ratio: When n-6 is high, the background shifts towards pro-inflammatory eicosanoids; lowering this ratio is one of the few levers that can be touched by diet and supplements.

What does it mean "on a plate"

• Shift the balance of fats:
  • Add 2-3 fish dishes per week (salmon, mackerel, sardines) or use products enriched with omega-3;
  • Maintain olive oil as a basic cooking fat instead of a mixture of vegetable oils with high n-6;
  • Don’t “hunt” for zero omega-6, but reduce the excess (processed foods, fast food, “hidden” oils).
• Supplements - as indicated:
  • Omega-3 capsules may reduce inflammatory markers;
  • Actual clinical effects depend on dose, form, duration and initial diet;
  • There are only a few drugs with evidence and approval, so self-medication is not a good idea; discuss doses and risks with your doctor, especially when taking anticoagulants.

Scientific agenda (where to look next)

• Duration and "aftereffect": why does the effect disappear after omega-3 is discontinued and how to maintain the "resolution" of inflammation? Protocols with sufficient duration and "pick-up" of nutrition are needed.
• Forms and bioavailability: free acids, ethyl esters, phospholipids - formulations differ in absorption and "integration" into membranes; this must be taken into account in clinical trials.
• Precise phenotypes: where will omega-3 "shoot" stronger - liver diseases with lipotoxicity? Chronic pain with SPM deficiency? Oncology, where the lipid signature of membranes is important? The special issue already outlines these "niches".

Summary

The editorial neatly draws together the disparate threads into a single picture: dietary fat is the body’s language for negotiating inflammation. By shifting the vocabulary toward omega-3s and “resolution,” we have a better chance of managing chronic diseases, from metabolic to cancer to pain. The next step is long, well-designed RCTs that take into account the n-6/n-3 balance, omega-3 form, membrane effects, and markers of resolution. In the meantime, the smart strategy is to fix your plate, not wait for “miracle capsules.”

Source: Falsetta ML, Chrysilla E. The Connections Between Dietary Fatty Acids, Inflammation, and Chronic Disease. Nutrients 17(14):2322, July 15, 2025. Open access. https://doi.org/10.3390/nu17142322