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Emerging Ingredients in Managing a Modern Epidemic – Dry Eye Disease

Dry eye disease (DED) is a widespread condition marked by tear film hyperosmolarity and ocular inflammation, significantly impacting quality of life. Recent research suggests that dietary supplements like omega-3 fatty acids, lutein, hyaluronic acid and bilberry extract can improve tear quality and reduce DED symptoms by addressing underlying inflammation and supporting ocular health.

Author: Daria Šurić, MPharm

Dry eye disease (DED) is common; its prevalence worldwide is up to 34%. Dry eye disease is seen with increased prevalence in patients with autoimmune diseases, which affect approximately 8% of the population, of whom 78% are women. Dry eye disease also more often affects postmenopausal women and the elderly, as well as younger population due to prolonged screen time. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland.

Dry eye is clinically subdivided into subtypes: one with decreased tear secretion (aqueous-deficient DED), and one with increased tear evaporation (hyperevaporative DED). It can also be mixed in aetiology. Symptoms include dryness, excessive tearing, light sensitivity, and blurred vision. This leads to reduced quality of life.

Managing DED focuses on enhancing tear quality, reducing inflammation, and implementing dietary and lifestyle modifications. Tear substitutes, commonly used as a first-line treatment, offer temporary symptom relief but do not address the underlying inflammation. While topical corticosteroids can effectively reduce inflammation, their long-term use is limited due to potential side effects such as cataracts and glaucoma. Another treatment option, topical cyclosporine A, faces challenges related to its variable efficacy and limited availability.

A dangerous vicious cycle ensures between ocular inflammation and dry eye, which in turn may lead to sight-threatening complications (Figure 1.)1. The underlying inflammation and symptoms of DED, are treated with various anti-inflammatory agents and autologous and/or allogeneic serum drops. Considering the role of lifestyle in DED pathophysiology, lifestyle modifications, including diet, sleep, and physical activity are getting more attention. Among them, supplementation with omega-3 fatty acids shows the most promising results in alleviating subjective and objective measures of DED through a direct effect on the stability and production of the tear film, inflammation markers, and corneal nerve regeneration2.

FIGURE 1. The vicious cycle of ocular surface inflammation1

Microbiome and nutrients impact on DED

Emerging evidence suggests that the ocular surface and gut microbiomes play a significant role in the symptoms of dry eye disease (DED), with similarities to inflammatory diseases in other organ systems. Nutrient deficiencies, both micro- and macronutrient, are key in maintaining healthy microbiomes and have been linked to ocular surface disease. However, there is a lack of comprehensive reviews on how these deficiencies contribute to DED. The following review2 examines the composition of healthy ocular and gut microbiomes and explores how nutrient deficiencies may alter these microbial populations, thereby affecting ocular health. It highlights the connection between vitamin B1 and iron deficiencies with reduced butyrate levels – a fatty acid associated with inflammatory conditions like ulcerative colitis, which is known to be linked to ocular surface diseases. Vitamin B12 is recognized for its role in sustaining gut microbial balance and its association with the severity of dry eye symptoms. Similarly, vitamin A and omega-3 polyunsaturated fatty acids have shown positive effects on gut microbial balance.

Selenium and calcium interact complexly with the gut microbiome and are involved in the development of thyroid orbitopathy. Additionally, diabetes mellitus is connected with changes in both the ocular microbiome and ocular surface diseases. Understanding how alterations in the gut and eye microbiomes impact DED could enhance our grasp of DED pathophysiology and lead to the development of more effective treatments.

There is emerging evidence that the ocular surface microbiome may be influenced by micro- and macronutrients such that diet may influence ocular surface disease. (Figure 2)3.

FIGURE 2. Visual graphic highlighting the complex relationship between diet, altered microbiomes, systemic inflammatory conditions, and DED3

This review highlights clear correlations between DED and the microbiomes of the gut as well as of ocular surface, and diet. The ocular surface microbiomes of patients with DED often displayed increased alpha diversity, with a predisposition to opportunistic and pathogenic bacteria. Furthermore, alterations in the gut microbiome, which are influenced by dietary intake, are associated with a wide spectrum of ophthalmic diseases that are not purely limited to the ocular surface.

Iron deficiency may lead to butyrate deficiency which decreases systemic inflammatory suppression, amongst other effects. Derangements in the intake of vitamin A, B1, B12, C, omega-3 fatty acids, calcium, and selenium are all associated with changes in the gut microbiome and linked to numerous ocular surface diseases. Associations of the translation between alterations of gut microbiota and those existing within the ocular surface need to be investigated, so that dietary or supplementation intervention may be a more objectively precise tool to utilize in managing dry eye. Beyond this, further investigation is warranted where individual dietary and supplementary factors are tested against the ocular microbiome and DED. Lastly, faecal microbiota transplantation for ophthalmic indications is an under-researched field, the exploration of which could lead to exciting discoveries in both the aetiology and treatment of ocular surface disease3.

The following study4 also speaks in favour of supplementing different nutrient combinations for DED symptoms improvement.

To examine the effect of a combined dietary supplement containing fish oil, lactoferrin, zinc, vitamin C, lutein, vitamin E, γ-aminobutanoic acid, and Enterococcus faecium WB2000 on dry eye.

This study involved a preliminary rat model and a human clinical trial to evaluate the effects of a dietary supplement on dry eye disease. Forty volunteers, aged 22 to 59, were randomly assigned to either a supplement group or a placebo group and treated daily for 8 weeks. In rats, dry eye was mechanically induced, and they were given either the supplement or a placebo. Tear production was measured afterwards. In humans, various assessments, including tear production, keratoconjunctival epithelial damage, and subjective dry eye symptoms, were conducted at baseline and after 4 and 8 weeks.

The dietary supplement dose-dependently reduced the decline in tear production in rats. In humans with confirmed dry eye, clinical symptoms improved more significantly in the supplement group than in the placebo group at both 4 and 8 weeks. The increase in tear production was also greater in the supplement group, and no adverse events were reported.

Omega 3 and DED

Emerging clinical evidence suggests that dietary essential fatty acids (FAs), particularly omega-3 FAs, may effectively manage DED by modulating inflammatory responses. Studies have shown that omega-3 FAs can influence the composition of the lacrimal gland and improve tear secretion.

The following meta-analysis5 aimed to determine whether supplementing with omega-3 fatty acids improves dry eye symptoms. The study analyzed data from 4,246 participants, with an average age of 48, of whom 57% were women and 43% were men. All participants were diagnosed with dry eye disease. Researchers conducted a meta-analysis of 19 RCTs involving varying doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The daily intake of these omega-3 fatty acids ranged from approximately 227 to 3,000 mg, with EPA making up 60% to 80% of the dose. The intervention periods ranged from 1 to 12 months.

Omega-3 fatty acid supplementation significantly reduced dry eye symptoms compared to placebo, showing a large effect size. Participants reported noticeable relief from dryness and irritation. The analysis found a substantial improvement in Tear Break-Up Time (TBUT), indicating better tear film stability in those taking omega-3 supplements. Although the improvement in Schirmer test scores was modest (small effect size), it still suggested enhanced tear production with omega-3 supplementation. Omega-3 supplements reduced tear osmolarity to a medium effect size, implying better tear quality and reduced tear film hyperosmolarity. Improvements in Corneal Fluorescein Staining (CFS) were modest but present, indicating some level of reduced corneal surface damage.

The study found that longer duration interventions, higher doses of omega-3s, and higher percentages of EPA generally improved dry eye symptoms, TBUT, and osmolarity. However, this trend was less evident for CFS.

While the findings are promising, the analysis noted significant heterogeneity among the included studies. This variability stemmed from differences in diagnostic criteria for dry eye, participant demographics, and underlying causes of dry eye. Another limitation was the lack of assessment of participants’ dietary intake of omega-3s, which could influence the outcomes.

The meta-analysis supports the potential benefits of omega-3 fatty acid supplementation in managing dry eye disease. By improving tear stability, reducing osmolarity, and alleviating symptoms, omega-3s offer a promising adjunctive treatment for DED. However, further research is needed to standardize dosing regimens and better understand the long-term effects and optimal formulations of omega-3 supplements.

For healthcare professionals and patients, incorporating omega-3 fatty acids into the dietary regimen could be a valuable strategy in the comprehensive management of dry eye disease.

Omega-6 

Omega-6 fatty acids, especially gamma-linolenic acid (GLA), have shown potential in managing dry eyes.

Omega-6 fatty acids, particularly GLA, are crucial for maintaining ocular health due to their anti-inflammatory properties and role in cell membrane function. They help manage dry eyes through several mechanisms:

  1. Anti-inflammatory effects: GLA is metabolized into dihomo-gamma-linolenic acid (DGLA), which produces anti-inflammatory prostaglandins, reducing inflammation on the ocular surface.
  2. Enhanced tear production: Omega-6 fatty acids support the production of the lipid layer of the tear film, helping to reduce tear evaporation and stabilize the tear film.
  3. Cell membrane integrity: They contribute to the structural integrity of cell membranes in the eye, promoting overall ocular surface health.

The following study has investigated the efficacy of omega-6 combined with omega-3 in dry eye management.

Participants with moderate to severe DED were enrolled in a prospective, randomized, double-masked parallel group study6. Participants ingested either the treatment supplement containing omega-3 and omega-6 fatty acids (1200 mg eicosapentaenoic acid, 300 mg docosahexaenoic acid, 150 mg γ-linoleic acid) or the placebo (coconut and olive oil) daily for 3 months. To determine compliance, Omega-3 Index blood tests were conducted. At baseline and at 1 and 3 months, the following assessments were conducted: Ocular Surface Disease Index (OSDI) questionnaire and Symptom Assessment Questionnaire in Dry Eye, noninvasive tear breakup time, tear meniscus height, tear osmolarity, ocular redness, surface staining, Schirmer test, and meibography.

Fifty participants completed the study: 24 randomized to treatment and 26 randomized to placebo. Although there was an improvement in OSDI score at 3 months for both groups participants with baseline OSDI scores >52 demonstrated an even larger significant improvement in symptoms with the treatment at 3 months compared with baseline. There were no significant changes in any of the ocular assessments at 1 or 3 months. After 3 months, Omega-3 Index increased by 34% in the treatment group and did not change in the placebo group.

Conclusion of the study: supplementation with eicosapentaenoic acid, docosahexaenoic acid, and γ-linoleic acid resulted in a significant and clinically meaningful improvement of dry eye symptoms in extremely symptomatic participants with DED (OSDI ≥52).

Sea buckthorn (Hippophae rhamnoides)

Sea buckthorn (Hippophae rhamnoides) has been used in Asian traditional medicine for centuries, and SB berries are included in the Chinese Pharmacopeia. Sea buckthorn oil is rich in lipophilic antioxidants and SB seed oil especially contains high proportions of (n-3) and (n-6) fatty acids. Positive effects of SB oil on skin and mucous membrane have been reported.

In double-blind, randomized, parallel trial7, 20- to 75-y-old women and men experiencing dry eye symptoms consumed 2 g of SB or placebo oil daily for 3 months from fall to winter. Clinical dry eye tests and symptom follow-ups were performed. Tear film hyperosmolarity is a focal factor in dry eye. There was a general increase in the osmolarity from baseline to the end of the intervention. Sea buckthorn oil attenuated the increase in tear film osmolarity during the cold season and positively affected the dry eye symptoms.

Lutein and zeaxanthin in the management of dry eyes

Lutein and zeaxanthin, carotenoids known for their role in eye health, have emerged as promising agents in the management of dry eyes. These nutrients are primarily recognized for their antioxidant properties and their role in protecting the macula, but recent studies suggest they may also alleviate symptoms of dry eye syndrome. This assay explores the potential benefits of lutein and zeaxanthin in dry eye management, providing a pharmacist’s perspective on their application in patient care.

Lutein and zeaxanthin are deposited in the retina and are known to filter harmful blue light and reduce oxidative stress, which can have secondary benefits for ocular surface health. Both lutein and zeaxanthin help neutralize reactive oxygen species (ROS) that can damage the corneal and conjunctival cells, which are often implicated in dry eye disease. By mitigating oxidative stress, these carotenoids reduce inflammation on the ocular surface, a key contributor to dry eye symptoms. Lutein and zeaxanthin may enhance the stability and quality of the tear film by protecting the epithelial cells responsible for mucin production, which is crucial for tear film integrity.

Emerging research supports the role of lutein and zeaxanthin combined with other ingredients in managing dry eye symptoms.

Hyaluronic acid

Hyaluronic acid is a naturally occurring substance known for its excellent moisture-retaining properties. It is widely used in ophthalmology, particularly in artificial tears and eye drops, to provide lubrication and relief from dry eye symptoms.

When taken as an oral supplement, hyaluronic acid may also contribute to ocular surface hydration by supporting the body’s natural production of tears and improving the quality of the tear film. Clinical studies have shown that oral hyaluronic acid can reduce the severity of dry eye symptoms, particularly in individuals with mild to moderate dry eye disease.

The following study8 aimed to evaluate the effectiveness of oral hyaluronic acid (HA) in treating DED. It was a prospective randomized controlled trial with 54 participants, who were divided into a study group and a control group. All participants received topical HA treatment, while the study group also received oral HA supplementation. Key ocular surface parameters – ocular surface disease index (OSDI), tear break-up time (TBUT), corneal fluorescein staining (CFS), and Schirmer test results – were measured.

The study found that the group receiving oral HA showed significant improvements in OSDI, TBUT, and CFS scores after 1 and 3 months of treatment compared to baseline measurements. Specifically, OSDI scores decreased significantly, indicating reduced symptoms, while TBUT and CFS improved, showing better tear stability and corneal healing.

The conclusion is that a combination of oral and topical HA provides more effective relief and corneal healing in DED patients than topical HA alone.

Bilberry (Vaccinium myrtillus L.)

Herbal extracts like bilberry have a long history of use in eye health, particularly in managing dry eyes and other ocular conditions. Bilberry is rich in anthocyanins, which have antioxidant and anti-inflammatory properties that can support the health of the retina and improve circulation in the eyes. These properties may also contribute to better tear production and ocular surface health.

The study investigated the bioavailability, effectiveness in alleviating dry eye symptoms, and antioxidant potential of a standardized bilberry extract (Mirtoselect®) derived from fruits. The research involved both animal and human trials. In the animal study, rats were given either Mirtoselect® or a highly purified anthocyanin-rich bilberry extract, and their blood was analyzed for anthocyanoside levels. The results showed that Mirtoselect® had higher bioavailability despite a lower anthocyanoside dosage.

In the human trial9, 22 participants with dry eye symptoms were randomly assigned to receive either Mirtoselect® or a placebo for four weeks. Ophthalmological tests, including Schirmer’s test for tear production and antioxidant potential measurements, were conducted before and after the treatment period. The bilberry extract group showed significant improvements in tear secretion and antioxidant potential compared to the placebo group, especially in participants with more severe dry eye symptoms.

The study concluded that Mirtoselect® is a more bioavailable form of bilberry extract, enhancing tear production and antioxidant levels in patients with dry eye disease.

Conclusion

Recent research highlights the potential of dietary supplements and lifestyle modifications in managing DED. Omega-3 and omega-6 fatty acids, for example, have shown promise in improving tear quality, reducing inflammation, and stabilizing the tear film. Additionally, emerging studies suggest that the gut and ocular surface microbiomes play a role in DED, with nutrient deficiencies potentially altering these microbial populations and exacerbating the condition.

Various nutrients, including omega-3, lutein, zeaxanthin, and hyaluronic acid, have been studied for their effectiveness in DED management. Omega-3 supplements have been shown to improve tear stability and reduce symptoms. Similarly, lutein and zeaxanthin, known for their antioxidant properties, may enhance tear film quality. Oral hyaluronic acid has also been found to improve tear production and corneal healing when combined with topical treatments.

Herbal extracts like bilberry, rich in anthocyanins, have demonstrated benefits in improving tear production and antioxidant potential, particularly in patients with severe DED symptoms.

Overall, these findings suggest that dietary supplementation, particularly with omega-3 and specific micronutrients, could offer significant benefits in managing DED, potentially improving patient outcomes by addressing both symptoms and underlying causes.

References:

  1. Bhavsar AS, Bhavsar SG, Jain SM. A review on recent advances in dry eye: Pathogenesis and management. Oman J Ophthalmol. 2011;4(2):50-56. doi:10.4103/0974-620X.83653
  2. Hodžić, Nejra et al. “The Potential of Omega-3 Fatty Acids in the Treatment of Dry Eye Disease: A Narrative Review.” Al- Anbar Medical Journal (2024): n. pag.
  3. Pilkington M, Lloyd D, Guo B, Watson SL, Ooi KGJ. Effects of dietary imbalances of micro- and macronutrients on the ocular microbiome and its implications in dry eye disease. Explor Med. 2024;5:127–47. https://doi.org/10.37349/emed.2024.00211
  4. Kawashima M, Nakamura S, Izuta Y, Inoue S, Tsubota K. Dietary Supplementation with a Combination of Lactoferrin, Fish Oil, and Enterococcus faecium WB2000 for Treating Dry Eye: A Rat Model and Human Clinical Study. Ocul Surf. 2016;14(2):255-263. doi:10.1016/j.jtos.2015.12.005
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  6. Ng A, Woods J, Jahn T, Jones LW, Sullivan Ritter J. Effect of a Novel Omega-3 and Omega-6 Fatty Acid Supplement on Dry Eye Disease: A 3-month Randomized Controlled Trial. Optometry and Vision Science : Official Publication of the American Academy of Optometry. 2022 Jan;99(1):67-75. DOI: 10.1097/opx.0000000000001826. PMID: 34882608.
  7. Larmo PS, Järvinen RL, Setälä NL, et al. Oral sea buckthorn oil attenuates tear film osmolarity and symptoms in individuals with dry eye. J Nutr. 2010;140(8):1462-1468. doi:10.3945/jn.109.118901
  8. Kim, Yeseul et al. “Oral Hyaluronic Acid Supplementation for the Treatment of Dry Eye Disease: A Pilot Study.” Journal of ophthalmology vol. 2019 5491626. 25 Sep. 2019, doi:10.1155/2019/5491626
  9. Riva, A et al. “The effect of a natural, standardized bilberry extract (Mirtoselect®) in dry eye: a randomized, double blinded, placebo-controlled trial.” European review for medical and pharmacological sciences vol. 21,10 (2017): 2518-2525.

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