Nutrition and diet for dry eye disease: Insights toward holistic management

Abstract

Dry eye disease (DED) is one of the most common eye problems in the aging population. Hyperosmolarity triggers the immune response in DED and consequently activates the self-perpetuating immune cycle, leading to chronic damage of the ocular surface. This event causes symptoms such as a burning sensation, irritation, redness, photophobia, and blurred vision in DED patients. Subsequently, the quality of life gets significantly affected. The rising demand for DED management and treatment solutions, and the desirable outcomes from innovative therapies that draw global interest provide evidence to demonstrate the role of diet and nutrition in DED. Nutritional deficiency and a Westernized diet contribute to the chronic systemic progression of DED symptoms. It has been revealed in several published studies that the use of nutrients and dietary supplements improves the ocular surface and acts as a protective factor against DED. - We reviewed nutrition and dietary aspects in managing DED and its associated consequences, based on published studies, and reached an evidence-based conclusion.

Dry eye disease (DED) is the consequence of tear film alteration, which is either caused by aqueous deficiencies (aqueous-deficient dry eye [ADDE]) or elevated evaporation rate (evaporative dry eye [EDE]), ultimately due to lipids’ modulations. ADDE and EDE lead to an increase in the solute concentration of tear film, consequently forming tear hyperosmolarity.[1] These conditions result in chronic inflammation that plays a crucial role in dry eye (DE) pathogenesis. Aging and oxidative stress trigger DED, where reactive oxygen species (ROS) form that may cause DE pathology that leads to chronic inflammation and cell damage.[2] Interestingly, the ocular surface of DED patients shows a distinct immune cell population. Sethu et al.[3] reported that DED severity was linked to higher levels of activated neutrophils and gamma delta T cells, as well as lower levels of natural killer cells.

DED can cause a broad range of signs and symptoms that stretch from foreign object sensation to severe visual impairment. In addition, the sensation of itching, grit, and DE have been reported to be the most frequent symptoms. Several medical treatments have been suggested to manage DED. In moderate cases, lubricants and tear supplements are utilized. Similarly, the use of steroids, autologous serum enriched or deficient in platelet factors, and immunomodulators such as cyclosporin A.[4] Hygienic practice and environmental modifications have also been demonstrated to decrease the damage of tear film, for instance, glasses with lateral protection and humidifier usage have been shown to slow down DED progression.

Several studies have shown the contribution of diets and nutrients in the management and prevention of DED.[5,6,7] The most common nutritional deficiency associated with DED is vitamin A.[8,9] Likewise, lower vitamin D was found in the tear of DED patients, which signifies its association with DED severity.[10] Murugeswari et al.[11] revealed that vitamin D has a therapeutic potential as it protects the retinal pigment epithelium and stimulates angiogenesis under hyperoxia conditions. Similarly, dietary supplements consisting of polyunsaturated fatty acids (PUFAs), for example, omega-3 or omega-6 fatty acids (FAs), have been reported to improve the tear film and exert preventive effects against DED.[12,13] Furthermore, the Mediterranean diet, which is a rich source of PUFA, has shown ample evidence of beneficial improvement against cardiovascular diseases as well as DED.[14,15] Dietary PUFA has preventive factors against DE symptoms, and it could promote an anti-inflammatory/proinflammatory ratio and reduce proinflammatory prostaglandin levels in the lacrimal gland.[16,17] The focus of this review is to explore various studies of diets/nutrients and take an in-depth look at them to present the potential evidence for the treatment of DED and their mechanism of prevention.

Effects of diet on the molecular pathway

The ocular surface is constantly exposed to biotic and abiotic stimuli, particularly sunlight with UV wavelengths, which induces oxidative stress through accelerating the creation of ROS. Oxidative stress has a crucial role in the progression of Sjögren syndrome, a systemic autoimmune disease, which affects the lacrimal and leads to severe DED. Elevated oxidative stress causes an increase in ROS, lipid peroxidation-associated membrane damage, and inflammatory reactions in DEs.[18] Moreover, aging is a well-known factor for oxidative stress. With aging, the concentration of ROS increases; in contrast, the concentration of endogenous antioxidant species significantly reduces with aging.[19] Hyperosmolarity is a major factor in DED and causes an acute immune reaction.[20] Oxidative stress–induced activation of an adaptive immune reaction triggers the inflammatory cascade, consequently causing damage to the ocular surface.[20] Several key molecular and cellular mediators linked to DED are involved in the inflammatory cascade resulting in DED. For instance, cytokines are signaling molecules that are responsible for intercellular communication. The osmotic stress and inflammatory or mechanical insults cause upregulation of the production of proinflammatory cytokines in the tears of DE patients.[21] A clinical study reported that the tear of DED patients showed the upregulation of cytokines such as interleukin (IL)‐1, IL‐6, tumor necrosis factor (TNF)-α, and transforming growth factor-β1.[21] Jackson et al.[22] revealed that interferon-gamma (IFN-γ) altered significantly in ocular surface diseases and showed a correlation with tear hyperosmolarity and ocular surface staining. This study supports evidence that a specific cytokine as a biomarker could be a potential tool for the diagnosis of DED diseases in future for clinical practice. Likewise, IL-8 is regularly observed in the tear film and conjunctiva of patients with DEs.[21] Acera et al.[23] reported that the tears of patients with ocular surface disease showed an increased pro‐MMP‐9 level and higher activity of MMP-9.

Methods

Search strategies

An electronic literature search was conducted in PubMed, Web of Science, and Google Scholar to sort human studies, rodent studies, and molecular studies published till 2022 and written in English, including the following keywords or word phrases: dry eye diseases (DED), DED + diet, DED + dietary intervention, DED + functional foods, and DED + vitamins. The articles within the search results were further manually curated for relevance to dietary influences in DED.

Study criteria

To be eligible, a report had to fulfill the following criteria: first, it had to be an original study regarding the relationship between dietary intervention and patients with DED. To reduce inaccuracy, only the most common dietary consumption was characterized from the articles. Smokers, diabetics, subjects who had recent surgeries or medication that affects the dietary outcomes, and women who were pregnant or might become pregnant were excluded from this review.

Dietary nutrition and DED management

In recent years, there has been increasing attention to the lifestyle factors associated with DED as the cost of public health and financial burden increases with the aging population. Lifestyle intervention [see Tables 1 and 2], precisely diet, could be a promising strategy to be more cost-efficient than disease treatment at the population level for DED management [see Fig. 1].

Table 1:

In vivo and in vitro studies of DED and dietary intervention

Treatment	Study and year	Study design	Disease	Intervention	Main findings
Calorie restriction	Kawashima et al.[24]	In vivo study	Age-related DED	6 months- calorie restriction, modified diet	Reduced body weight, preserved the lacrimal functions
Vitamins	Zhang et al.[25]	In vivo study	DEDs	Eye drops containing vitamin E for 5 and 10 days	Soothed the tear film lipid layer, enhanced TBUT and corneal epithelial damages, reduced ROS production and inflammatory molecules
	Vicario-de-la-Torre et al.[65]	In vivo and in vitro	DEDs	Liposome-based artificial tear containing vitamin E	Reduced signs and symptoms of DED, enhanced the lipid layer of the tear film
	Zhang et al.[25]	In vivo study	DEDs	Vitamin A-containing eye drop	Suppressed the apoptosis of epithelial cells in mice with DED
PUFA	James et al.[26]	In vivo study	DEDs	0.5% Docosahexaenoic acid in diet for 77 days	Crossed the blood–retina barrier, protected against lipid peroxidation
Amino acids	Pehlivan et al.[27]	In vivo and in vitro study	DEDs	Cyclosporin A	Improved the healing time
	Mori et al.[28]	In vivo study	DEDs	PES_103- synthetic - Matrix metalloproteinases (MMPs) inhibitor-artificial tears- twice a day	Enhanced tear production
Functional food	Chung et al. 2012[29]	In vivo study	Ovalbumin allergen-induced allergic conjunctivitis	18 days protocol Ovalbumin- 0, 7, 15, and 18 days Curcumin- 14 and 17 days	Curcumin decreased infiltration of IL-4–and IL-5–producing cells in the conjunctival stroma
	Chen et al. 2010[30]	In vitro study	NaCl 90 mM induced hyperosmoticity	Cells exposed to the hyperosmotic medium for 24 h followed by curcumin for 30 min	Curcumin decreased the elevated IL-1β, IL-6, and TNF-α proteins induced by hyperosmotic stress
	Hong et al. 2020[7]	In vivo and in vitro study	PBS-diluted scopolamine injection- twice daily 2.5 mg/ml	A. koraiensis extraction- oral administration	Improved TBUT and enhanced tear production from the lacrimal glands

DED=dry eye disease, IL=interleukin, PBS=phosphate-buffered saline, ROS=reactive oxygen species, TBUT=tear film breakup time, TNF-α=tumor necrosis factor-alpha, A. koraiensis=Aster koraiensis

Table 2.

Dietary intervention and human studies

Figure 1.

Self-perpetuating cycle of dry eye diseases and it’s management through dietary components

Dietary restriction

Excessive consumption of calories causes acceleration in aging and oxidative stress and increases the risk of aging-associated diseases including obesity, diabetes, and cardiovascular disease. Caloric restriction (CR) diets have been shown to improve health and extend lifespan by modulating physiological and pathophysiological changes associated with aging and oxidative stress, despite their complexity.[46,47,48] CR has demonstrated attenuation of oxidative stress-associated impairment in the lacrimal gland with the protection of lacrimal gland functions in rats.[24] One clinical study showed that a CR diet for 2 months improved DED as well as the quality of life and productivity.[31] Moreover, a Mediterranean diet supplemented with extra virgin olive oil and nuts showed a significant improvement in DE signs compared to standard intervention.[32]

Vitamins

Vitamin A is a crucial factor for visual pigments and the integrity of the ocular surface.[49] Alanazi et al.[33] showed that short-term oral vitamin A supplementation is crucial for preserving the health of the ocular tear film and can reduce the symptoms of DED. Another study has shown that oral vitamin A supplements delivered results more efficiently compared to topically applied vitamin A eye drops for the management of eye dryness.[34] Vitamin D has the potential to enhance the tear quality and ocular surface conditions in DED.[35,36] The fundamental mechanism of vitamin D could be its antioxidation, anti-inflammatory, and immune regulatory effects.[50] Macri et al.[37] evaluated the impacts of preservative-free eyedrops comprising hyaluronic acid 0.15% and vitamin B12, an antioxidant, on oxidative stress in DE patients and revealed that eye drops reduced oxidative stress and eased DE symptoms. Vitamin E and vitamin C show a decrease in oxidative damage generated by nitric oxide and other free radicals and lead to the recovery of the ocular surface milieu.[38]

Polyunsaturated fatty acid

Essential FAs are crucial for maintaining good health; however, they cannot be synthesised by the human body.[51] The derivative of ω-3 FAs, eicosanoids, possess antioxidant and anti-inflammatory properties, while ω-6–derived eicosanoids exert proinflammatory effects[52] and suppress inflammation.[53] Intake of a high level of ω-3 FAs and a moderate level of ω-6 FAs leads to modulating FA composition and promotes tear stabilization while preventing blocked meibomian ducts.[39] The anti-inflammatory properties of ω-3 and -6 FAs could be a probable mechanism for the Mediterranean diet, rich in fish and olive oil, showing results of improvement in DE condition via reducing the inflammatory process on the ocular surface.[32] Similarly, a diet supplemented with eicosapentaenoic acid, docosahexaenoic acid, and gamma-linoleic acid led to a significant recovery from DE symptoms in extremely symptomatic participants with DED.[54] Oral treatment of primrose oil, containing ω-6 FAs, caused a decrease in contact lens discomfort and related DE symptoms.[40] Primrose oil derivatives linoleic acid and γ-linolenic acid improved the symptoms and increased overall lens relief in patients with contact lens–linked DE and subsequently improved tear production.

Amino acids

Amino acids (AAs) are naturally found in human tears, and studies have shown that the relative concentration of AAs varies from what is observed in serum.[55,56] This concentration fluctuates due to ocular dryness in DE patients.[56] A pilot clinical study on 20 candidates with mild to moderate DEDs treated for 2 weeks with saline eye drops rich in Leu, Gly, Pro, and Lys showed a significant recovery in signs and symptoms of DEs as treatment reduced the tear film protein expression of IL-1β, IL-6, TNF-α, and IFN-γ compared to that in those receiving hyaluronic acid alone.[41] Treatment with taurine, an amino-sulfonic acid, changes the tear proteome of DE patients and shifts it toward the profile of healthy control candidates.[42] Taurine has antioxidant properties and leads to recovery of mitochondrial function through stabilizing the Electron Transport Chain (ETC) cycle and preventing ROS production.[57]

Functional foods

Turmeric is one of the most important medicinal herbs. Its extract consists of phenolic and flavonoid compounds along with monosaccharides and polysaccharides, which can boost the immune system.[58] Curcumin, a derivative of turmeric, possesses anti-inflammatory activity. Particularly, it has shown inhibition properties against proinflammatory cytokines, such as IL-4 and IL-5, in the DED model of rodents.[29] In an in vitro hyperosmolarity-induced DE model, curcumin reduced the elevated production of IL-1β, IL-6, and TNF-α induced by hyperosmotic stress in human corneal epithelial cells.[30] Red ginseng is applied as a remedy for treating endocrine and immune disorders.[43] Bae et al.[43] reported that ginsenoside, a derivative of red ginseng, demonstrated anti-inflammatory properties. Oral intake of red ginseng revealed improvements in signs and symptoms of DED in two studies.[43,59] Bilberry extract, a rich source of the flavonoids anthocyanins, was reported to possess antioxidant, antiallergic, anti-inflammatory, antiviral, antiproliferative, and antimicrobial properties.[60] Riva et al.[44] showed that extracts from bilberry significantly improve tear secretion. Tea, Camellia sinensis, is one of the most consumed drinks globally. Green tea comprises several polyphenols such as catechins that possess antioxidant and immunomodulatory[45] as well as antiviral activities.[61] Green tea has been reported to act against oxidative stress, chronic diseases,[62] and serum lipid.[63] A double-blind, placebo-controlled study examined the efficacy of green tea and reported that it improves DE and meibomian gland dysfunction as it exerts antioxidative, antibacterial, antiandrogen, immunomodulatory, and anti-inflammatory properties[45] and revealed that it improves meibomian gland health and ocular comfort scores after 1 month of intervention. The probable reason could be the presence of epigallocatechin gallate, which exhibits inhibitory action against inflammation through the inhibition of IL-1, IL-6, MCP-1, TNF-α, and NF-kB” - Nejabat M et al (2017) reported that green tea improved clinical symptoms of dry eye where the main components from green tea is Epigallocatechin Gallate (EGCG). The substance has an inhibitory effect on inflammation, through the suppression of IL-1, IL-6, MCP-1 and TNF-α and through inhibition of NF-kB’s activation. This observation was supported Kaszkin M et al (2004) and Cavet M et al (2011).

Conclusion

Ocular disease is at an epidemic level in both developing and developed countries, with nearly 285 million individuals suffering from visual disorders. To meet this challenge, the development of affordable and novel therapies that provide not only a cure for DED but also improve the quality of lifestyle is crucially needed worldwide. Vitamins, AAs, and omega-3 FAs modulate many biochemical processes in the eye. Likewise, dietary modification and the involvement of functional food in the diet lead to several health benefits. Evidence obtained from various in vivo, in vitro, and diet-related clinical trials has assisted clinicians to manipulate nutritional recommendations for lifestyle- and age-related eye disease. A systemic procedure, comprising the intake of dietary supplements and lifestyle intervention, should be applied in addition to conventional treatment. For instance, adequate CR and/or calorie restriction CR mimetic therapy such as Mediterranean diet[32,64] or ketogenic diet[65] may be synergistic and important interventions against various DE disorders. Studies regarding the effects of CR on eye disease need to continue, with the aim of elucidating the molecular mechanisms underlying its favorable effects on age-related and inflammatory ocular disorders. CR mechanism-based agonists, such as food-derived or naturally occurring sirtuin activators and AMP-activated protein kinase (AMPK) upregulators, are anticipated to be utilized to facilitate the broad application of CR in clinical studies.

Financial support and sponsorship

The author declares that financial support was received by Co-corresponding – Dr. Rohit Shetty for by the research and publication of this article.

Conflicts of interest

All authors declare that there is no conflict of interest.