# The Case for a More Holistic Approach to Dry Eye Disease: Is It Time to Move beyond Antibiotics?
## 1 Introduction  
Dry eye disease, a multifactorial disorder characterized by a loss of homeostasis of the tear film and hyperosmolarity, visual disturbance and ocular surface inflammation [1] encompasses ocular surface inflammatory disorders such as blepharitis (inflammation of the eyelids), ocular rosacea [2], and meibonian gland dysfunction (MGD) which is the most frequent cause of dry eye disease (DED) [3]. DED is an inflammatory disease that has many features in common with autoimmune disease [4]. The onset and progression of MGD is a vicious cycle of altered meibum consistency, bacterial proliferation on the eyelid, bacterial toxin production, fatty acid production, inflammation and tear film instability [3]. This cycle can be entered at different points. Exposure of ocular surface epithelium to hyperosmolarity contributes to the release inflammatory mediators [5], triggering further damage to epithelial cells, apoptosis, and goblet cell and glycocalyx mucin loss [6]. Altered immunity is a significant factor in DED. As articulated by [PERSON] and colleagues [7], increasingly DED is recognized as a localized autoimmune disease driven by dysregulated immunoregulatory and inflammatory pathways of the ocular surface. Mucosal tolerance disruption is integral in the pathogenesis of DED [8], initiated when the immune balance of the ocular surface is altered due to internal or external factors. Stress to the ocular surface initiates a cascade of acute response cytokines and sequestering of auto response T cells that results in a chronic autoimmune response [7]. In addition to the localized autoimmunity, it has long been recognized that systemically delivered antibiotics can ameliorate ocular surface inflammation [9]. A number of antibiotics, both topical and oral, have been trialled for the treatment of MGD [10], pleharitis and (ocular) rosacea [11; 12; 13; 14]. Complicating the situation however, a review by the American Academy of Ophthalmology into useof oral antibiotics for MGD-related ocular surface disorders [15] reported (despite \"several review articles suggesting these agents as a mainstay of ocular surface disease care\") only scant level II and level III evidence to indicate efficacy while highlighting risk factors for systemic antibiotic use. Muddying the waters further are extant reports in the literature of germ-free mice and systemic antibiotic treatment animal models actually recapitulating DED rather than ameliorating it [16; 17]. These diverse observations highlight the complex interplay of immunity, inflammation and the role of the ocular and gut microbiomes in the development, exacerbation or amelioration of DED. Although ocular surface disease is one of the most common reasons for visiting an ophthalmologist, it is currently considered largely incurable [6]. The purpose of this review is to explore the use of antibiotics in treating dry eye; as antimicrobial agents and/or anti-inflammatory mediators and to showcase the emerging field of DED treatment that seeks to redress the autoimmune dysfunction of DED through pro-biotics, pre-biotics and functional foods with a view to perhaps eventually moving beyond antimicrobial therapy with all its associated disadvantages. Beyond antimicrobial agents, there are many over the counter treatments on the market for DED that are directed against symptoms, offering immediate but transient relief. A Cochrane review from 2016 studied 43 randomized trials (comprising 3497 dry eye subjects). The article was critical of the lack of homogeneity in variables such as diagnostic criteria, interventions, outcome measures and so forth, to the extent that the authors highlighted these constraints as potential confounders in their meta-analysis. Given these limitations (which illustrate a deficiency in many clinical trials for dry eye products) the authors concluded that overall there is little certainly that over-the-counter (OTC) drops offer any greater relief than placebo. Dry eye ophthalmic drugs aim to provide relief in both signs and symptoms.