EYEZONE: Brien Holden Vision Institute


Bacteria and the eye: a probiotic future?

By Dr Judith Flanagan







A recent editorial in Clinical and Experimental Ophthalmology[1] was headlined “Meibomian gland disease and the microbiotome: is it time for ocular probiotics?” Such a posit would have been unthinkable just a few years ago, but along with the explosive interest in the microbiome associated with other tissues in the body, the ocular surface microbiome (or microbiotome; the collective genome of the microbiota[2]) is now being explored as both cause and cure in ocular surface disease. The word ‘probiotic’ is derived from the Greek ‘for life’ and was coined by Lilley and Stillwell in 1965 to describe substances produced by one microorganism that advantageously affected growth of another [3] while the definition that is now commonly understood was developed in 1974 and redefined as late as 1989 as: “A live microbial feed supplement which beneficially affects the host animal by improving intestinal microbial balance [3].” More generally Glasson et al. describe probiotics as “food supplements that contain live organisms … that confer a health benefit to the host [4].” These definitions stress the need for viable bacteria to be used but as will be explored further below, nonviable bacteria are now known to exert positive ‘probiotic’ effects as well, and whether the effect is necessarily administered through the intestine will also be further explored.

Although the terminology is very recent, evidence of probiotic use extends back thousands of years: Genesis records the use of fermented milk drinks which were probably some of the earliest fermented foods while the Sumarian paintings from 2500 B.C. also depicted fermentation of milk via inoculation [5]. This article explores our emerging understanding of the ocular microbiome and its implications for tackling eye diseases including uveitis, microbial keratitis, irritable eye syndrome, diabetic corneal neuropathy and dry eye.THE OCULAR MICROBIOME Using traditional culture techniques around 75 to 80% of conjunctival swab samples are culture positive [6] and our understanding of the role of bacteria in health and disease has been shaped by our ability to culture micro-organisms. It was recently reported that our present knowledge is biased by those bacteria that are readily cultured. Common dogma suggests we can only culture 1 to 5 percent of the bacteria that inhabit various niches on and within us though it has been recently shown that many more bacteria can be grown using targeted phenotypic culturing [7]. Hence, one of the biggest challenges in the study of the human microbiome is to align evidence from culture and cultureindependent studies since results vary by orders of magnitude in the number of species identified and to reconcile culture independent studies that produce wildly different results, both to culture and to each other.

The ocular surface includes the mucosal tissues of the bulbar conjunctiva, conjunctival fornix, and palpebral conjunctiva and has been described as paucibacterial [8] (from ‘pauci’ in Latin meaning few) with a composition distinct from that of adjacent skin [8]. Cultured species from the ocular surface comprise, Gram-positive species including Coagulase Negative Staphylococcus (CNS), Staphylococcus aureus, Streptococcus spp., Corynebacterium sp., Micrococcus, Bacillus sp., Lactobacillus sp. and Propionibacterium [9]. Less commonly cultured are Gram negative species such as Haemophilus and Neisseria [10].

Analogously to the gut which is much more diverse (containing 100-1000 bacterial species, widely divergent between individuals such that each person’s gut microbiome can be thought of as a microbiome fingerprint [11]), many functions related to homeostasis, immune competence and pathogen resistance conferred to the ocular surface by the resident microbiome are still not fully understood. However, functions can potentially be inferred from culture-independent studies that indicate a much more diverse ocular microbiome than could have been imagined previously.

Kugadas and colleagues reviewed the impact of the (culturable) microbiome on ocular health [12]. They found that culture rates differed drastically in different studies from 17% to 89% for CNS. Further, 80% of swabs from one study had a single organism while only 17% had more than one species, suggesting a microbiome with very limited diversity. We recently assessed the diversity of the ocular microbiome in a healthy population [13]. Sampling from the lower lid margin, the most common species/strains identified were Propionibacterium (59%), and Staphylococcus epidermidis (36%) with average bacterial counts higher in males than females (162 ± 1 56 vs. 105 ± 187 cfu per swab; p < 0.05). These numbers are higher than other studies sampling the lid [14] that yielded 10-100 cfu/swab in 3% of cases only, with the majority of samples in the range of 0-10 cfu/ swab (59%). Conjunctival swabs are reported to have even lower numbers (0-4 cfu/swab) in 75% of swabs [15]) suggesting a limited abundance of viable, sustainable species on the ocular surface, and raising the question of whether such low biomass is sufficient to exert any substantial homeostatic influence.

It is becoming apparent that divergent culturing techniques can bias results. A variety of swabs (calcium alginate, cotton, rayon, flocked) are used to sample bacteria from the eye. The swabs collect and release species and numbers of bacteria with differing efficiencies [16]. Additionally, the area swabbed can variously include the lower conjunctival sac/inferior fornix or upper bulbar conjunctiva and a number of different media are used for cultivation [17]. Adding an additional layer of complexity, with improvement in DNA and RNA technologies, noncultivatable bacteria are now being identified, leading to wildly divergent estimates for the number of bacteria inhabiting various niches of the human body. Dong et al. identified 221 species-level phylotypes on the ocular surface (DNA sequence reads sharing 97% identity) per subject in a healthy cohort [18], yielding 12 ubiquitous genera out of 59 identified. Graham et al. [19] identified around 9 different genera using DNA sequencing in healthy and dry eye subjects, while a study in Gambia revealed 610 genera belonging to 22 phyla in healthy and trachomatous eyes with differences in the ocular flora between children and adults [20]. Shin et al. found higher diversity on the ocular surface than skin around the eye [21]. Sundin and colleagues determined culture-independent profiles very similar to reports from culture studies with most frequent genera being Staphylococcus (50%), Corynebacterium (4%) and Propionibacterium (2%), with the most common species being Staphylococcus epidermidis (4%) [22]. Sundin et al. stressed that the ocular flora is a distinct community from the peri-ocular skin microbiome.

Doan et al. [8] attempted to reconcile the huge number of operational taxonomic units (OTUs) — a grouping of sequences of similar identity (usually 97%) — identified on the ocular surface: as many as 460 OTUs from normal conjunctiva and a total of 7392 from 107 samples [21]. Using quantitative PCR, Doan and colleagues determined the presence of about 1 bacterium for every 20 corneal epithelial cell, suggesting more like 40 bacteria or fewer per swab [8].

Hence, to elucidate the role of the ocular bacterial community, standardised methods of detection are needed.


A hotly debated area of discussion is whether these more complex communities being identified represent a stable community that confers resistance against opportunistic pathogens and/or a resident microbiota that educates the immune system locally or systemically, or even if these numbers are inflated due to contamination during DNA analysis.

In relation to whether the bacterial community is stable or transient, Graham and colleagues determined temporal stability over three months in healthy and dry eye subjects [19], while Ozkan and colleagues [23] reported an absence of common OTU between 45 healthy individuals over three months; no commonality either at all time-points within an individual, or between individuals. Ozkan et al. did, however, identify 26 OTUs that were present in one or more individuals at any time, suggesting a possible core microbiome.

Not surprisingly, temporal, geographic, and individual stability of the microbiome, and relative abundance of bacteria on the ocular surface, are still being hotly debated but what is becoming increasingly clear is that the resident bacteria play an important role in health and disease in the eye. Though it is now accepted that there is an ocular microbiome, the question that remains to be answered is: how transient or otherwise is the ocular bacterial community and does it contribute to or defend against pathogenesis? Answers require cross-sectional and longitudinal studies which are now being undertaken.


Antimicrobial therapy has been a stalwart treatment for pathogenic disorders of the eye. However, increasing resistance to antibiotics has raised the spectre of these therapies becoming ineffective [24]. Development of antibiotic resistance was observed as early as the 1940s [25] and is now a huge and ever growing problem for human health.

In relation to ocular bacterial resistance to antibiotics, the ARCANE study (Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation) [26] provided evidence that repeated use of macrolide or fluoroquinolone ophthalmic antibiotics rapidly selects for resistant conjunctival strains of coagulasenegative staphylococcus (CNS) at the expense of other commensal flora [27]. Fontes et al. showed that orally administered trimethoprim-sulfamethoxazole was associated with an altered conjunctival microbiota including increased resistance profiles [28] and Yin et al. also showed a shift in conjunctival flora with antibiotic use following intravitreal injection, wherein repeated use of moxifloxacin increased resistance of the ocular surface microbiota [29]. Hence, it is timely to elucidate the positive role our ocular microbiome plays, the harm we inflict on our commensal bacteria with antibiotic therapy, and the potential that probiotics might offer as an alternative.


The aetiology of many ocular diseases (including dry eye disease, chronic follicular conjunctivitis, uveitis and other inflammatory ocular diseases) is not well understood but there is a potential role for ocular microbiome dysbiosis, i.e. when the otherwise healthy community of bacteria that offers resistance to opportunistic pathogens and pathobionts becomes altered and weakened in a loss of homeostasis [26].

Immunity and the microbiome

Do the relatively small numbers of bacteria on the ocular surface have a measurable and significant impact on ocular immunity?

One animal study concluded that the ocular microbiome plays an important role in protecting against Pseudomonas aeruginosa-induced keratitis through bacterial production of IgA in the tear film, providing signals that regulate the magnitude of neutrophil recruitment during infection and resistance of these neutrophils to infection [9]. These authors elegantly showed that a reduction in ocular commensal diversity increases susceptibility to keratitis. They went on to show that monocolonisation of germ free ((GF) mice lacking a commensal microbiota) with CNS spp. isolated from conjunctival swabs, was sufficient to confer resistance to MK, suggesting that the ocular microbiome participates in “immune priming.”

Dry Eye Disease

There have been a number of studies into the microbiome of the healthy eye versus that of sufferers from dry eye disease (DED). Graham and colleagues identified an increase in the bacterial burden accompanied by a decrease in goblet cells and mucin production, leading to a thinner tear film and thus making the ocular surface more susceptible to opportunistic pathogens [19]. They reported an increased presence of CNS species in addition to other commensals such as Corynebacteria and Propionibacteria in non-autoimmune dry eye disorders [19] DED proteomics studies [12] revealed a decrease in bacteriocidal proteins such as lactotransferrin, lysozyme, polymeric immunoglobulin receptor and lacritin [30] in the tear film of affected subjects, suggesting these changes are related to changes in microbiota and state of ocular surface barrier. Lu and Liu [26] suggest that analogously to the gut microbiome, secretion of glycans and polysaccharides might promote growth of specific bacteria that are protective to the ocular surface. These authors suggest that DED and contact lens wear alter the ocular microbiome or vice versa; for example, the increased osmolarity in DED might offer a selective advantage to certain pathological species [26].

Finally, Albietz et al. [31] showed elevated numbers of CNS and S. aureus in lid and conjunctiva of Sjogrens syndrome (SS) patients, which is interesting in light of the discussions about an associated change in ocular microbiome with inflammation, chronic or acute. A knockout mouse model with chronic inflammation consistent with SS, showed increased commensal burden over time that correlated with spontaneous disease development, suggesting elevated presence of commensals might serve as an exacerbating factor for disease progression.


Autoimmune uveitis is a sight-threatening disease that arises without a known infectious aetiology [32]. Evidence of a gut microbiota connection with autoimmune uveitis can be found in a number of recent studies. Zarate-Blades and colleagues report that retina-specific T-cells are influenced by cross-reactive antigens derived from the gut microbiota [32]. Horai et al. [33] showed depletion of gut microbiota (through antibiotics) or rearing of experimental autoimmune uveitis model mice in a germ-free environment, results in attenuation of the autoimmune uveitis and reduction in ocular inflammation. Similarly, Nakamura and colleagues reported in mouse models of induced uveitis that even temporary changes in the gut microbiome can affect the immune system and modulate the severity of inducible auto-immune uveitis [34]. Such work provides evidence of a protective gut microbiome and conversely a ‘uveitogenic’ microbiome, opening the way for treatment or prevention through probiotic treatment.

Microbial Keratitis

Kugadas and colleagues’ keratitis model [9] shows protective immunity to be dependent on both the oral and gut microbiome. A single topical dose of CNS from conventionally reared mice applied to germ-free mice (lacking an innate microbiome) was sufficient to colonize the ocular surface two weeks later and further, was shown through faecal sampling to have colonized the gut, increasing resistance to infection [9] and conferring a similar level of resistance to that of the conventionally housed mice. However, the gut microbiota had a more profound effect on resistance to infection than the local ocular microbiome (discussed further below).

Kugadas and colleagues reported that localised reduction of ocular commensals increases susceptibility to infection but of even more interest, reduction in gut bacteria diversity through oral antibiotic administration (while maintaining ocular microbiome) increased susceptibility to P. aeruginosa keratitis. An indication of mechanism was provided by the presence of elevated pro-inflammatory responses to infection in the absence of a healthy gut microbiome.

Contact lens wear

Contact lens wear, although not a disease, is associated with ocular discomfort and a disturbed ocular flora and is a risk factor for microbial keratitis and other inflammatory conditions of the eye [35]. The ocular microbiome of contact lens wearers has been described in some studies as more ‘skin like’ [21] than non-wearers with an increased representation of skin bacteria that are classically considered opportunistic pathogens [21], again suggesting a dysbiosis that might be correlated with lens related infections and discomfort. A more recent study suggested that the diversity between individuals is wider than any differences seen collectively in lens wearers versus non-wearers [36]. Generally, bacterial diversity decreases with lens wear which is usually a sign of a less robust bacterial community. Sullivan (quoted in [12]) showed environmental antigen exposure at the ocular surface doesn’t regulate B cell activation, suggesting the commensal trigger for B cell activation might occur at a site other than ocular surface and, hence, reinforcing the idea that communication of the gut microbiota is important.

Role of the non-ocular microbiome in disease Secretory IgA (sIgA) is the predominant antibody at the ocular mucosal surface and induces tolerance at these sites [37]. sIgA concentrations in the tear film of conventionally housed (not germ free) mice are reduced through oral antibiotics, suggesting the gut microbiome stimulates sIgA presence in the tear film [38].

Kugadas [9] explored whether the ocular microbiome or other mucosal (nasal or gut) microbiota were responsible for regulating B cell activation in the eyeassociated lymphoid tissue, since sIgA- committed B cells can be recruited from nasal or gut associated mucosal tissue.

The gut microbiome stimulates neutrophil development in bone marrow while the ocular microbiome provides signals that regulate the magnitude of neutrophil recruitment. It has been shown consistently that reconstituting commensal bacterial species facilitates clearance of enteric opportunistic pathogens [39] and thus one could extrapolate that reconstituting the ocular microbiome might help in resisting infection, offering a probiotic alternative to antibiotic therapy. Though, as mentioned above, the enteric reconstitution is more powerful.


Glaucoma patients have a relatively increased oral bioburden relative to controls [40]. Astafurov et al. [40] suggest that in glaucoma, a higher oral bacterial load might induce chronic subclinical inflammation and hence (non-ocular) microbiome dysbiosis may contribute to neurodegeneration in glaucoma raising the possibility of oral probiotics in ameliorating this degeneration.

Irritable eye syndrome

It is well known that acute peripheral inflammation due to infection, or artificially induced through injection of LPS (bacterial lipopolysaccharide), can effect changes in the central nervous system that elicit what is known as ‘sickness behaviour’, suggesting a direct effect of inflammation of CNS neurodegeneration.

Irritable eye syndrome is a triad of symptoms comprising ocular hypersensitivity, gut disorders associated with certain foods, and anxiety-depression symptoms [41]. Successful probiotic treatment of ‘irritable eye syndrome’ [42] suggests that through the mucosal associated lymphoid tissue contiguous from the gut, to the respiratory system, and nasolacrimal system, subclinical inflammation affecting the ocular surface can arise from gut dysbiosis. An interesting finding in this study (as opposed to the idea of probiotics being living organisms), was that the use of bacterial lysate proved as effective as live bacteria.


Advances in sequencing technology and bacterial community modelling, in addition to the rising crisis of antibiotic resistance are reframing the way we think of, and treat, many diseases. If we work within an ‘ecological’ framework, striving to reconstitute a healthy microbiome, either locally at the site of disease, or perhaps even more importantly, enterically, we can begin to explore new avenues of treatment and prophylaxis.

Treatment of irritable eye syndrome with an oral combination of omega-3 fatty acids, probiotic lysate and vitamins, provides proof-of-principle that subclinical inflammation contributing to an ocular disorder can be treated enterically through targeting gut dysbiosis [42]. In the Pseudomonas aeruginosa keratitis model [9], reduction in gut microbiota has a more significant effect in increasing susceptibility to disease than the local (ocular) microbiota, supporting the idea that resistance is driven largely from the gut microbiome priming neutrophils. It has been suggested that to elicit some of the positive outcomes of probiotics use, fragmentation of probiotic lysates is more effective than live bacteria [42]. Live bacteria are required to interact with commensals to help ‘rebalance’ the community. Bacterial lysates however might be superior in some instances. To regulate epithelial barriers and secretion of mucus and antimicrobial peptides, as well as stimulating the neuro-hormonal immune system, probiotic bacteria need to be fragmented by host enzymes and under some inflammatory conditions, this ability of the host is compromised [42]. Very recent work using topical probiotics evaluates supplementation of Bifiobacterium lactis and Bifidobabcterium bifido on tear film quality in subjects suffering from dry eye [43]. The bacteria were administered topically as part of a substitute tear mixture. The authors report a “successful full treatment in ameliorating dry eye syndrome” [43]. Our laboratory is interested in applying this new understanding to the treatment of diabetic corneal neuropathic pain. There has been limited human research into the use of probiotics to alter the inflammatory and neuropathic symptoms experienced by people with Type 2 diabetes mellitus (T2DM). However, a 2016 meta-analysis of randomized clinical trials exploring the effect of probiotics on metabolic profiles in T2DM [44] concluded that probiotics can improve glycaemic control and lipid metabolism. A number of animal studies exploring central nervous system modulation by the gut microbiome have identified a direct link between the gut microbiome and depressive/ stress episodes [45] suggesting that bacteria directly contribute to pain sensitization (central sensitization). Hence, oral probiotic administration is one potential avenue to reduce this neuropathic pain.

The microbiota has been shown to have a direct effect on priming of neutrophil activity against bacteria. With the emerging evidence of an ocular dysbiosis implicated in a number of eye disorders, there is much potential to be explored in the use of probiotics.

The editorial that opened the dialogue into whether it is time for probiotics in the treatment of meibomian gland diseases cautions that there is still much to be learned in mastering appropriate techniques to faithfully catalogue and model ocular bacterial communities before new therapeutics can be rationally evaluated. But with the explosion of interest in this field within optometry and ophthalmology the future of probiotics for ocular disorders is very promising.


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