Authors: Shannan Berzack (aHerbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA;), Anat Galor (bBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.)
Categories: Article, dry eye disease, gut microbiome, glaucoma, uveitis
Source: Clinical & experimental optometry
Authors: Shannan Berzack, Anat Galor
The relationship between the gut microbiome and ocular health has garnered increasing attention within the scientific community. Recent research has focused on the gut-eye axis, examining whether imbalances within the gut microbiome can influence the development and course of ocular diseases, including dry eye disease, uveitis, and glaucoma. This review of the literature on this topic focuses on relationships between gut microbiome alterations and select ocular diseases. It also discusses the therapeutic potential of gut microbiome modulation through antibiotics, prebiotics, probiotics, and faecal microbiota transplantation as strategies to improve gut microbiome health and mitigate ocular diseases.
Ocular diseases such as dry eye disease, uveitis, and glaucoma can significantly impair visual function and quality of life. Management of these disorders, particularly dry eye disease, has primarily focused on symptomatic relief, with limited success in addressing the underlying pathophysiology. As the global prevalence of these conditions rises, the need for innovative treatment approaches becomes imminent. The emerging concept of the gut-eye axis suggests a connection between the gut microbiome and ocular health, introducing the idea of targeting the microbiome for therapeutic purposes.^1^
The gut microbiome, composed of trillions of microorganisms, includes six primary Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, Verrucomicrobia, and Proteobacteria.^2^ Firmicutes and Bacteroidetes account for 90% of the gut microbiome.^3^ The gut microbiome is critical for maintaining bodily functions, with key roles in digestion, metabolism, and immune system modulation (Figure 1).
To understand how the gut microbiome can influence ocular diseases, it is important to first explore its local impact. A critical component of immune modulation involves T cells, specifically T helper 17 cells (Th17) and regulatory T cells (Treg). T helper 17 cells, characterised by their production of interleukins 17, 22, and 23, are the major contributors of inflammation and essential defenders against infections.^4–6^ On the contrary, regulatory T cells act as mediators of anti-inflammatory responses and are crucial in maintaining immune tolerance. A disruption in the balance of these two lymphocyte subsets can result in the onset of various autoimmune and inflammatory diseases.^7^
Commensal gut bacteria have been shown to influence T cell mediated inflammatory responses. For example, ATP produced by commensal bacteria has been shown to stimulate the differentiation of naïve T cells into Th17 cells in the lamina propria of mice.^8,9,10^ The same study also found that germ-free mice exhibited reduced ATP levels and fewer Th17 cells in their gut compared to specific-pathogen-free mice.^10^ When the germ-free mice were treated with an ATP analog, Th17 numbers in the gut significantly increased. Another study demonstrated that the presence of segmented filamentous bacteria significantly increased Th17 cell proliferation in germ-free mice.^11^ These studies emphasise the importance of specific commensals, such as segmented filamentous bacteria, in modulating Th17 responses in the gut.^12^
Beyond Th17 cell modulation, researchers have explored how certain bacteria stimulate Treg proliferation in the colon. In one study, colonisation with Clostridium led to the greatest increase in Tregs compared to colonization with Bacteroides, Lactobacillus or segmented filamentous bacteria.^13^ This study illustrates how different commensal bacteria can have varying effects on T cell responses, with Clostridium strains showing the strongest impact on Treg production.
Other groups have focused on the impact of short-chain fatty acids (SCFA), mainly formate, acetate, propionate, and butyrate, on immune responses and barrier protection.^14^ SCFA are produced by most bacterial groups through saccharolytic fermentation of carbohydrates.^15^ Butyrate, in particular, has garnered significant attention as it has been shown to promote Treg proliferation in the colon.^16^ It achieves this by inhibiting histone deacetylases, enzymes that normally suppress the activation of the Foxp3 gene in deoxyribonucleic acid (DNA). This inhibition enhances transcription at the Foxp3 locus, which is responsible for promoting the proliferation of Treg cells.^17,18^ In one study, mice treated with butyrate showed increased antimicrobial activity in colonic macrophages, however the bone marrow-derived macrophages did not exhibit the same effects, suggesting a local response limited to intestinal macrophages.^19^
Butyrate has also been shown to strengthen the integrity of the epithelial barrier, as demonstrated in both in vitro human intestinal cells and anti-biotic treated mice, where butyrate supplementation restored barrier integrity by upregulating hypoxia-inducible factor-1α levels.^20–22^
Given the important role of the commensal gut microbiome in T cell regulation, macrophage health, and intestinal barrier integrity maintenance, it is unsurprising that disruptions in the gut microbiome composition, known as dysbiosis, have been associated with various abnormalities, including autoimmune diseases such as Sjögren’s disease (SjD)^23^, multiple sclerosis^24^, rheumatoid arthritis^25^, and others. Dysbiosis can result in inappropriate immune responses, chronic inflammation, the breakdown of immune tolerance, and increased intestinal permeability.
Dysbiosis can also have a profound impact on ocular health.^26^ The gut-eye axis represents a multifaceted communication system, where immune modulation, neural signaling, and the release of microbial metabolites likely play integral roles.^27^
Understanding the influence of the gut microbiome on ocular surface disorders is essential to the development of novel therapeutic approaches. In particular, microbiome-based treatments, such as antibiotics, the use of prebiotics and probiotics, and faecal microbiota transplantation, hold promise as gut microbiome modulation may be one approach to improving ocular health.^1,28^ This review paper provides an overview of the microbiome’s influence on ocular disorders and explores the potential of microbiome-based therapeutics in managing these conditions.
The interdependence between the gut microbiome and ocular health introduces a novel paradigm in understanding and treating ocular diseases.^29^ Several investigators have examined the link between the gut and eye using several experimental models.
Some research has focused on the link between the gut microbiome and dry eye disease, a heterogenous group of disorders that can manifest with symptoms and/or various signs (e.g., decreased tear production, increased tear instability, epithelial disruption).^30^ In one study, researchers investigated the impact of the gut microbiome on dry eye disease using germ-free mice.^31^ Mice colonised with SjD faecal material had fewer Tregs (CD4+ Foxp3+) within their cervical lymph nodes compared to control mice. Clinically, mice colonised with SjD material had increased corneal epithelial disruption when exposed to desiccating stress compared to controls. These findings suggest that SjD-associated dysbiosis contributes to T cell dysregulation and the development of dry eye disease symptoms.
Other studies have explored the gut-eye axis in experimental autoimmune uveitis, a laboratory model of human uveitis. Uveitis represents a group of diseases with various phenotypes driven by inflammation in the iris, ciliary body, and/or choroid.^32^ In this model, retinal antigens are used to sensitise T cells, which then migrate to eye and trigger an immune response that mimics human uveitis.^33^ One study used transgenic mice with photo-convertible proteins to track immune cell migration from gut to retina, where they found increased colonic T cell migration in uveitis mice compared to controls.^34^
Intestinal diversity, microbiome abundance, and permeability have also been studied in experimental autoimmune uveitis.^35^ In one study, one week after disease induction, mice showed significant reduction in α-diversity compared to control mice, indicating a less varied bacterial population. Reduced bacterial diversity has been linked to a number of diseases, including inflammatory bowel disease^36^, cirrhosis^37^ and atopic eczema.^38^ Beyond diversity, 16S ribosomal ribonucleic acid (rRNA) gene sequencing of cecal contents also revealed specific changes in levels of specific bacteria, with an increase in abundance of the genus Prevotella, genus Anaeroplasma, family Lactobacilli, and family Clostridia compared to the controls.
Other groups have studied the impact of gut microbiome composition in diseases related to uveitis, namely in Behcet’s disease.^39^ Behcet’s disease is a complex inflammatory disease that can present with variety of signs including skin rashes, mouth and genital sores, and uveitis. In one study, faecal matter was collected from 32 individuals with active Behcet’s disease and 74 controls. Mice that received faecal transplants from Behcet’s disease patients exhibited the most severe disease, with clinical scores ranging from 2 to 4.5, compared to the control-recipient and phosphate buffer solution-treated groups, with clinical scores ranging from 0 to 1.5.
Histologically, Behcet’s disease transplanted mice showed significant retinal folding and massive infiltration of inflammatory cells throughout the retina, choroid, and in the vitreous cavity, whereas these findings were not noted healthy-recipient and phosphate buffer solution control mice. This study supports the hypothesis that gut microbiome alterations induced by faecal transplantation can significantly impact the development and severity of experimental autoimmune uveitis in mice.
The gut-eye axis has also been examined in glaucoma. One study examined the relationship between the gut microbiome and intraocular pressure (IOP).^40^ Different strains of immune deficient mice (lacking B and/or T cells) were compared to normal mice following IOP elevation. Glaucoma was induced through unilateral IOP elevation via microbead injection into the right anterior chamber. In the first two weeks, a similar loss of retinal ganglion cells and axons was observed across all mouse groups. However, disease progression from two to eight weeks post induction was different between the groups, with normal mice experiencing a greater loss of retinal ganglion cells and axons.
This study also examined the impact of microbiome composition on disease progression. In this experiment, the same model was repeated in germ-free mice vs. specific-pathogen-free mice, with controls receiving saline injections. When subjected to IOP elevation, specific-pathogen-free mice, but not germ-free mice, exhibited a T cell response in the retina and neurodegeneration of retinal ganglion cells and axons. Specifically, two weeks after disease induction, the number of T cells per retina in specific-pathogen-free mice was ~20 after microbead injection compared to ~0 in saline-injected animals. This trend continued at eight-weeks, with ~ 37% vs. ~ 0% retinal ganglion cell loss noted in specific-pathogen-free vs. germ-free mice. This supports the hypothesis that the gut microbiome and immune system have an impact on disease progression in an animal model of glaucoma.
Overall, these studies demonstrate a link between the gut microbiome, immune responses, and ocular pathology in three common diseases, namely dry eye disease, uveitis, and glaucoma. Given these findings, there is a need to explore the impact of microbiome manipulation as a potential therapeutic approach for treating ocular diseases (Table 1).
Various approaches have been examined as methods to modify the gut microbiome. Dietary interventions are one such approach that aims to create an environment conducive to a healthy and diverse gut microbiome.^28^ The use of prebiotics and probiotics represents another avenue for microbiome modulation. Prebiotics are substances that promote the growth and activity of beneficial microorganisms, while probiotics consist of live microorganisms with potential health benefits when consumed in adequate amounts. Faecal microbiota transplant involves the transfer of faecal material from a healthy donor to a recipient, aiming to restore microbial balance in individuals with dysbiosis.
Given the heterogeneity in faecal microbiota composition between individuals, investigators have been building on this concept and attempting to standardise therapy by manipulating faecal microbiota transplantation to develop products in which the composition of the organisms is known. Understanding the specific roles and mechanisms of these interventions is crucial for tailoring treatments to individual needs and optimizing therapeutic outcomes.
The following sections will delve deeper into each of these microbiome-based treatments, examining their implications for ocular diseases. This review emphasises the significance of these interventions in the gut-eye axis and presents current understanding of their potential benefits and limitations.
Dry eye disease is a multifactorial disorder of the ocular surface characterised by symptoms (e.g., pain, visual disturbances) and signs (e.g., tear film instability, reduced tear production, epithelial disruption).^30^ Dry eye disease can be co-morbid with autoimmune diseases such SjD, where chronic CD4+ T cell infiltration and cytokine release lead to the destruction of salivary and lacrimal glands, or can be seen as a disease isolated to the eye.^41^ Dry eye disease can also present with various phenotypes including insufficient tear production (e.g., aqueous tear deficiency) or tear instability in the setting of adequate production (e.g., evaporative disease), each with varying degrees of symptoms, ocular surface inflammation, and epithelial disruption.
Numerous studies have examined the relationship between gut dysbiosis and dry eye disease sub-types, with particular focus on SjD associated dry eye disease. A South Korean study examined stool samples of 36 subjects, 14 with evaporative dry eye disease, 10 with primary SjD and 12 controls.^23^ Individuals with SjD exhibited gut dysbiosis compared to both the evaporative dry eye disease and control groups, defined by an increased abundance of the Phylum Bacteroidetes and the genus Prevotella, a decreased abundance in the genus Bifidobacterium, a decreased Firmicutes/Bacteroidetes ratio, and a decreased abundance in the family Clostridia. Notably, a decreased Firmicutes/Bacteroidetes ratio has also been noted in inflammatory diseases such as systemic lupus erythematosus^43^ and systemic sclerosis.^43,44^
Furthermore, dry eye disease severity was correlated with gut composition, with Bacteroidetes positively correlating and Bifidobacterium negatively correlating with corneal staining, indicating better ocular surface health in those with lower Bacteroidetes and higher Bifidobacterium abundances. There is potential biologic relevance to these noted associations as Bifidobacterium promotes the breakdown and utilization of SCFAs.^45^ Interestingly, individuals in the evaporative dry eye disease group were more similar to controls than SjD cases, indicating that within the large umbrella of dry eye disease, gut microbiome abnormalities may not be uniform, with data more strongly supporting the role of dysbiosis in autoimmune associated dry eye disease.
Based on the potential impact of gut dysbiosis in some dry eye disease sub-types, researchers have investigated probiotic therapy as a treatment option. A randomized, controlled pilot study conducted in Italy assessed the effects of a 30-day supplementation of Bifidobacterium lactis and Bifidobacterium bifido on tear characteristics in dry eye disease.^46^ In this study, 20 individuals received symbiotic treatment and artificial tears, while another 20 received artificial tears alone. After 30 days, the probiotic supplementation group showed better tear production and stability compared to the control group. This study suggests that probiotic therapy may have some beneficial effect on tear parameters.
Other probiotics have also been evaluated in dry eye disease. One randomised, masked, trial in Japan assessed the efficacy of Enterococcus faecium WB2000, a probiotic used to treat gastrointestinal issues in Japan.^47^ The study included 39 participants, 19 in the experimental and 20 in the control group, and found no significant differences in tear parameters between cases and controls with respect to tear stability, tear production, and corneal staining at 8 weeks. These findings highlight the need for further research to identify the most effective bacterial products and regimens for treating dry eye disease.
Prebiotics as a method to enhance the probiotic effect has also been studied in dry eye disease. An randomized Australian study involving 41 individuals with dry eye disease evaluated the combination of probiotics (Streptococcus, Lactobacillus, and Bifidobacterium) and a prebiotic (NutriKane D) vs. a placebo (maltodextrin).^48^ At four months, the treatment group showed a significant reduction in Ocular Surface Disease Index scores, improved tear film stability, and preserved tear meniscus height compared to controls. One month after discontinuing treatment, the benefits persisted. This study suggests that the combination of probiotics and prebiotics has potential, however, the field remains in its infancy and the optimal strains of bacteria, their combinations, dosages, and durations have yet to be determined.
Faecal microbiota transplantation has also been applied to the treatment of dry eye disease. Faecal microbiota transplantation is highly effective in treating Clostridium difficile infections^49,50^ but has only recently been applied to the treatment of autoimmune diseases. A recent meta-analysis of 13 randomised clinical trials targeting faecal microbiota transplantation use in ulcerative colitis revealed a significant advantage over control treatments in achieving clinical remission.^49^
To date, there has only been one study on faecal microbiota transplantation and dry eye disease. In a non-randomised study conducted in United States, faecal microbiota transplantation was investigated as a treatment in 10 individuals with autoimmune dry eye disease, 5 of which met criteria for SjD.^50^ Initially, 8 out of 10 microbiomes migrated towards the donor microbiome, yet by three months most participants’ gut flora reverted to their original state. Notably, 5 of 10 individuals experienced subjective improvement in both gastrointestinal and dry eye disease symptoms after the treatment. While the study established faecal microbiota transplantation as safe, its limited efficacy suggests that more research is needed to ascertain the most effective method of faecal microbiota transplant procurement and administration in the appropriate patient population.
In conclusion, oral probiotics, prebiotics, and faecal microbiota transplantation delivered through enema have been applied to the treatment of dry eye disease (variably defined). While the most effective administration methods for such treatments are still under investigation, the current data suggest that modulating the gut microbiome may have some impact on dry eye disease symptoms and signs. However, the optimal types of bacteria for probiotics, the need for supplemental prebiotics, the most effective method for administering therapy, and the optimal patient population remain areas for further research.
As research continues to unravel the complex interactions between the gut microbiome and ocular health, these approaches may offer new strategies for managing dry eye disease and potentially other autoimmune conditions associated with ocular manifestations.
Uveitis encompasses a spectrum of inflammatory conditions affecting the uvea, which includes the iris, ciliary body, and choroid.^32^ This inflammation is a significant contributor to visual impairment and recognised as one of the leading causes of blindness globally.^51^ The condition is broadly categorised based on its root cause, the location of inflammation, its onset, and course.^52^ Non-infectious uveitis is more prevalent and can occur as an isolated ocular condition or a local manifestation of a systemic inflammatory disorder such as sarcoidosis, Behcet’s disease and Vogt-Koyanagi-Harada disease.^53^
Research into the gut microbiome’s influence on uveitis has provided insights into its contributory role in disease. A study in India compared the gut microbiomes of 13 individuals with uveitis (10 idiopathic, 3 Vogt-Koyanagi-Harada) and 13 controls, matched for age, sex, diet and ethnicity.^54^ Using stool samples, 16s rRNA gene sequencing revealed significantly lower levels of anti-inflammatory genera such as Faecalibacterium, Bacteroides, Lachnospira, and Ruminococcus (all within the phylum Firmicutes) in cases compared to controls.
In contrast, cases had higher abundances of Prevotella, a pro-inflammatory genus within the phylum Bacteroidetes, and Streptococcus, a pathogenic genus within the phylum Firmicutes. Furthermore, individuals with idiopathic uveitis vs.Vogt-Koyanagi-Harada had similar gut microbiome profiles, distinct from controls. This suggests that similar gut microbiome-related mechanisms may underlie various forms of uveitis, regardless of their aetiological distinctions.
No human studies have investigated the impact of gut microbiome modulation with antibiotics, pre and probiotics, or faecal microbiota transplantation in uveitis. However, this question has been explored in animal models of disease.^55^ In one study, following induction of experimental autoimmune uveitis, mice were treated with a combination of antibiotics (oral ampicillin, neomycin, metronidazole, and vancomycin) either orally or intraperitoneally, with water given orally as a control.^55^ Over a period of four weeks, the oral antibiotic-treated mice had lower experimental autoimmune uveitis clinical scores compared to controls, while the intraperitoneally treated mice had similar scores to controls. When antibiotics were administered individually, oral metronidazole and vancomycin significantly mitigated the inflammatory responses, while neomycin and ampicillin had negligible effects, as compared to controls.
The researchers further investigated the impact of antibiotics use on immune responses in experimental autoimmune uveitis. From as early as one week, the combination oral antibiotic regimen increased Treg numbers in the gut lamina propria, which remained statistically significant throughout the four-week period compared to the controls. In the peripheral lymph nodes closest to the eye, an increase in Treg frequencies manifested gradually, with a notable increase at the three-week mark in the antibiotic group compared to controls, suggesting a time-dependent effect of the gut microbiome on local immune responses. In a similar manner, differences were noted between the groups with respect to retinal T cells profiles, assessed on whole mounts.
Antibiotics treated mice had lower levels of nonspecific T cells in the retina but a higher proportion of Tregs (CD4+ Foxp3+) compared with controls. Overall, this study highlights that altering the gut microbiome through oral antibiotic treatment can have an influence on T cells responses and clinical manifestations of uveitis.
The effect of probiotics on uveitis progression has also been studied. In one study, researchers induced experimental autoimmune uveitis in C57BL/6 mice.^56^ Immediately following the induction, mice were divided into groups to receive either a combination of probiotics (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus) or phosphate buffer solution through daily oral gavage for three weeks. Experimental autoimmune uveitis mice that received probiotics exhibited significantly less destruction of the retinal photoreceptor layer and fewer infiltrating inflammatory cells compared to the phosphate buffer solution group.
Further immunological assessments using fluorescence-activated cell sorting examined T cell populations within the cervical lymph nodes. Probiotic treated mice showed a decreased percentage of pro-inflammatory CD8+ interleukin (IL) 17 T cells and CD8+ interferon (IFN) γ T cells in all and an increased percentage of Tregs in majority of the models, compared to controls. However, the increase in Tregs was not consistent across models, which suggests that benefits of probiotics do not rely exclusively on Treg enhancement.
In total, these studies highlight the potential of targeting the gut microbiome as a novel approach to managing uveitis. While direct studies in humans are lacking, animal models provide evidence that modifying the gut microbiome with antibiotics or probiotics can influence immune responses and potentially mitigate the severity of uveitis.
Glaucoma impacts more than 70 million individuals globally and is the second leading cause of blindness behind cataracts.^57^ It is characterised by the gradual degeneration of retinal ganglion cells and irreversible loss of vision. Recent insights suggest that the gut microbiome might play a crucial role in the pathogenesis of neurodegenerative diseases, including glaucoma, through mechanisms such as a leaky gut-vessels barrier, chronic low-grade inflammation, immune response alterations, and neuroinflammation.^58,59^ Beyond inflammation, other mechanisms implicated in glaucoma include glutamate excitotoxicity, ischemia, glial cell activation, and oxidative stress^60–63^, and the impact of the microbiome on these mechanisms is still being investigated.
Studies have highlighted distinct gut microbiome profiles in individuals with glaucoma compared to controls. A Chinese study assessed faecal and fasting blood samples in 30 individuals with primary open angle glaucoma and 30 sex and age-matched controls.^64^ DNA sequencing revealed increased abundances of the family Prevotellaceae, family Enterobacteriaceae, and Escherichia coli (species of bacteria within Enterobacteriaceae family), and decreased abundance in the genus Megamonas and Bacteroides plebeius (species within the genus Bacteroides) in cases compared to control.
There is potential biological relevance to the bacterial species noted to be more abundant in glaucoma. For example, E. Coli generates lipopolysaccharide, a compound that activates toll-like receptor 4 and elicits inflammation and complement activation.^65^ The study also explored the associations between gut microbial species and disease severity. For example, a positive correlation was noted between Streptococcus and retinal nerve fiber layer thickness, suggesting a possible protective role of certain bacterial strains on retinal health.
Furthermore, serum analysis identified alterations in metabolite levels in cases vs. controls. Of the 1,337 metabolites identified, 35 showed significant variations between the primary open angle glaucoma and control groups, with 20 significantly elevated and 15 significantly reduced in the primary open angle glaucoma group. One of the metabolites significantly decreased in primary open angle glaucoma was citric acid, a key intermediate in the production of energy through aerobic cellular respiration.^64^ Citric acid has been shown to decrease lipid peroxidation and inflammation in the brain, suggesting its reduction could indicate a potential avenue for therapeutic manipulation.^66^ Future research is needed to further explore these ideas.
Other studies have focused on toxic gut metabolites in the context of glaucoma. Specifically, a Polish study investigated the levels of trimethylamine, a toxic metabolite produced by gut microbiome, in both the aqueous humor and blood samples of 40 individuals, 20 undergoing phacoemulsification and 20 undergoing phacotrabeculectomy.^67^ Significantly elevated levels of trimethylamine were observed in the aqueous humour of cases compared to controls, while blood trimethylamine levels remained similar between the two groups. Given that trimethylamine has been shown to impair the function of smooth muscle cells, it is proposed that this compound may adversely affect smooth muscle activity in the trabecular meshwork, leading to reduced filtration.^68^
Additionally, trimethylamine has been shown to exacerbate the breakdown of lactate dehydrogenase, an enzyme important in the hypoxic response, which is known to be impaired in individuals with glaucoma.^68^ As such, trimethylamine might aggravate the ocular defense mechanisms against hypoxic stress, potentially contributing to the development or progression of glaucoma. Taken together, studies have linked decreased beneficial bacterial metabolites, such as citric acid, and increased harmful bacterial metabolites, such as trimethylamine, with glaucoma.
Translating these findings into a therapeutic potential, the impact of gut microbiome manipulation has been studied in glaucoma. A Chinese study recruited 11 individuals with primary open angle glaucoma and 11 controls and found increased abundance of the family Dysgonamonadaceae and decreased abundance of the family Barnesiellaceae in cases vs. controls.^69^ In addition, SCFA, including isovalerate, propionate, and caproate, were significantly elevated in individuals with primary open angle glaucoma. Mouse models were then employed to investigate the effect of gut microbiome, specifically SCFA, alteration on glaucoma. C57BL/6J mice were treated with either an oral antibiotic cocktail (to deplete gut bacteria) or a SCFA cocktail containing acetate, propionate, and butyrate (to mimic the metabolic profile observed in primary open angle glaucoma patients) and controls were given water orally for four weeks. After three weeks, an acute ocular hypertension model was induced and the effects of retinal microglia activation, inflammatory cytokine production and retinal ganglion cell loss was evaluated.
Interestingly, SCFA treatment exacerbated retinal microglia activation, increased inflammatory cytokine production of tumor necrosis factor (TNF)-α, IL-6, IL-1b and IL-10, and led to greater retinal ganglion cell loss in the acute ocular hypertension model compared to both antibiotic-treated and control mice. While SCFA have been recognised for their anti-inflammatory properties in the gut and potential to modulate ocular diseases, this evidence above suggests that SCFA can also exert detrimental effects on the eye, indicating a nuanced role in ocular health and disease that warrants further investigation.
Building upon these findings, after two-weeks of antibiotic treatment, mice were administered a faecal suspension daily by oral gavage for a week from individuals with primary open angle glaucoma or healthy controls. On the fourth day of the regimen, the same model of acute ocular hypertension was induced. Like the SCFA supplementation group, a week post-transplantation, mice that received faecal microbiota transplantation from individuals with primary open angle glaucoma had higher numbers of activated retinal microglia, higher expression of TNF-α, IL-6, IL-1b and IL-10 in the retina, and a greater degree of retinal cell loss compared to control transplanted mice.
These data suggest that altered gut microbiome profiles and their metabolic byproducts impact the development of glaucoma and open new pathways for therapeutic interventions that target the gut microbiome or their byproducts in modulating neuroinflammation and retinal health.
Several studies have investigated the impact of antibiotics on the gut microbiome in ocular diseases such as dry eye disease, uveitis, and glaucoma. These findings suggest that antibiotics can reduce inflammation by altering immune responses, particularly through increasing regulatory T cells. In dry eye disease, antibiotic treatment reduced clinical signs of inflammation, potentially by boosting Treg cell populations, which help balance the immune response.
In uveitis models, antibiotics such as metronidazole and vancomycin effectively mitigated inflammation and improved clinical outcomes. Glaucoma studies have shown that antibiotic-induced changes in gut bacteria can modulate immune responses, delaying the progression of neurodegeneration. However, limitations exist. These studies were primarily conducted in animals, and it remains uncertain how these findings translate to humans. Furthermore, long-term antibiotic use carries the risk of broad-spectrum disruption of beneficial bacteria, potentially causing more harm than good.
Moreover, antibiotics may offer temporary solutions rather than sustained benefits, especially in chronic ocular conditions which require prolonged management. Therefore, while antibiotics provided valuable short-term improvements of disease status in animal models, their translation into humans must be judiciously considered with alternative strategies to maintain long-term gut health explored.
The application of prebiotics and probiotics to modulate gut health in ocular diseases may offer a more sustainable approach than antibiotics. Studies have shown benefits in enhancing tear production and reducing inflammation in dry eye disease, while uveitis models indicate that probiotics can lessen immune-driven damage to the retina. However, the effectiveness of these treatments remains uncertain due to limited human trials and variability in outcomes.
A key strength of these studies is their potential to provide a targeted therapeutic approach that avoids the adverse effects of antibiotics. Nevertheless, variability in bacterial strains and dosages, along with individual differences in gut microbiomes, present challenges in standardising such treatments. Although prebiotics and probiotics have potential, further research is required to establish protocols for their use and determine their efficacy in maintaining long-term ocular health.
Faecal microbiota transplantation represents a more direct approach to restoring gut microbiome balance by transferring faecal material from a healthy donor. In dry eye disease, this approach has demonstrated safety but underwhelming clinical results, with microbiome composition reverting to baseline by 3 months. Faecal microbiota transplantation studies have not yet been explored in glaucoma and uveitis. The main advantage of faecal microbiota transplantation is its ability to rapidly restore gut diversity; however, the challenges lie in standardising donor selection, the method of administration, and the duration of its effects.
This review examines the role of the gut-eye axis in ocular diseases such as dry eye disease, uveitis, and glaucoma. The relationships outlined herein emphasise the potential of microbiome-based therapeutics to modify ocular disease, some of which have been testing in humans, and others only in animal models. By delving into the mechanisms through which gut dysbiosis influences immune regulation and inflammation, this review outlines how interventions such as antibiotics, probiotics, prebiotics, and faecal microbiota transplantation have been applied to the study and treatment of ocular diseases. While compelling, further research is necessary to better understand the appropriate target population and intervention for optimizing treatments as they pertain to specific ocular disease states.