To date, the majority of dry eye disease (DED) approaches have focused on the ocular surface; however, pioneers in the field have realized that another anatomical ecosystem influences this condition—the gut.
In this episode of Interventional Mindset, Anat Galor, MD, MSPH, a Professor of Ophthalmology at the Bascom Palmer Eye Institute and staff physician at the Miami VA Healthcare System, takes us through a history of investigations in this area—and addresses the questions yet to be answered.
Overview of the link between the gut microbiome and ocular surface health
The hypothesis that the gut microbiome might have some level of influence on ocular surface disease isn’t a new line of thought, as it’s believed that over 2,400 years ago Hippocrates stated that all disease begins in the gut, explained Dr. Galor.
However, more recently, Cintia De Paiva, MD, PhD, a Professor at the Baylor College of Medicine had a formative effect on this line of thought based on the results of studies that evaluated the microbiome of mice with dry eye disease.1,2
The De Pavia studies
Two murine studies conducted by Dr. De Pavia in the late 2010s were particularly influential. In the first, she induced a desiccating stress model of dry eye through injection of scopolamine hydrobromide and exposure to a low-humidity, drafty environment.1
When these mice were given antibiotics, they experienced a severe dry eye phenotype—including increased epitheliopathy and infiltration of T-cells—compared to mice that did not receive antibiotics.1
The second study used CD25 knock-out mice, which spontaneously develop Sjögren’s disease-like inflammation.2 When such mice grew up in a germ-free environment, they again demonstrated more severe dry eye phenotypes.
There are potential limitations to the transferability of these results to human populations; for example, neither of these murine models recapitulated the full signs and symptoms of dry eye in humans.1,2 However, these studies did provide an introduction to the idea of the gut microbiome influencing the ocular surface phenotype.
Establishing a connection between the gut and eye
Trying to answer the question of how exactly an individual patient’s gut microbiome relates to their phenotype is a question that Dr. Galor admits has been difficult to answer. Researchers have been able to establish connections between a variety of autoimmune conditions and alterations in the composition of a patient’s gut microbiota.3
For example, multiple sclerosis patients demonstrate decreases in several commensals, including a number of Bacteroides, Faecalibacterium, and other short-chain fatty acid (SCFA)-producing bacteria4—with treatment using disease-modifying drugs resulting in the increase in another commensal, Prevotella histicola.5 However, across studies, no consistent dry eye microbiome signatures have been detected.
But, as Dr. Galor explains, simply establishing a connection between autoimmune conditions and the gut microbiome isn’t enough to explain the underlying mechanism that results in dysfunction. It is also important to understand what is driving the noted associations.
Some thoughts on mechanisms include:
- Looking not just at the composition of the bacteria present in the gut microbiome, but also their activity.
- A primary focus here has been on the production of SCFAs such as butyrate, with research demonstrating both a lowered butyrate-producing capacity within patients with systemic autoimmune diseases,6 and the alteration of autoimmune disease state through SCFA supplementation.7
- Another potentially explanatory factor is where exactly the bacteria within a patient’s microbiota reside.
- To illustrate this, Dr. Galor points to small intestinal bacterial overgrowth (SIBO)—the potential fermentation of carbohydrates and bile salts by excess bacteria in the gut, resulting in symptoms and malabsorption—and its potential association with dry eye-relevant diseases, such as rheumatoid arthritis.8
- This may be especially relevant in individuals with dysautonomia and impaired gut mobility, described in individuals with autoimmune disorders,9 which may risk displacement of gut bacteria, leading to issues.
Clinical implications of gut dysbiosis in dry eye disease
Although there’s still a great deal of work to be done in understanding the role of gut dysbiosis in ocular surface disease signs and symptoms, it is worth considering what steps clinicians can take to address this in dry eye patients. Though Dr. Galor emphasized that changing a patient’s gut microbiome could theoretically be a strong approach, actually inducing and maintaining such a transformation might be easier said than done.
Focusing on a patient’s diet may be one potential starting point;10 however, as she explains, while we may have general ideas of dietary changes that may be beneficial, there isn’t any certainty regarding the best autoimmune diet, which may indeed vary from patient to patient. Even if such a diet is identified, getting a patient to stick to it may prove difficult.
Pre- and probiotics are another potential option, but similar to the idea of dietary changes, there’s more understanding needed to identify which of these products would have the greatest efficacy for each patient. A more direct approach may be to transfer bacteria from the gut microbiome of a healthy individual to the patient via fecal microbial transplant (FMT).
The delivery dilemma
Up until this point, the two primary ways of delivering such a product have been oral capsules and endoscopy, but as Dr. Galor explains, both of these methods have their drawbacks. Oral capsules require sufficient saliva to be delivered to the target area, something Sjögren’s disease patients may lack, and endoscopy needs to be delivered in a gastrointestinal suite.
This is why Dr. Galor and her team explored a potential third administration method: enemas, which she mentions have already been used in other diseases relevant to dry eye, such as graft-versus-host disease and other autoimmune conditions like ulcerative colitis.
In a small proof-of-concept study, Dr. Galor and her team delivered two FMT doses from a healthy donor to 10 individuals with autoimmune dry eye (5 with Sjögren’s disease, mean age of 60.4) via enema.11
Although they observed changes to these patients’ gut microbiomes that resulted in closer resemblance to that of the FMT donor after 1 week, 3 months post-FMT, the gut microbiomes of the autoimmune dry eye patients had reverted to baseline. Additionally, Dr. Galor and her team did not observe any changes to dry eye signs or symptoms.
In conclusion
Although there’s certainly still work to be done, the finding that we can alter the gut microbiome of dry eye patients in the setting of an autoimmune condition may be a step forward in understanding the gut–ocular surface axis.
And Dr. Galor encourages everyone, especially younger practitioners, to keep an eye on this burgeoning field. “This is an interesting topic that needs way more in the way of supportive data to ultimately help us to figure out how to best treat our patients,” she concludes.
