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A Integrative Ophthalmologist's Perspective
You may have heard of the gut’s connection to many other organ systems in the body - the immune system, the brain, the skin, and even the cardiovascular system.
But did you know that recent research has shed light on another surprising but important connection? One that extends from the digestive system to the windows of our soul: the eyes, known as the gut-eye axis.
In this blog, I'll delve into the interplay between the gut microbiome and eye health, uncovering how imbalances in gut bacteria may contribute to a wide range of ocular conditions.
Before we can understand how gut health can impact the eyes, it’s important to first talk about the gut microbiome.
Within the gastrointestinal tract live at least 40 trillion organisms, collectively known as the gut microbiome. This is a diverse ecosystem of bacteria, viruses, fungi, and yeast.
An estimated 1,000 species of bacteria alone live in the human digestive system, with 10 times the number of genes than found in the human genome! To date, only a few of these microbes are well understood.
It is as if, in a vast orchestra, only a handful of instruments can be heard. But these early notes may lead to better understanding of how the gut microbiome plays a role in disease processes, and ultimately, their treatment.
Many of the bacterial species found in the gut are beneficial, known as commensals. Others are pathogenic, and may be associated with dysregulation and disease. It is a delicate balance between commensal “good” bacteria, and pathogenic “bad” bacteria. If there is overpopulation of pathogenic bacteria, there can be a state known as “gut dysbiosis.”
Beyond its digestive functions, the gut microbiome influences the immune system. The human gut houses up to 70% of the body’s immune system, and the gut microbiome is linked to both innate and adaptive immune function.
The Human Microbiome Project, propelled by advances in RNA gene sequencing, has elucidated the gut microbiome’s impact on a wide range of immune-mediated diseases, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and ankylosing spondylitis, as well as cardiovascular disease.
In ophthalmology, recent research has investigated the link between the gut microbiome, specifically gut dysbiosis, and the pathogenesis of several common and potentially blinding eye diseases.
1. Uveitis, Gut Dysbiosis, and "Leaky Gut"
When it comes to gut health and the eye, the most studied ocular condition is uveitis, a group of conditions characterized by inflammation of the eye. Uveitis can be divided into various categories, depending on which part of the eye is involved - the anterior, intermediate, or posterior segments, and also whether the inflammation is infectious or non-infectious.
In non-infectious uveitis, there is an imbalance in the retina in the ratio of effector T cells —including both T helper (Th1) and Th17 cells—to regulatory T cells (Tregs). Effector T cells are involved in inciting the inflammatory cascade, while regulatory T cells normally prevent autoimmune diseases from occurring.
Based on animal models of experimental autoimmune uveitis, known as EAU, certain strains of bacteria have been shown to promote pro-inflammatory effector T cell types, like Th17. This differential T-cell induction, based on changes in the intestinal microbiome, may result in either protection from or worsened autoimmune uveitis.
Researchers at the National Eye Institute have shown that T cells could be activated in the gut to respond to retinal antigens through a process referred to as molecular mimicry. It is hypothesized that these activated effector T-cells travel from the gut to the eye via the bloodstream, cross the blood-retinal barrier (which normally protects the retina from exposure to immune cells and inflammation) and trigger uveitis. However, it is not yet known which bacterial species or molecules from bacteria are involved in this pro-inflammatory process in the gut that then negatively impacts the eye.
Uveitis has also been linked to increased intestinal permeability, commonly known as “leaky gut syndrome.” Researchers in Oregon have found that changes in intestinal permeability can be associated with increased severity and perhaps even the pathogenesis of ocular inflammation in uveitis.
Other research linking the gut to ocular inflammation showed that mice with EAU who were given a dose of short-chain fatty acids, naturally occurring metabolites of intestinal bacteria fermentation of dietary fiber, experienced decreased severity of uveitis. The short-chain fatty acids also promoted intestinal bacterial changes that increased regulatory T-cells in the gut.
Another study showed decreased severity of EAU in mice given oral antibiotics, suggesting a link between the eradication of certain bacterial species in the gut with reduced ocular inflammation. Again, it is not fully understood which exactly bacterial species are associated with these changes.
Aside from these animal studies, human studies have revealed differences in the gut microbiome between uveitis patients and healthy controls. One study from the NEI found that uveitis patients had less diversity in microbiota and fewer anti-inflammatory microbes.
One particular form of uveitis, known as Vogt-Koyanagi-Harada (VKH) disease, has clearly been linked to gut dysbiosis. This research from China led to a VKH classifier, based on 37 differentially depleted or enriched microbes. The classifier distinguishes patients with good prognoses from those unlikely to respond to immunosuppressive therapy. For example, enrichment with Prevotella species and depletion of Clostridium species helped to shift the gut microbiome from dysbiosis toward normal.
2. Dry Eye Syndrome, Gut Dysbiosis, and Fecal Transplants
Dry eye syndrome is a common condition in which the ocular surface dries out. It affects over 50 million people, both adults and children. Dry eye is also more common in women, suggesting a hormonal component.
In dry eye, the tear film that normally coats the cornea and conjunctiva evaporates quickly, leaving the ocular surface dry and irregular. Dysfunction of tiny glands in the eyelids, known as meibomian glands, that secrete oils for the tear film, is a common underlying root cause of dry eye. Inflammation of these glands and the ocular surface plays a key role in the pathogenesis of dry eye.
Research suggests that an imbalance in gut bacteria, or gut dysbiosis, may contribute to the development of dry eye syndrome. An imbalance can lead to an inflammatory response affecting the eyes, potentially contributing to the discomfort and dryness characteristic of dry eye syndrome.
An animal study of dry eye showed that germ-free mice without bacteria in their gut have a more severe dry eye phenotype with corneal staining and surface inflammation. When these germ-free mice were put in a cage with healthy mice with normal gut microbiomes, the mice ate each other’s stool. The guts of the germ-free mice were thus recolonized with bacteria, with improvement of their dry eye.
Researchers from Miami performed a study looking at the potential benefit of a fecal microbiota transplant for patients with immune-mediated dry eye. The study participants were given two enemas with fecal microbial transplants; while the symptoms of some patients improved, others remained stable. The researchers are now looking into whether the gut microbiome was altered with two fecal transplants, or whether more treatments are necessary.
3. Age-Related Macular Degeneration, Gut Dysbiosis, and Complement Activation
Age-related macular degeneration (AMD), is a leading cause of irreversible blindness, estimated to affect at least 200 million people worldwide. AMD tends to affect older individuals above 50 years, with the prevalence rising with age. In AMD, the central retina, called the macula, is affected and central vision may be lost.
One root cause of AMD is inflammation, with complement activation implicated. Researchers are looking at whether gut dysbiosis may activate complement, that then may result in ocular disease.
Another study found changes in certain metabolic pathways, represented by intestinal bacteria, in AMD patients compared to controls.
4. Glaucoma, The Oral Microbiome, and Gut Dysbiosis
Glaucoma is a common eye disease that can cause irreversible vision loss and even blindness. In glaucoma, there is characteristic damage to the optic nerve, which connects the eye to the brain, with resultant loss of peripheral vision.
The association between oral and gut microbiome and the development of glaucoma is another emerging area of investigation. Some patients with primary open-angle glaucoma, the most common form of glaucoma, have an abundance of certain bacterial species in their oral cavity, specifically streptococci. Though this finding suggests an association, it is far from proving causation and a direct link to developing glaucoma.
It has been hypothesized that gut dysbiosis triggers changes in cytokine signaling and complement activation in the immune system, which subsequently may be linked to changes in glaucoma.
How to Keep Your Gut-Eye Connection Healthy
Much of the research on the gut-eye axis is still in its infancy, and we have much to learn about the exact mechanisms linking gut health to ocular disease.
However, one thing is clear - not just for vision health, but for overall health - it is important to maintain a healthy gut microbiome and to reduce intestinal permeability.
There are some simple, yet effective ways by which to support gut health (and eye health!) using nutrition and the principles of functional medicine. To learn more, please check out my next blog entitled, Tips for Keeping the Gut-Eye Connection Healthy.
Also, don't forget to watch my YouTube video that will introduce you to the fascinating world of the gut-eye connection. You can watch the full-length video HERE.
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