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Gut microbiota and eye problems
Modern medicine views the human body as a 'machine' composed of different 'parts', considering the body as a simple integration of various organs and systems, believing that each organ system functions independently of other parts.
However, the organ systems of the human body are interconnected and influence each other; the various organ systems of the body do not work independently. Each organ in the body communicates and affects other organs, and the intestines are no exception. In fact, the intestines are connected to other organs in our body.Because the intestines not only help us digest food and absorb nutrients, it can be said that the intestines themselves are the health center of the body.
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Recent studies have further confirmed the existence of the 'gut-eye axis', indicating that dysbiosis of the gut microbiota may be associated with the occurrence of many ophthalmic problems.This article will review the relationship between gut microbiota and ophthalmic issues, including autoimmune uveitis, diabetic retinopathy (DR), age-related macular degeneration (AMD), and primary open-angle glaucoma (POAG).
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Illustration: The direct and indirect effects of gut dysbiosis on the eyes.
Diet, environmental exposure, diseases, or medications may lead to maladaptive changes in the microbial communities of the oral/gut mucosa, thereby affecting various aspects of eye physiology.
Autoimmune Uveitis
Uveitis is an inflammation occurring in the uvea of the eyeball, usually associated with systemic infections or autoimmune diseases, primarily manifested as decreased vision, possibly accompanied by eye pain. It can occur in both young and elderly individuals, often recurring, and may lead to vision loss.
The gut microbiota of uveitis patients has undergone significant changes. Studies of human fecal samples have shown a decrease in gut microbial diversity under uveitis conditions. Genetic sequencing of gut microbiota from uveitis patients and healthy controls revealed a decrease in the abundance of Ruminococcus and Campylobacter in uveitis patients. Another study found a reduction in the well-known anti-inflammatory genera such as Faecalibacterium, Bacteroides, Clostridium, and Spirulina in uveitis patients, while an increase in Prevotella was observed. These findings indicate that gut microbiota plays an important role in the pathogenesis of autoimmune uveitis.
At the same time, numerous studies have mentioned the mechanisms by which gut microbiota influences autoimmune uveitis, including four hypotheses:
01. Microbial Metabolites
Microbes in the gut can produce many metabolites, including butyrate and short-chain fatty acids, which have protective properties in inflammation. Changes in gut microbiota composition can lower the levels of beneficial microbial metabolites, exacerbating the inflammation of uveitis.
02. Damage to the Gut Barrier
Weakening of the gut barrier due to dysbiosis can lead to the leakage of pathogenic microbial products into the systemic circulation. For example, lipopolysaccharides can settle in the uvea and trigger an immune response, leading to uveitis.
03. Imbalance of Gut Immune Homeostasis
An imbalance between Th17 cells and regulatory T cells leads to excessive production of interleukin-17 (IL-17), triggering inflammatory pathways and worsening uveitis.
04. Antigen Mimicry
This refers to T cells that can recognize self-antigens in the uvea being influenced by microbial peptides in the gut.
These hypothesized mechanisms may not be mutually exclusive in the pathogenesis of autoimmune uveitis, as they reflect the complex interactions between immune cells and gut microbiota dysbiosis.
Diabetic Retinopathy
Diabetic retinopathy (DR) is a serious eye problem caused by diabetes and is one of the three major ophthalmic issues leading to blindness as reported by the World Health Organization (WHO). In the early stages, the retina may exhibit varying degrees of bleeding, exudation, and macular edema, leading to decreased vision and difficulty seeing distant objects and shadows in front of the eyes. In the late stages, there may be significant bleeding in the retina, sudden vision loss, and even neovascular glaucoma, accompanied by eye pain and headaches, potentially leading to complete blindness.
In studies using a type 2 diabetes mouse model, it was found that a healthy gut microbiome can improve DR. Intermittent fasting (IF) can induce a shift in gut bacteria from Bacteroides to Firmicutes, reduce the impact of retinal microglia and the infiltration of peripheral immune cells into the retina, and increase the overall survival rate of the mice. Firmicutes can metabolize primary bile acids into secondary bile acids, such as tauroursodeoxycholic acid (TUDCA), a compound that has protective effects on retinal neurons in rats.
The mechanism by which TUDCA improves DR outcomes was explored in diabetic rat retinal experiments. TUDCA can reduce the expression of immune mediators and angiogenic factors (such as nitric oxide synthase, ICAM-1, NF-κB p65, and VEGF) in diabetic rat models. In retinal neurons cultured with high glucose concentrations, TUDCA reduces cell mortality by decreasing the release of apoptosis-inducing factors from mitochondria and reducing oxidative damage. Animal experiments have also demonstrated that TUDCA's receptor TGR5 may play a role in DR pathology.
In summary, IF can shift the gut microbiota towards Firmicutes, thereby increasing bile acid metabolism and TUDCA production. TUDCA may play multiple roles in preventing the progression of DR, such as reducing inflammation and preventing cell death in retinal lesions of DR.
Age-related Macular Degeneration
Age-related macular degeneration (AMD) is a complex issue that increasingly afflicts many people. There is a strong interaction between diet, age, metabolomics, and gut microbiota, all of which play a role in the pathogenesis of AMD.
Two case-control studies from the same group found that AMD patients have higher levels of bacteria associated with high-fat diets and inflammation (such as anaerobic bacteria) in their feces, while Bacteroides are reduced, which is related to the protection against autoimmune diseases and the fermentation of indigestible carbohydrates.
The authors discovered C3−/−The connection between the complement system and changes in the gut microbiome in C3 knockout mice (with a genetic background that negatively affects the aging retina) includes an increase in the ratio of Firmicutes to Bacteroides and an increase in the abundance of Fusobacterium. In humans, similar changes in the gut microbiome are associated with single nucleotide polymorphisms in the complement factor H gene, indicating a relationship between complement deficiency, specific changes in the gut microbiome, and AMD. Metabolic pathway inferences suggest that the gut fatty acid elongation rate is reduced in AMD patients, while L-alanine fermentation, glutamate degradation, and arginine biosynthesis are increased, which may affect retinal health.
Researchers validated these studies and found that wild-type mice fed a high-fat diet showed altered choroidal neovascularization in response to experimental laser damage, increasing the ratio of Firmicutes at the expense of Bacteroidetes, while gut permeability and systemic and choroidal inflammation also increased. Normalizing the gut microbiota through fecal transplantation also restored the laser-induced choroidal neovascularization to normal dietary levels, regardless of diet, indicating that the gut microbiome is a necessary mediator for diet-induced increases in choroidal angiogenesis.
These results suggest that changes in the gut microbiome may be a factor in the pathogenesis of AMD. The mechanisms may include increased systemic inflammation through the penetration of antigens, lipids, or bacterial metabolites or dietary vitamins or micronutrients due to a compromised intestinal mucosal barrier.
Primary open-angleglaucoma
Glaucoma is a group of eye diseases characterized by irreversible damage to the optic nerve due to increased intraocular pressure or other factors. The most common type is primary open-angle glaucoma (POAG). Research on the impact of the microbiome on the intraocular pathology of glaucoma has accelerated, typically focusing on autoimmune or inflammatory aspects.
A comparative study of 30 POAG patients and 30 healthy individuals found metabolic differences in their gut microbiota. The authors found that fecal samples from POAG patients were relatively rich in Escherichia coli and Prevotella, while Bacteroides and Acinetobacter were relatively reduced.
Regarding the mechanisms of action, the article mentions two aspects: one is the connection between the oral microbiome and glaucoma. Studies have found that Helicobacter pylori infection can exacerbate glaucoma through systemic inflammation, increased vascular activity, reactive oxygen species, or cross-reactivity of antigens and antibodies. In 2000, researchers discovered a correlation between glaucoma and the gut microbiome, with histological evidence of H. pylori infection found in 88% of POAG patients. In small trials involving POAG patients, successful eradication of H. pylori infection improved intraocular pressure and visual fields, but eradication in patients with peptic ulcers without POAG did not change the risk of POAG. There is still insufficient evidence to determine whether a causal relationship exists. Subsequent studies on the gut microbiome in POAG indicated that dysbiosis is a risk factor for H. pylori infection and POAG.
The second aspect is the immune response mediated by gut microbiota to heat shock proteins. In 1998, autoantibodies to heat shock proteins were found in the serum of POAG patients, leading to attempts to study their role in the pathogenesis of glaucoma. Heat shock proteins are immunogenic and highly conserved, and the loss of tolerance to homologs of symbiotic bacterial heat shock proteins is thought to be a cause of many autoimmune and neurodegenerative diseases. In 2018, research found that increased intraocular pressure (IOP) can induce T cell infiltration into the retina, leading to degeneration of retinal ganglion cells, which persists even after IOP returns to normal levels. However, germ-free mice do not exhibit T cell infiltration or degeneration of ganglion cells, suggesting that T cell infiltration triggered by the symbiotic microbiota may play an important role in the pathogenesis of glaucoma.
Currently, research on the gut microbiome and eye health faces an exciting prospect. Maintaining a healthy gut and gut microbiota can help protect our eye health to some extent; at the same time, certain nutrients are also necessary for eye health, and their normal absorption relies on a healthy gut and gut microbiota.
References:
[1] Josh Axe. Eat Dirt [M], Wang Lingbo, Beijing United Publishing Company, 2018.
[2] Patrick Donabedian. Gut Microbes and Eye Disease [J]. Ophthalmic Research 2022; 65: 245–253.
[3] Maria B. Grant. Inside out: Relations between the microbiome, nutrition, and eye health [J]. Experimental Eye Research 224 (2022) 109216
Gut-eye axis, gut microbiota
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