Gut-eye axis

Abstract

Background: The gut microbiome, colonizing the human gastrointestinal tract, is increasingly recognized for its symbiotic relationship with the immune system in maintaining overall host health. This emerging understanding raises intriguing questions about potential connections between the gut microbiome and anatomically distant organs, such as the eye, possibly mediated through immune pathways.

Main text: This review synthesizes contemporary research on ocular diseases with the framework of the burgeoning "gut-eye axis" concept. Investigations spanning from the ocular surface to the fundus suggest correlations between the gut microbiome and various ocular disorders. By elucidating the putative pathogenic mechanisms underlying these ocular conditions, we offer novel perspectives to inform future diagnostic and therapeutic interventions in ophthalmology.

Conclusions: By presenting a critical analysis of current knowledge regarding the role of gastrointestinal microbiota in ocular health, this review shed light on the complex interplay between gut dysbiosis and eye disorders. Our work endeavors to catalyze interdisciplinary research and foster innovative clinical applications, thereby bridging the gap between the gut microbiota and the ocular well-being.

Keywords: Gut microbiota; Gut-eye axis; Immune dysregulation; Microbial-derived metabolites; Ocular disease; The leaky gut.

Graphical abstract

Fig. 1

The hypothesis of Gut dysbiosis–Ocular surface–Lacrimal gland Axis. Gut dysbiosis may induce dry eye disease by the following five mechanisms. Myeloid cell migration theory: Gut dysbiosis-mediated CD103⁺ or CXCR1⁺ dendritic cells or monocyte/macrophages migrate to drainage lymph nodes, ocular surface and lacrimal glands in order to prime T cells or secrete pro-inflammatory cytokines. Effector lymphocyte imprint theory: Gut-derived helper T 1 (Th1) and 17 (Th17) cells migrate to the ocular surface and lacrimal gland, or gut-derived Treg cells are less circulated. Molecular mimicry theory: Microbial-derived antigens cross-prime autoreactive CD4⁺ T cells helping B cells to produce autoantibodies. Metabolite circulation theory: Microbial metabolites, such as short-chain fatty acids, decrease to enter systemic circulation reaching ocular surface and lacrimal gland. Neuropeptide circulation theory: Homeostatic circulation of gut-derived neuropeptides is distributed to reach lacrimal gland and influence tear secretion.

Fig. 2

Microbe-derived metabolites, microbes-activated LPS-TLR4 pathway, and HSP-mediated T-cell activation in glaucoma. Various microbe-derived metabolites are altered in glaucoma patients, suggesting metabolites may play crucial roles in glaucoma development. Bacterial LPS triggers an upregulation of TLR4 and the complement system in the retina. Microbial HSPs activate T-cells, producing HSP-specific autoreactive T-cells by antigenic mimicry, mediating RGC axon loss and degeneration.HSP, Heat stress protein; LPS, lipopolysaccharide; MHPG, 3-Methoxy-4-hydroxyphenylglycol; TLR4, toll-like receptor 4; TMA, trimethylamine.

Fig. 3

Four interrelated proposed mechanisms of the intestinal microbiome that lead to ocular autoimmunity, and the gut-eye axis. Dysbiosis leads to a decrease in SCFAs, among other intestinal changes. These alterations promote increased intestinal permeability and an imbalance of T cells with an excess of effector T cells and a loss of regulatory T cells. Excess effector T cells are activated by mimicker microbial antigens primed against host ocular antigens (molecular mimicry) and cause uveitis. Increased intestinal permeability leads to translocation of bacterial products to remote host locations (including the eye), causing a nidus of inflammation. SCFAs, short-chain fatty acids.

Fig. 4

Targeting the intestinal microbiota to treat uveitis. Various approaches can be considered, from re-establishing intestinal immune homeostasis by increasing Tregs, reducing intestinal permeability, or by re-setting a maladaptive dysbiosis with various strategies (fecal microbial transplant, antibiotics, immunosuppressive agents, probiotics) to reduce inflammation via multiple mechanisms. Tregs, regulatory T cells.

Fig. 5

The role of gut microbiota in the pathogenesis of DR. Dysbiosis of GM can lead to the increase of gut permeability, which eventually resulting microbial translocation and microbiota-derived metabolites into vein. Subsequently, the progression of DR is promoted via multiple mechanisms. The binding of VEGF and GPR91 may be directly involved in the pathogenesis of DR. In addition, increased TMAO may induce insulin resistance and dyslipidemia, eventually leading to DR. Meanwhile, decreased SCFA may induce DR development by secreting more proinflammatory cytokines. At the same time, reduction of TUDCA decreased TGR5, which collaboratively with INT-767 to prevent DR. DR, diabetic retinopathy; GM, gut microbiota; GPR91, G protein-coupled receptors 91; SCFAs, short-chain fatty acids; TMAO, trimethylamine-N-oxide; TUDAC, tauroursodeoxycholic acid; VEGF, vascular endothelial growth factor.

Fig. 6

The Gut-Eye Axis. Two mechanisms are proposed to explain the link between GM and ocular diseases. GM dysbiosis disrupts immune homeostasis, inducing systemic inflammation via proinflammatory cytokines and Th17/Treg imbalance, which may contribute to ocular tissue damage. Additionally, increased gut barrier permeability ("the leaky gut") facilitates the translocation of microbial products such as LPS into circulation, potentially reaching the eye and triggering localized inflammation through complement activation, molecular mimicry, and monocyte-macrophage. GM, gut microbiota; LPS, lipopolysaccharides; Tregs, regulatory T cells. (created with BioRender.com.).