Gut microbiome and uveitis: Evaluating the gut-eye axis hypothesis

The role of the gut microbiome in health and disease has been extensively studied over the past two decades. Comprising approximately 100 trillion microorganisms across hundreds of species and unique to each individual, the gut microbiome is now regarded as an active metabolic organ that continuously interacts with the host immune system and dynamically responds to diet, environmental factors, and antibiotic exposure. Dysbiosis, defined as an imbalance in the baseline composition of gut bacterial species, has been linked with multiple health conditions, including metabolic syndrome, obesity, asthma, inflammatory bowel disease, arthritis, and even Parkinson’s disease.[1,2] Among these associations, the link with inflammatory bowel disease appears strongest, with dysbiosis being consistently associated with ulcerative colitis.[3] Ulcerative colitis is an inflammatory disorder of the colonic mucosa, in which active inflammation is apparently triggered by alterations in the colonic microbiota. This relationship may be bidirectional, with mucosal barrier disruption itself acting as a driver of alterations in the gut microbiome. Recognition of this association with inflammatory bowel disease prompted researchers to explore links with inflammatory disorders affecting other organ systems. Terms such as gut-brain axis, gut-lung axis, and even gut-eye axis are now encountered in medical literature.[4] Most of these proposed axes remain hypothetical constructs, with their clinical relevance yet to be conclusively established, although animal studies appear to indicate that there may be some truth in this. THE GUT-EYE AXIS HYPOTHESIS The gut–eye axis hypothesis proposes that immune cells activated in the gut (due to an imbalance in the gut microbiome) may traffic via lymphatics and bloodstream to the eye, disrupting the blood-ocular barrier, gaining entry to this immune-privileged organ and initiating a local inflammatory process.[5] The proposed mechanism involves gut dysbiosis triggering activation of antigen-presenting cells (particularly dendritic cells) in the intestinal mucosa, which secrete proinflammatory cytokines including IL-6, IL-1β, and IL-23.[6] These cytokines activate the transcription factor STAT3 in naive CD4+ T cells, which then differentiate into T helper 17 (Th17) cells. Under normal conditions, Th17 cells maintain mucosal integrity by producing IL-17A, IL-17F, and IL-22. However, when dysbiosis occurs, pathogenic Th17 cells secrete excessive IL-17, which activates NF-κB signaling and attracts neutrophils, resulting in inflammation. The hypothesis is that these activated Th17 cells, shaped by the altered gut microbiome, can migrate from the gut, disrupt the blood-ocular barrier, enter the eye and initiate a chronic recurrent inflammatory process. This represents one of the proposed mechanisms of autoimmune and idiopathic uveitis.[7] The pathogenesis of autoimmune and idiopathic uveitis can be conceptually divided into downstream effector mechanisms and upstream triggering events. While the downstream events—comprising various immune cells and cytokines acting on ocular tissues—are well described, the upstream triggers remain incompletely understood. The hypothesis that an altered gut microbiome drives aberrant immune responses has the potential to address this gap, particularly from studies involving mice where dysbiosis has been linked with autoimmune uveitis. In mice, experimental autoimmune uveitis resolves with oral antibiotics (metronidazole/vancomycin), while recolonization triggers recurrence, further supporting the gut-eye axis as a viable hypothesis at least in animal models.[8] This observation has not yet been confirmed in human studies. None of the guidelines issued by academic ophthalmology societies have included microbiome-based interventions in treatment protocols for uveitis. Chakravarthy et al. reported Prevotella enrichment in the gut microbiome of uveitis patients compared to healthy controls.[9] The presence of Prevotella in the gut microbiome is common among individuals consuming carbohydrate-heavy diets, a phenomenon prevalent across India.[10] Replication of these findings in larger, diverse cohorts would strengthen human evidence for the gut-eye axis. LIMITATIONS OF THE GUT-EYE AXIS THEORY While the gut microbiome is an attractive hypothesis for explaining uveitis, there are several reasons why uveitis does not fit this model perfectly.[11] First, if T cells originated in the gut and traveled to the eye through the bloodstream, the process would need to be bilateral, which is not always the case. Secondly, it does not adequately explain the intermittent nature of uveitis, characterized by relapses interspersed with periods of remission; persistent dysbiosis would be expected to result in continuous inflammation. Thirdly, the prevailing treatment of autoimmune uveitis does not involve manipulating the microbiome, yet results are achieved. Thus, the microbiome association is more likely to fit models of inflammatory bowel disease, Behçet’s disease and experimental autoimmune uveitis in animal models.[12] BLOOD-OCULAR BARRIERS AND IMMUNE PRIVILEGE Being an immune-privileged organ, the eye is armed with two barriers: the blood-retinal barrier and the blood-aqueous barrier.[13] The latter is involved with anterior uveitis and the former is linked with chronic immune-mediated posterior uveitis. It is possible that CD4 Th1/Th17 cells shaped by the gut microbiome initiated the inflammation. The blood–aqueous barrier is located in the anterior segment of the eye and consists of iris capillaries and tight junctions in the ciliary epithelium, regulating protein entry and restricting the passage of inflammatory cells. The blood–retinal barrier, located in the posterior segment of the eye, consists of two components: an inner barrier formed by tight junctions between retinal capillary endothelial cells, and an outer barrier composed of tight junctions of the retinal