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 pigment epithelium that separate the neurosensory retina from the choroidal circulation. Similar in purpose to the blood-brain barrier, it serves to protect the retina, which is technically neural tissue and does not have the capability of regenerating in the event of damage. Besides, retinal antigens such as rhodopsin and recoverin are highly immunogenic and hidden behind this blood-retinal barrier. Several barriers separate human tissue from environmental bacteria. Although their chief role is to shield the body against bacterial invasion and consequent inflammation, their resilience to inflammation is variable. The first category includes the gut and skin, which tolerate inflammation well and also have the ability to regenerate efficiently. At the other extreme is the blood-retinal barrier; the retina does not tolerate inflammation or regenerate. The liver falls in between, with moderate degree of tolerance and recovery. Although several hypotheses exist, the precise initiating event that leads to inflammation of the eye remains unclear.14 Further research is required to confirm the possibility of dysbiosis being a specific cause of autoimmune uveitis. If confirmed, future treatment strategies could potentially include targeted manipulation of the gut microbiome using antibiotics and probiotics. MICROBIOME IN OTHER EYE CONDITIONS Although most discussions of the gut–eye axis have focused on uveitis, alterations in gut and ocular surface microbiota have also been reported in other ocular conditions. In dry eye disease, studies have described gut dysbiosis with alterations in microbial diversity and relative abundance of specific taxa. Patients with Sjögren-associated dry eye tend to have a lower Firmicutes/Bacteroidetes ratio and depletion of Actinobacteria and Bifidobacterium in the gut microbiome. Compared with healthy controls, gut dysbiosis appears most pronounced in autoimmune dry eye, intermediate in environmental dry eye, and partly correlated with disease severity.15 It remains unclear whether dysbiosis is a driver of dry eye disease or a secondary epiphenomenon. Deng et al. demonstrated that the intraocular environment is not sterile, identifying bacterial DNA and intact bacteria in intraocular samples from over 1000 human eyes using multiple complementary methods. Similar low-biomass intraocular microbiota was also detected in normal eyes of multiple mammalian species, with microbial patterns varying across species. Distinct microbial signatures were observed in age-related macular degeneration and glaucoma.16 Kumar et al. characterized the ocular surface microbiome in keratoconus and found a distinct microbial signature compared with healthy controls, despite similar overall diversity. Several bacterial genera correlated with disease severity, tear cytokines, and local immune cell profiles, suggesting an association between ocular surface microbiota and local immune dysregulation, without establishing causality.17 Whether the altered microbiome contributes to disease pathogenesis or reflects secondary changes related to epithelial disruption, contact lens use, or the altered ocular surface environment remains uncertain. Evidence for a functional role of microbiota in ocular health comes from experimental studies of ocular commensals. In murine models, stable colonization of the conjunctival mucosa by the resident commensal Corynebacterium mastitidis induced IL-17 production from mucosal γδ T cells, leading to recruitment of effector leukocytes and increased secretion of antimicrobial peptides into the tear film, thereby limiting corneal infection by opportunistic pathogens such as Candida albicans and Pseudomonas aeruginosa. This protective effect appeared dependent on the presence of the commensal organism and was apparently lost in germ-free or antibiotic-treated mice, supporting a proof of concept of a central ocular microbiome. Early-life acquisition was inferred because Corynebacterium mastitidis was detected on the ocular surface of offspring born to colonized mother mice despite no direct experimental exposure. In contrast, prolonged co-housing failed to transmit the organism, pointing to vertical rather than environmental transmission.18 Although derived from animal models, these findings suggest that, similar to the gut microbiome’s role in resisting invasive pathogens, specific ocular commensals may reinforce barrier immunity at the ocular surface. As with the gut–eye axis in uveitis, these observations support biological plausibility, but the available evidence is insufficient to support microbiome-targeted therapies in routine clinical practice. LIMITATIONS OF PROBIOTIC THERAPY Oral consumption of probiotics is subject to several limitations.19 First, the commercial products are not truly representative of the vast variety of natural gut bacteria. Many beneficial colonic bacteria are strict anaerobes, which means that exposure to oxygen could destroy them before they get a chance to colonize the gut. The available probiotic supplements are restricted to a few species that are commercially viable, can be stored on the shelf and will not be destroyed upon exposure to oxygen or gastric acid. Not all colonic bacteria can be used, therefore, as supplements. Second, probiotics consumed orally are subject to colonization resistance, whereby resident mucosal bacteria competitively exclude newcomers through niche competition and antimicrobial activity. Colonization resistance is reduced following antibiotic exposure. However, antibiotics also disrupt the existing gut microbiota. When probiotics are administered in this context, the introduced strains may colonize more readily; paradoxically, they can delay restoration of the native microbiome by competing for ecological niches, potentially slowing the gut’s natural recovery.20,21 These limitations highlight persistent challenges in translating microbiome research into effective clinical interventions. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Rajeev Jayadevan (Thu,) studied this question.