In this study, through MR analysis, we found that there is a potential causal relationship between the gut microbiota and exudative AMD, which provides valuable insight and serves as a solid foundation for future research in this field.
The human gut microbiota is a sophisticated ecosystem populated by diverse microorganisms, including bacteria, viruses, archaea, and eukaryotes, that reside in the gastrointestinal tract. The indispensable functions carried out by the gut microbiota for the human host highlight its profound importance[19]. Integral to numerous host functions, the human gut microbiota contributes significantly to nutritional metabolism, immune system modulation, protection against pathogens, and the maintenance of intestinal barrier integrity[20].
In 2005, Eckburg et al. conducted pioneering metagenomic research to classify the gut microbiota into six primary phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, and Fusobacteria. Among them, Bacteroidetes and Firmicutes were the main dominant bacterial groups. In 2010, the EU Meta HIT project team published a gene catalogue of human gut microbiota in Nature, obtaining a total of 3.3 million effective reference genes for human gut metagenomes, representing an approximately 150-fold increase over the size of the human genome. From this gene set, it is estimated that there are at least 1000-1150 bacterial species present in the human gut, with an average of approximately 160 dominant bacterial species per host. Subsequent investigations categorized the gut microbiota in populations of varying ages, body weights, sexes, and nationalities into three main types: Bacteroides, Prevotella, and Ruminococcus[21]. However, ongoing research is refining our understanding of gut microbiota diversity, and these classifications may evolve with further investigation.
A study of the microbiota in the intraocular environment of healthy individuals and patients with ocular diseases provided preliminary evidence that the intraocular environment of patients with AMD exhibits disease-specific microbial characteristics, indicating that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions[22]. These findings provide preliminary evidence that microbial characteristics within the intraocular environment of AMD patients may differ from those of healthy individuals, suggesting a potential association between microbial translocation and the development or progression of this sight-threatening condition. Although the precise mechanisms regulating the gut-eye axis remain incompletely understood, the impact of the gut microbiota on eye diseases cannot be overlooked. It holds potential as a therapeutic target for certain ocular conditions. "Dysbiosis of the gut microbiome, characterized by an imbalance in microbial communities, is linked to chronic inflammation and increased intestinal permeability. This dysbiosis can profoundly affect local metabolic and inflammatory pathways with systemic consequences, potentially extending to peripheral tissues such as the eye. The gut microbiota exerts its influence through local metabolic and inflammatory pathways, which have systemic implications. These systemic effects may extend to peripheral tissues, including the eye, impacting the pathogenesis of eye diseases.
With advancing age, changes in the microbiome composition occur, potentially contributing to age-related degenerative diseases such as AMD. Dysfunction of the gut microbiota can affect the metabolism and absorption of constant and trace nutrients in the intestinal barrier and is associated with increased intestinal permeability. Metabolites produced by the gut microbiota can potentially initiate autoimmune reactions in the eyes through the activation of retinal-specific T cells. The gut microbiota plays a crucial role in metabolic diseases, influencing factors such as blood glucose control and fat metabolism, which are significant considerations in AMD development[23]. Prolonged consumption of a high-fat diet and obesity can compromise the integrity of the intestinal barrier, leading to systemic inflammation and contributing to the development of various biological disorders. Microbial molecular pattern molecules and proinflammatory cytokines, which originate from the compromised intestinal barrier, can enter the systemic circulation and initiate immune responses in the retina. The reactivity of microglia and recruitment of inflammatory macrophages contribute to stromal support, promoting angiogenesis and ultimately leading to choroidal neovascularization. Dysbiosis in AMD patients disrupts intestinal homeostasis, leading to the accumulation of stimulator of interferon genes (STING) in the gut. Subsequent translocation of microbial products into the blood allows access to the retina via the impaired blood‒retinal barrier, resulting in chronic activation of the STING pathway in the retina and contributing to disease progression[24].
Some articles[25, 26] have demonstrated that a high-sucrose and high-fat diet exacerbates choroidal neovascularization by altering the gut microbiota. Intestinal dysbiosis leads to increased intestinal permeability and chronic low-grade inflammation characterized by the production of inflammatory factors, including IL-6, IL-1b, and TNF-α, and the production of vascular endothelial growth factor-A increases, ultimately exacerbating pathological angiogenesis.
An MR analysis was conducted in this study using summary statistics data on the gut microbiota extracted from the Dutch microbiome, while summary-level data for AMD were obtained from the FinnGen biobank. The objective of this study was to identify the causal relationship between the gut microbiota and AMD. The family Peptococcaceae, genus Parasutterella and genus Faecalibacterium are related to an increased risk of AMD, while the class Melainabacteria and family Rikenellaceae can reduce the risk of AMD. Several articles have studied the relationship between the gut microbiota and AMD. Li et al[27] indicated that Eubacterium, Parabacteroides, Ruminococcaceae and Lachnospiracea may have a protective effect against AMD. Conversely, both the weighted median and IVW estimates suggest that Dorea may increase the risk of AMD. Mao et al.[28] demonstrated that the genera Anaerotruncus, Candidatus Soleaferrea, and unknown id.2071 were protective factors against AMD. The Eubacterium oxidoreducens group, genus Faecalibacterium, and genus Ruminococcaceae UCG-011 were risk factors for AMD. Liu[29] demonstrated that the order Rhodospirillales, family Victivallaceae, family Rikenellaceae, genus Slackia, genus Faecalibacterium, genus Bilophila, and genus Candidatus Soleaferreaw were suggestively associated with AMD. In the replication stage, only the order Rhodospirillales passed validation.
Both Faecalibacterium and Rikenellaceae have consistently been shown to be related to AMD. Parasutterella occupies a specific intestinal niche and affects microflora and host metabolism. Changes in bile acid levels are accompanied by alterations in bile acid transport genes in the ileum and bile acid synthesis genes in the liver, indicating a potential role for bacteria in maintaining bile acid homeostasis and cholesterol metabolism. The metabolism of L-cysteine may be related to the development of type 2 diabetes, while the link with the fatty acid biosynthesis pathway is related to weight gain in carbohydrate-rich diets during the development of obesity[30]. Faecalibacterium, a normal intestinal symbiotic bacterium and a dominant member of Clostridium softeners, is considered a crucial bacterial indicator of healthy intestines, accounting for more than 5% of the total number of bacteria in the intestines of healthy individuals.
Faecalibacterium is capable of producing butyric acid, which plays a crucial role in regulating the intestinal immune system, reducing oxidative stress, and modulating the metabolism of colonic epithelial cells. Furthermore, Faecalibacterium secretes anti-inflammatory compounds into the surrounding environment, which has been shown to reduce the incidence of inflammatory diseases in mice. Recently, a study showed that oral administration of Faecalibacterium could significantly improve fatty liver in mice[31]. The presence of genes for vitamin biosynthesis in gut Melainabacteria members suggests their potential utility to the host, with potential connections to neurodevelopment, neurodegeneration, obesity, allergic rhinitis, and gastrointestinal, respiratory, and eye diseases.[32] The first study[33] on gut bacterial ClpB-like gene function in humans revealed that the relative abundance of Rikenellaceae was lower in subjects with obesity, while it was positively associated with gut bacterial ClpB-like gene function. All of these findings prove the existence of a gut-eye axis.
Enhanced intestinal permeability or a dysregulated microbiota can impair nutrient absorption in the intestinal barrier, leading to increased mobility of bacteria, including endotoxins and lipopolysaccharides. These can trigger low-level inflammation in various tissues by activating pattern recognition receptors. When these processes occur in the retina, they can induce the expression of macrophages and retinal pigmented epithelial cells, ultimately causing eye inflammation, such as age-related macular degeneration.
With the discovery of a large number of genetic variations closely related to specific traits in the field of biology, researchers have gained valuable insights into disease etiology. Large-scale GWASs have provided researchers with hundreds of thousands of aggregate data points, facilitating the study of relationships between exposure, disease, and genetic variation in large sample datasets. Moreover, these advancements enable researchers to estimate genetic associations in large sample datasets efficiently and at low cost, primarily through MR studies. Our study included only participants of European ancestry, which limits the generalizability of our results to individuals of non-European ancestry. Further research is necessary to assess the association between the gut microbiota and AMD risk in other ethnic groups. Further research is needed to determine the universality of the association between the gut microbiota and the risk of AMD in other ethnic groups. Additionally, our study is subject to methodological limitations, including but not limited to issues such as linkage disequilibrium, pleiotropy, and developmental compensation.
From a clinical perspective, this article presents a promising avenue for the treatment of AMD by targeting the gut microbiota. Adjusting the balance of the intestinal microbiota through dietary changes may lower the incidence of AMD or slow its progression. Additionally, advancements in medical technology offer the possibility of developing novel methods to enhance the human gut microbiota, facilitating the treatment of various diseases, including AMD. However, it is essential to acknowledge that this field is still in its early stages, and further research is needed to confirm and establish the best treatment strategies. Furthermore, given the complexity and diversity of the human gut microbiota, personalized and targeted intervention measures are necessary to effectively address individual patient needs.