Gut Microbiota-Derived Indole-3-Acetic Acid (3-IAA) Suppresses High Myopia Progression by Promoting Type I Collagen Synthesis

Background

High myopia (HM) is a serious vision-threatening ocular condition associated with complications such as glaucoma, cataracts, and macular degeneration. Currently, effective interventions for high myopia are lacking. Previous research has predominantly focused on localized ocular pathologies, neglecting potential systemic factors. Recently, the relationship between gut microbiota and systemic health has gained widespread attention, particularly with the concept of the “gut-eye axis,” which posits the involvement of gut microbiota in ocular diseases. However, the specific role of gut microbiota in high myopia remains unclear.

Type I collagen, a major component of the scleral extracellular matrix, is critical for maintaining scleral structural integrity. In high myopia, the sclera thins and Type I collagen levels decrease, leading to excessive axial elongation of the eye. Studies have shown that gut microbiota can influence host collagen metabolism through metabolites such as short-chain fatty acids and tryptophan derivatives, which affect fibrosis. This study hypothesizes that gut microbiota and its metabolites could influence high myopia development by regulating scleral collagen metabolism.

Study Origin

This research was conducted by a collaborative team from the Eye and ENT Hospital of Fudan University and affiliated institutions, published in Cell Discovery in 2024. The lead authors are Hao Li and Yu Du, with Yi Lu and Xiangjia Zhu as corresponding authors.

Research Methods and Design

Study Population and Data Collection

The study recruited 97 participants, including 52 high myopes and 45 healthy controls, alongside an independent validation cohort. Clinical characteristics such as age, sex, and body mass index (BMI) were matched, and individuals with other ocular or systemic diseases were excluded. Fecal and blood samples were collected for 16S rRNA sequencing and metabolomic analysis.

Gut Microbiota Analysis

16S rRNA sequencing revealed significant differences in gut microbiota composition between high myopia patients and healthy controls, despite no significant changes in microbial richness or diversity. Certain genera, such as Akkermansia, were significantly reduced in high myopia patients, while others like Lautropia were increased. The abundance of Akkermansia was negatively correlated with axial length (AL), suggesting a protective role against high myopia.

Fecal Microbiota Transplantation (FMT) Experiment

To explore the effects of gut microbiota on high myopia, fecal microbiota transplantation (FMT) was performed on antibiotic-treated mice. Feces from healthy controls or high myopia patients were transplanted into these mice. Results showed that mice receiving feces from healthy donors exhibited significantly less axial elongation and refractive error progression in a high myopia model, maintaining higher Type I collagen expression in the sclera.

Metabolomic Analysis and the Role of 3-IAA

Targeted metabolomic analysis identified significantly lower plasma levels of 3-IAA in high myopia patients, which correlated with reduced Akkermansia abundance. Animal experiments demonstrated that daily supplementation of 3-IAA could slow high myopia progression and maintain Type I collagen expression in the sclera.

Molecular Mechanism Exploration

Cell experiments confirmed that 3-IAA promotes the expression of the Type I collagen gene (COL1A1). Mechanistic studies revealed that 3-IAA enhances the binding of transcription factor SP1 to the COL1A1 promoter, activating its transcription. This regulatory pathway was independent of the aryl hydrocarbon receptor (AHR) signaling pathway.

Results and Conclusion

This study revealed that gut microbiota dysbiosis in high myopia patients leads to reduced plasma 3-IAA levels, which suppress Type I collagen expression in the sclera, accelerating myopia progression. Restoring gut microbiota or supplementing 3-IAA effectively alleviated this process. These findings highlight the gut-eye axis and provide new insights into the pathogenesis of high myopia.

Significance

The study is the first to demonstrate the pivotal role of gut microbiota and its metabolites in high myopia, proposing a novel therapeutic strategy: regulating gut microbiota or supplementing key metabolites like 3-IAA to intervene in myopia progression. This provides a new research direction and clinical foundation for high myopia prevention and treatment.

Highlights

1. Innovative Discovery: Introduced the concept of the “gut-eye axis” in high myopia research.
2. Comprehensive Validation: Combined patient data, animal models, and cellular experiments to validate the gut microbiota-myopia relationship.
3. Mechanistic Insights: Revealed the molecular mechanism of 3-IAA-mediated regulation of Type I collagen.
4. Clinical Potential: Proposed practical therapeutic strategies for high myopia intervention.

This research not only advances the understanding of high myopia pathogenesis but also serves as a paradigm for exploring the systemic effects of gut microbiota in other diseases.