A recent study published in the journal Cell reveals groundbreaking findings from a collaborative research effort led by the Zhongshan Ophthalmic Center at Sun Yat-sen University. Over the course of 8 years, they have identified for the first time that gut bacteria mediate hereditary retinal diseases, proposing a novel approach for prevention and treatment involving antibacterial/gene therapies.
"We have uncovered, for the first time, that mutations in the CRB1 gene disrupt the barrier between the gut and retina, allowing harmful bacteria from the gut to migrate to the retina. This challenges the conventional belief that the human eye is sterile," shared Dr. Wei Lai, co-corresponding author of the paper and visiting professor at the Zhongshan Ophthalmic Center, with Chinese Science Bulletin. He further emphasized that this research breakthrough is poised to have a significant impact on the treatment of hereditary retinal degenerative diseases, potentially offering new therapeutic opportunities in the field.
Eight Years of Dedication
Hereditary retinal degenerative diseases represent a group of severe, irreversible blinding disorders that predominantly affect children and adolescents, with an incidence of approximately 1 in every 2000 individuals, and so far, there have been virtually no effective treatments available.
"Congenital achromatopsia and retinitis pigmentosa are two relatively common types of hereditary retinal degenerative diseases," explained Dr. Wei. "The onset of these diseases is associated with over 250 genes, with CRB1 being one of them, although the specific pathogenic mechanisms were previously unclear."
He noted that congenital achromatopsia manifests from birth, with blindness typically occurring before the age of one, while retinitis pigmentosa generally begins in adulthood, progressing from blurry vision to blindness over a span of 10-20 years. "These conditions are easily diagnosed but notoriously difficult to treat."
To tackle these ocular disorders, 8 years ago, the research team at the Zhongshan Ophthalmic Center initiated a comprehensive scientific endeavor. After years of persistent efforts, they have finally achieved a breakthrough:
They have unveiled for the first time that mutations in the CRB1 gene disrupt the barrier between the gut and retina, allowing harmful bacteria from the gut to enter the retina, leading to blinding eye diseases—hereditary retinal degeneration. They have proposed that antibiotic therapy along with gene therapy may effectively prevent or halt the occurrence and progression of related ocular diseases.
Research Overview: Insights from Participants' Contributions
"While the eye disease we studied is a rare cause of blindness, it's a significant factor in blindness among the working-age population, and it holds potential significance for age-related diseases like age-related macular degeneration," said Richard Lee, co-corresponding author of the paper and Clinical Director at the National Eye Institute, NIH. He highlighted a groundbreaking avenue in research by demonstrating the potential for gut bacteria to migrate from the intestines to the eyes.
Dr. Lin Haotian, Director and President of Zhongshan Ophthalmic Center, Sun Yat-sen University, emphasized that this innovative breakthrough resulted from the dedicated collaboration and hard work of teams led by professors Wei Lai and Zhang Feng. He underscored the unique advantages and outstanding achievements of Zhongshan Ophthalmic Center and the National Key Laboratory for Prevention and Treatment of Eye Diseases in cultivating high-level talent and leading the field of ophthalmology.
An Unexpected Discovery: "Our research was sparked by an unexpected discovery."
Discussing the backstory, Wei Lai explained that eight years ago, a student found that retinal lesions disappeared mysteriously in Crb1 gene mutant mice raised in a sterile environment, only to reappear upon returning to a normal environment. This unexpected finding led the team to ponder where these bacteria in the closed environment of the eye came from and how they entered the retina, sparking new avenues of exploration.
In their preliminary research, the team found that the previous notion of the eye being completely sterile was inaccurate. They identified seven types of bacteria in the degenerative areas of the retina, with up to five being known gut bacteria. Consequently, they turned their attention to the rich microbial community in the gut. Through extensive investigation and validation, they ultimately discovered CRB1 expression in the colonic epithelial cells.
Peng Shanzhen, co-first author of the paper and a doctoral student at Zhongshan Ophthalmic Center, explained that while previous studies found CRB1 gene expression only in the eyes and brains of humans and mice, its expression outside the retina and brain was unclear. Their research team discovered CRB1 gene expression in colonic epithelial cells, establishing a barrier structure that helps combat pathogens and harmful bacteria.
"To capture bacteria on tissues magnified thousands of times is like finding a needle in a haystack," Peng Shanzhen remarked, explaining the challenges of their experiments. By labeling bacteria, the team demonstrated that gut bacteria breached the intestinal mucosal barrier, then further penetrated the blood-retinal barrier, ultimately reaching the retina. After systemic antibiotic treatment to remove most gut bacteria in mice, there was a noticeable improvement in retinal lesions.
Two Paths for Treatment: "This breakthrough offers two potential paths for treatment."
"As a fundamental research achievement, this finding holds great promise for the treatment of CRB1-related genetic blinding diseases," remarked Zhang Feng, co-corresponding author of the paper and professor at Zhongshan Ophthalmic Center. Based on mouse experiments, the study suggests that antibiotic therapy and gene therapy may effectively prevent or halt the progression of retinal degeneration.
"However, this is still in the realm of research, and there's a long way to go before clinical practice. We do not recommend blind antibiotic therapy for patients with genetic retinal diseases," Zhang Feng emphasized.
CRB1, explained Zhang, is a transmembrane protein that acts as a link between two cells, akin to cells holding hands tightly. When mutated, it fails to function, leading to gaps or defects between cells. The research team's revelation that gut bacteria can migrate to the retina and participate in its pathogenesis is significant.
In 2013, Wei Lai joined Zhongshan Ophthalmic Center as a high-level recruit, followed by Zhang Feng in 2019. "Detecting bacteria in lesions is challenging due to their low abundance. Initially, it required painstaking slicing and testing of the entire retina," Zhang Feng admitted, highlighting the difficulties in the research process. "We and Wei Lai's team conducted a series of exclusion and validation experiments, ultimately revealing that the breakdown of both the intestinal barrier and the blood-retinal barrier led to bacterial translocation."
"This achievement not only suggests a significant shift in the treatment approach for genetic retinal degenerative diseases but also provides new clues for the involvement of 'microbiota-host immunity' in other chronic degenerative diseases, marking a major breakthrough in interdisciplinary research," commented Li Tao, director of the Emergency Department and Ophthalmic Trauma Service at Zhongshan Ophthalmic Center.
It's worth noting that this is the first paper published by Zhongshan Ophthalmic Center in the journal Cell and serves as a "gift" for Sun Yat-sen University's centennial celebration this year.
Related Paper Information: https://doi.org/10.1016/j.cell.2024.01.040
