Inherited retinal degeneration (IRD) is a group of disorders characterized by progressive loss of retinal photoreceptor cells; it affects vision and eventually results in incurable blindness [
1]. Genetic factors play a major pathogenic role in IRD, as hundreds of mutated genes are linked to these diseases. The complexity and diversity of genetic variations in these diseases impede the development of therapeutic strategies for retinal degeneration [
1]. Mutations in the crumbs homolog 1 (
CRB1) gene are known to cause severe retinal degeneration, which may present as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), macular dystrophy, or early-onset severe retinal dystrophy. Globally,
CRB1 mutations account for 7%–17% LCA cases and approximately 4% RP cases [
2,
3]. Therefore, strategies targeting
CRB1-related retinal degenerations may help alleviate the burden of blindness such as LCA and RP.
CRB1 encodes a transmembrane protein with 1406 amino acids, and it is mainly expressed in the retina and brain tissues of humans and mice. As an important regulator of adherens junction (AJ) protein, CRB1 is critical for normal polarity, cell–cell adhesion functions, and integrity of the structure of retinal cells [
3]. Strikingly, a recent publication in the journal of
Cell by Peng
et al. [
4] demonstrated that
CRB1 mutations enable gut bacteria to translocate to the eye, which can cause retinal damage. In their project, the naturally occurring retinal degeneration 8 (Rd8) mouse with a 1 bp deletion in
CRB1, causing a nonsense mutation and resulting in degradation of the CRB1 protein, was used as a model of
CRB1-associated retinal degeneration. Two barriers (intestinal epithelial barrier and blood retinal barrier (BRB)) prevent bacteria from the gut to the retina. Therefore, the retinas must be sterile because of protective epithelial barriers. However, with multidisciplinary approaches, they unexpectedly observed seven bacterial species in the retinal lesions of Rd8 mice, which were housed in a specific pathogen-free environment; five of them were known gut bacteria, whereas no bacteria were found in normal retinal regions. Previous studies have suggested that the
CRB1 gene is exclusively expressed in the eye and the central nervous system of humans and mice [
5]. However, Peng and his colleagues [
4] first found that CRB1 is also expressed at the apex of colonic enterocytes, playing a crucial role in maintaining AJ integrity between enterocytes and apical polarization of colonic epithelium. Consistently, Rd8 mutation mice lacked AJ and disrupted colonic epithelial barriers, leading to an increase in intestinal permeability. Similarly, relatively weak expression of CRB1 in retinal pigment epithelium (RPE), outer limiting membrane (OLM), and Bruch’s membrane, accompanied with disrupted cellular junctions and impaired BRB, was observed in Rd8 mice. Therefore, these two defective epithelial barriers in the colon and retina (leaky retina and leaky gut) allowed intestinal bacterial translocation to the peripheral blood and retinal tissues, leading to the inflammatory response and retinal degeneration with a
CRB1 mutation of Rd8 mice (Fig.1).
LCA is the most severe and early onset form of IRD, which is associated with mutations in approximately 38 genes, including common mutations
GUCY2D, RPE65, CRB1, CEP290, and
RDH12 [
6]. Currently, gene therapy with adeno-associated virus (AAV) vectors has emerged as a promising strategy for treating retinal dystrophies like LCA [
7]. Among these clinical trials, Luxturna, a gene therapy drug based on AAV-RPE65, was first approved by the Food and Drug Administration (FDA) in 2017 [
8], and other clinical trials of IRDs, including RP and choroideremia, are currently underway. Recently, Liu
et al. [
9] proposed a dual-action strategy using the AAV-hRPE65-BCL-2-L10 vector, delivering the
RPE65 gene and anti-apoptotic factors
Bcl-2, which enhanced and sustained retinal protection in animal models. Similarly, Peng
et al. [
4] revealed that the reintroduction of normal
CRB1 gene with the AAV vector in enterocytes successfully restored the integrity of AJ in the intestinal epithelial barrier, which significantly reduced bacterial translocation and retinal lesions. Thus, restoration of CRB1 expression in the gut could alleviate retinal degeneration in Rd8 mice.
CRB1-associated retinal degeneration is dependent on bacteria in the retinas, so targeting these bacteria may provide an alternative strategy for these disorders. Notably, removal of the bacteria either by germ-free derivation or antibiotic treatment to newborn Rd8 mice effectively prevented the occurrence of retinal damage. However, whether antimicrobial treatment has similar effects when retinal degeneration already occurs needs to be further elucidated in the future. Taken together, these results supported the conclusion that additional environmental factors could trigger retinal degeneration in
CRB1-mutated diseases and explained the phenomenon “
CRB1: one gene, many phenotypes” because seven species of bacteria instead of single bacteria strains were found in the retinal lesions of Rd8 mice [
3].
Recently, numerous studies in ophthalmology have suggested that gut microbiota dysbiosis might contribute to the pathogenesis of multiple ocular diseases, including uveitis, age-related macular degeneration, dry eye, and glaucoma, confirming the existence of a gut–eye axis [
10]. Deng
et al. [
11] first identified the presence of intraocular microbiota from over 1000 human eyes via quantitative PCR, electron microscopy, culture, and metagenomic sequencing technologies. Labetoulle
et al. [
12] demonstrated that gut microbiota impacts ocular surface homeostasis and induces related disorders. Although the mechanism underlying these associations remains unclear, supplementation with probiotics and prebiotics appears a feasible and convenient approach to prevent aforementioned diseases [
10]. In this project, Peng
et al. [
4] suggested a new mechanism linking the gut and eye through the translocation of bacteria from the leaky gut to the retina caused by
CRB1 mutation. Recently, Jin
et al. [
13] revealed that among
CRB1-related early onset RD in 11 Chinese children under the age of 9, 81.8% (9/11) present as LCA; thus, whether bacterial delivery and
CRB1 gene therapy also have the same effects in LCA must be explored in further studies. In addition, investigations on whether clinical patients with
CRB1-associated retinal diseases have intestinal defects and systemic bacterial translocation would be beneficial to disease pathogenesis and antibacterial therapies.
Taken together, all the results elucidated the key pathogenesis of CRB1-associated retinal blindness. Systemic antibiotic treatment and local gene therapy in the gut have the potential to ameliorate this genetic retinal disorder.
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