High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

Nadeem, Urooba; Xie, Bingqing; Movahedan, Asadolah; D'Souza, Mark; Barba, Hugo; Deng, Nini; Leone, Vanessa; Chang, Eugene B.; sulakhe, Dinnath; Skondra, Dimitra

doi:10.1101/2020.10.01.318949

Cited by 8 publications

(8 citation statements)

References 91 publications

(106 reference statements)

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“…To further elucidate the biological connections between the diet-gut-retina axis, we aimed to investigate how diet affects the retinal transcriptome independently of the gut microbiome [30]. Germ-free mice, raised without exposure to any microbes, provide an ideal model to investigate this hypothesis [46].…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

Dao

Xie

Nadeem

et al. 2021

Cells

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The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.

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“…Although some associative studies have been performed over the last decade, we have only recently begun to explore the retinal transcriptional signatures linking the microbial organ and retinal homeostasis and physiology relating to AMD. Using high-throughput RNA sequencing, our team detailed the transcriptional profile of retinas from germ-free mice revealing significant differentially expressed genes (DEGs) and altered retinal pathways, including VEGF, mitochondrial biogenesis via peroxisome proliferatoractivated receptor gamma coactivator 1-alpha (PGC-1a), oxidative stress and AMP-activated protein kinase (AMPK) signalling critical to AMD pathogenesis [45]. These studies not only reinforce the complexity of the gut-retina axis but also highlight its potential integral role in AMD pathogenesis at even the transcriptomic level.…”

Section: Key Pointsmentioning

confidence: 99%

Gut microbiome and retinal diseases: an updated review

Nadeem

Boachie-Mensah²,

Zhang³

et al. 2022

Current Opinion in Ophthalmology

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Purpose of reviewThe gut microbiome, trillions of microorganisms residing in our digestive tract, is now believed to play a significant role in retinal diseases. Breakthroughs in computational biology and specialized animal models have allowed researchers not only to characterize microbes associated with retinal diseases, but also to provide early insights into the function of the microbiome in relation to biological processes in the retinal microenvironment. This review aims to provide an update on recent advances in the current knowledge on the relationship between the gut microbiome and retinal disorders. Recent findingsRecent work demonstrates distinct gut microbial compositions associated with retinal diseases such as agerelated macular degeneration and retinopathy of prematurity. Currently, it is believed that gut dysbiosis leads to increased gut permeability, elevated circulation of bacterial products, microbial metabolites and inflammatory mediators that result in immune dysregulation at distant anatomic sites including the retina.

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“…Using high-throughput RNA sequencing in GF mice, Skondra and colleagues has also revealed key aspects of retinal gene regulation important in AMD pathogenesis that are modulated by the intestinal microbiota. Their study revealed that the top modified pathways include vascular endothelial growth factor (VEGF) receptor signaling, mitochondrial biogenesis, oxidative stress, autophagy, longevity, and AMP-activated protein kinase (AMPK) signaling [ 57 ]. In the same study, one of the top differentially expressed genes of the gut–retina axis was revealed to be the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which is the master regulator of mitochondrial biogenesis, oxidative stress, and lysosomal lipid trafficking [ 58 , 59 , 60 ].…”

Section: Genes and Gene Expression In Amd: A Link To The Microbiotamentioning

confidence: 99%

A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration

Lin

McClintic

Nadeem

et al. 2021

JCM

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Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing.

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“…However, the abundance of Oscillospira, Blautia , and Dorea was reduced in AMD subjects compared with healthy controls ( Lin, 2018 ; Lin, 2019 ). Using high-throughput RNA sequencing in GF mice, Skondra and colleagues revealed key aspects of retinal gene regulation in AMD that are modulated by the intestinal microbiota ( Nadeem et al., 2020 ). Although the exact pathogenesis of AMD remains poorly understood, certain inflammatory mechanisms associated with innate immunity have been identified.…”

Section: Role Of Microbiota In Ocular Diseasementioning

confidence: 99%

Microbiota and Ocular Diseases

Xue

Zou

et al. 2021

Front. Cell. Infect. Microbiol.

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Recent advances have identified significant associations between the composition and function of the gut microbiota and various disorders in organ systems other than the digestive tract. Utilizing next-generation sequencing and multiomics approaches, the microbial community that possibly impacts ocular disease has been identified. This review provides an overview of the literature on approaches to microbiota analysis and the roles of commensal microbes in ophthalmic diseases, including autoimmune uveitis, age-related macular degeneration, glaucoma, and other ocular disorders. In addition, this review discusses the hypothesis of the “gut-eye axis” and evaluates the therapeutic potential of targeting commensal microbiota to alleviate ocular inflammation.

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“… 15 The relationship between gut microbiota and ocular abnormalities including uveitis, glaucoma, and age-related macular degeneration (AMD) has been increasingly revealed, and the concept of a “microbiota–gut–retina axis” has been put forward. 16 , 17 However, little has been understood regarding the molecular mechanisms of intestinal dysbiosis and how they induce retinopathy in patients with DM. Recently, data indicate that changes in the gut microbiome act as a key internal environmental modulator which favorably affects the pathogenetic processes underlying the micro-complications of DM such as DR. 18 …”

Section: Introductionmentioning

confidence: 99%

Recent Insights into the Role of Gut Microbiota in Diabetic Retinopathy

Jiao¹,

Yao²,

Yao³

et al. 2021

JIR

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The microbiome has become a hot issue in recent years. The composition, modification, alteration, and disturbance of gut microbiota were found to influence important physiological processes, including energy metabolism and microenvironmental homeostasis, and lead to various diseases, including obesity, type 2 diabetes mellitus and chronic kidney disease. Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and one of the leading causes of blindness and vision impairment. The underlying mechanisms in DR pathogenesis remain limited. Recently, important insights have been made regarding possible connections between gut microbiome dysbiosis and ocular disease including DR, uveitis, glaucoma, and age-related macular degeneration, and the concept of a “microbiota–gut–retina axis” has been put forward. Hence, we reviewed current understanding of the relationship between DR and gut microbiota. We summarized potential pathophysiological mechanisms that contribute to the role of the gut microbiota on DR, including hyperglycemia, anti-diabetes drugs, microbial metabolites, and inflammatory properties. We aimed to find novel effective therapeutic options to prevent the onset and development of DR.

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High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

Cited by 8 publications

References 91 publications

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

Gut microbiome and retinal diseases: an updated review

A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration

Microbiota and Ocular Diseases

Recent Insights into the Role of Gut Microbiota in Diabetic Retinopathy

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