Sodium butyrate ameliorates diabetic retinopathy in mice via the regulation of gut microbiota and related short-chain fatty acids.

BACKGROUND: Diabetic retinopathy (DR) development is associated with disturbances in the gut microbiota and related metabolites. Butyric acid is one of the short-chain fatty acids (SCFAs), which has been found to possess a potential antidiabetic effect. However, whether butyrate has a role in DR remains elusive. This study aimed to investigate the effect and mechanism of sodium butyrate supplementation on DR. METHODS: C57BL/6J mice were divided into three groups: Control group, diabetic group, and diabetic with butyrate supplementation group. Type 1 diabetic mouse model was induced by streptozotocin. Sodium butyrate was administered by gavage to the experimental group daily for 12 weeks. Optic coherence tomography, hematoxylin-eosin, and immunostaining of whole-mount retina were used to value the changes in retinal structure. Electroretinography was performed to assess the retinal visual function. The tight junction proteins in intestinal tissue were evaluated using immunohistochemistry. 16S rRNA sequencing and LC-MS/MS were performed to determine the alteration and correlation of the gut microbiota and systemic SCFAs. RESULTS: Butyrate decreased blood glucose, food, and water consumption. Meanwhile, it alleviated retinal thinning and activated microglial cells but improved electroretinography visual function. Additionally, butyrate effectively enhanced the expression of ZO-1 and Occludin proteins in the small intestine. Crucially, only butyric acid, 4-methylvaleric acid, and caproic acid were significantly decreased in the plasma of diabetic mice and improved after butyrate supplementation. The deeper correlation analysis revealed nine genera strongly positively or negatively correlated with the above three SCFAs. Of note, all three positively correlated genera, including norank_f_Muribaculaceae, Ileibacterium, and Dubosiella, were significantly decreased in the diabetic mice with or without butyrate treatment. Interestingly, among the six negatively correlated genera, Escherichia-Shigella and Enterococcus were increased, while Lactobacillus, Bifidobacterium, Lachnospiraceae_NK4A136_group, and unclassified_f_Lachnospiraceae were decreased after butyrate supplementation. CONCLUSION: Together, these findings demonstrate the microbiota regulating and diabetic therapeutic effects of butyrate, which can be used as a potential food supplement alternative to DR medicine.

Gut microbiota induced abnormal amino acids and their correlation with diabetic retinopathy.

AIM: To explore the correlation of gut microbiota and the metabolites with the progression of diabetic retinopathy (DR) and provide a novel strategy to elucidate the pathological mechanism of DR. METHODS: The fecal samples from 32 type 2 diabetes patients with proliferative retinopathy (PDR), 23 with non-proliferative retinopathy (NPDR), 27 without retinopathy (DM), and 29 from the sex-, age- and BMI- matched healthy controls (29 HC) were analyzed by 16S rDNA gene sequencing. Sixty fecal samples from PDR, DM, and HC groups were assayed by untargeted metabolomics. Fecal metabolites were measured using liquid chromatography-mass spectrometry (LC-MS) analysis. Associations between gut microbiota and fecal metabolites were analyzed. RESULTS: A cluster of 2 microbiome and 12 metabolites accompanied with the severity of DR, and the close correlation of the disease progression with PDR-related microbiome and metabolites were found. To be specific, the structure of gut microbiota differed in four groups. Diversity and richness of gut microbiota were significantly lower in PDR and NPDR groups, than those in DM and HC groups. A cluster of microbiome enriched in PDR group, including Pseudomonas, Ruminococcaceae-UCG-002, Ruminococcaceae-UCG-005, Christensenellaceae-R-7, was observed. Functional analysis showed that the glucose and nicotinate degradations were significantly higher in PDR group than those in HC group. Arginine, serine, ornithine, and arachidonic acid were significantly enriched in PDR group, while proline was enriched in HC group. Functional analysis illustrated that arginine biosynthesis, lysine degradation, histidine catabolism, central carbon catabolism in cancer, D-arginine and D-ornithine catabolism were elevated in PDR group. Correlation analysis revealed that Ruminococcaceae-UCG-002 and Christensenellaceae-R-7 were positively associated with L-arginine, ornithine levels in fecal samples. CONCLUSION: This study elaborates the different microbiota structure in the gut from four groups. The relative abundance of Ruminococcaceae-UCG-002 and Parabacteroides are associated with the severity of DR. Amino acid and fatty acid catabolism is especially disordered in PDR group. This may help provide a novel diagnostic parameter for DR, especially PDR.

Potential disease biomarkers for diabetic retinopathy identified through Mendelian randomization analysis.

Background: Diabetic retinopathy (DR), a leading cause of vision loss, has limited options for effective prevention and treatment. This study aims to utilize genomics and proteomics data to identify potential drug targets for DR. Methods: We utilized plasma protein quantitative trait loci data from the Atherosclerosis Risk in Communities Study and the Icelandic Decoding Genetics Study for discovery and replication, respectively. Genetic associations with DR, including its subtypes, were derived from the FinnGen study. Mendelian Randomization (MR) analysis estimated associations between protein levels and DR risk, complemented by colocalization analysis to examine shared causal variants. Results: Our MR analysis identified significant associations of specific plasma proteins with DR and proliferative DR (PDR). Elevated genetically predicted levels of WARS (OR = 1.16; 95% CI = 0.095-0.208, FDR = 1.31×10-4) and SIRPG (OR = 1.15; 95% CI = 0.071-0.201, FDR = 1.46×10-2) were associated with higher DR risk, while increased levels of ALDOC (OR = 1.56; 95% CI = 0.246-0.637, FDR = 5.48×10-3) and SIRPG (OR = 1.15; 95% CI = 0.068-0.208, FDR = 4.73×10-2) were associated with higher PDR risk. These findings were corroborated by strong colocalization evidence. Conclusions: Our study highlights WARS, SIRPG, and ALDOC as significant proteins associated with DR and PDR, providing a basis for further exploration in drug development. Additional studies are needed to validate these proteins as disease biomarkers across diverse populations.

Diabetes Reshapes the Circadian Transcriptome Profile in Murine Retina.

Purpose: Diabetic retinopathy (DR) is a common complication of diabetes and has a high prevalence. Dysregulation of circadian rhythmicity is associated with the development of DR. This research aimed to investigate rhythmical transcriptome alterations in the retina of diabetic mice. Methods: C57BL/6J mice were used to establish a diabetes model by intraperitoneal injection of streptozotocin (STZ). After 12 weeks, retinas were collected continuously at 4-hour intervals over 1 day. Total RNA was extracted from normal and STZ-treated retinas and RNA sequencing was performed. Meta2d algorithm, Kyoto Encyclopedia of Genes, Phase Set Enrichment Analysis, and time-series cluster analysis were used to identify, analyze and annotate the composition, phase, and molecular functions of rhythmic transcripts in retinas. Results: The retina exhibited powerful transcriptome rhythmicity. STZ-induced diabetes markedly modified the transcriptome characteristics of the circadian transcriptome in the retina, including composition, phase, and amplitude. Moreover, the diabetic mice led to re-organized temporal and clustering enrichment pathways in space and time and affected core clock machinery. Conclusions: Diabetes impairs the circadian rhythm of the transcriptomic profile of retinas. This study offers new perspectives on the negative effects of diabetes on the retina, which may provide important information for the development of new treatments for DR.

Intravitreal Ranibizumab Had Limited Effect on Cystoid Macular Edema Due to Albumin-Bound Paclitaxel: A Case Report and Literature Review.

Angiographically silent cystoid macular edema (CME) is a rare complication from nab-paclitaxel. Here we report a 45-year-old woman with breast cancer who developed CME after several months of treatment with albumin-bound paclitaxel (nab-paclitaxel). Her visual acuity did not improve significantly with the cessation of nab-paclitaxel and intravitreal ranibizumab treatment. Then, brinzolamide eye drops were prescribed. One month later, her vision improved, with the macular edema significantly subsided. Finally, we reviewed other cases of CME induced by nab-paclitaxel that have been reported in the literature and discussed the underlying pathogenesis of nab-paclitaxel-induced CME.