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

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Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-04259-4.

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Most cited references 50

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Global Prevalence and Major Risk Factors of Diabetic Retinopathy

Joanne Yau, Sophie L. Rogers, Ryo Kawasaki … (2012)

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

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Host-gut microbiota metabolic interactions.

Jeremy K Nicholson, Elaine Holmes, James Kinross … (2012)

The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.

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Gut metagenome in European women with normal, impaired and diabetic glucose control.

Fredrik Karlsson, Valentina Tremaroli, Intawat Nookaew … (2013)

Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.

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Author and article information

Contributors

Jiansu Chen: chenjiansu2000@163.com

Shibo Tang: tangshibo@vip.163.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 7 July 2023

Publication date PMC-release: 7 July 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 451

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Aier School of Ophthalmology, , Central South University, ; Changsha, China

[2 ]Aier Eye Institute, Changsha, China

[3 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, , Wenzhou Medical University, ; Wenzhou, China

[4 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, National Clinical Research Center for Ocular Diseases, Eye Hospital, , Wenzhou Medical University, ; Wenzhou, China

[5 ]Department of Ophthalmology, Nanchang Aier Eye Hospital, Nanchang, China

[6 ]Department of Ophthalmology, Changsha Xiangjiang Aier Eye Hospital, Changsha, China

[7 ]GRID grid.258164.c, ISNI 0000 0004 1790 3548, Key Laboratory for Regenerative Medicine, Ministry of Education, , Jinan University, ; Guangzhou, China

[8 ]Changsha Aier Eye Hospital, Aier Eye Hospital Group, Hunan, China

Article

Publisher ID: 4259

DOI: 10.1186/s12967-023-04259-4

PMC ID: 10329333

PubMed ID: 37420234

SO-VID: 8a6fcb8f-24c6-4e86-9a82-8dc800f12436

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 March 2023

Date accepted : 9 June 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: NSFC-RGC

Award ID: 32061160469

Award ID: N_CUHK432/20

Award Recipient : Jiansu Chen

Funded by: Science and Technology Project of Guangdong Province

Award ID: 2021A0505110005

Award Recipient : Jiansu Chen

Funded by: FundRef http://dx.doi.org/10.13039/501100013064, Key Research and Development Program of Jiangxi Province;

Award ID: 20203BBGL73193

Award Recipient : Jiansu Chen

Funded by: Natural Science Foundation of Hunan Province

Award ID: 2020JJ5002

Award Recipient : Shibo Tang

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: diabetic retinopathy,gut microbiota,short-chain fatty acids,sodium butyrate,4-methylvaleric acid,caproic acid

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ScienceOpen disciplines: Medicine

Keywords: diabetic retinopathy, gut microbiota, short-chain fatty acids, sodium butyrate, 4-methylvaleric acid, caproic acid

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

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

Related collections

Karger: Ophthalmology

Most cited references 50

Global Prevalence and Major Risk Factors of Diabetic Retinopathy

Host-gut microbiota metabolic interactions.

Gut metagenome in European women with normal, impaired and diabetic glucose control.

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Cited by 18

Most referenced authors 1,057