The microbiome in diabetes and DR

The microbiome is broadly defined as “the collection of all microbes, such as bacteria, fungi, viruses, and their genes, that naturally live on our bodies and inside us.”¹ Whipps et al described microbiome as a combination of the words micro and biome, naming a “characteristic microbial community” in a “reasonably well-defined habitat which has distinct physio-chemical properties” as their “theatre of activity.”² This second definition sheds light on the fact that microbial species often inhabit distinct regions of our bodies (eg, nasal passages, mouth, skin, genitourinary tract, gastrointestinal [GI] tract, and ocular surface) and that interactions among microbial communities have functional effects on the health of the host organisms (ie, human beings). The term microbiota refers to the collection of microbial species and cells themselves, whereas microbiome refers to the cells and their functional interactions as they relate to health and disease.

Cells belonging to microbial species on and within human beings typically outnumber the human cells by a factor of 10. More strikingly, microbial genes outnumber human genes by a factor of 1000 if we consider the totality of the human microbiome (100:1 ratio in the human GI tract alone).³ Molecular-genetic analysis has revealed more than 3000 species.⁴ Interestingly, species diversity is typically quite low on the ocular surface, with evidence showing a range from 6 to 47 and demonstrating differences in microbial diversity among individuals that may affect the risk of eye disease.⁵

Moreover, a “gut-eye axis” has been demonstrated that links GI microbiome activity to ocular lymphatics that may have indirect impacts on ocular disease; for instance, in mice engineered to have glaucoma via induced ocular hypertension, use of broad-spectrum oral antibiotics mitigates ongoing optic nerve fiber damage by eye-associated lymphatics and lymphocytes.⁶ Similarly, oral agents like methotrexate and sulfasalazine are believed to help prevent recurrent attacks of HLA-B27 uveitis in human patients by inhibiting bacterial overgrowth of injurious species that promote inflammation as well as by promoting butyrate-producing, anti-inflammatory species, suggesting that selective destruction of particular gut microbes (or preservation of competing microbial species) benefits distinct forms of eye disease.^7,8

A loss of microbiome diversity in the GI tract is a distinct feature of both type 1 (T1D) and type 2 (T2D) diabetes.^9,10 This lack of biodiversity has been shown to occur up to a year before the onset of hyperglycemia in T1D, whereas the same phenomenon emerges as insulin resistance characteristic of T2D and worsens over time. Translocation of gram-negative bacterial cell walls (lipopolysaccharides) through an inflamed gut wall results in endotoxemia (“leaky gut”), resulting in inflammation that worsens insulin sensitivity and fosters autoimmune attack on pancreatic β-cells.¹¹ Strategies to improve microbiome diversity (low dietary intakes of saturated fat, refined carbohydrates, and alcohol, combined with adequate sleep and moderate physical activity) may, in fact, reduce rates of incident diabetes (primary prevention) as well as improve metabolic control for lowering the risk of vascular diabetes complications, including retinal disease.¹²

A recent systematic review and meta-analysis of the role of the microbiome on the pathogenesis of diabetic retinopathy (DR) compared patients with T2D and no DR with those with DR.¹³ A marked increase in Bacteroidetes species (a diverse phylum of anaerobic, gram-negative organisms that maintain intestinal mucus lining integrity but also promote inflammation in the setting of leaky gut with endotoxemia) was seen in those with vs those without DR, as well as a decline in Firmicutes, Proteobacteria, and Actinobacteria species. Both “good” Bacteroidetes and Firmicutes species produce short-chain fatty acids (SCFAs; these include butyrate, propionate, and acetate) via fermentation of nondigestible dietary fiber, thereby providing requisite energy for intestinal epithelial cells. The reduction of microbial species that produce SCFAs, especially butyrate, is highly linked with intestinal barrier dysfunction and inflammatory bowel disease.¹⁴ Interestingly, an increased Firmicutes:Bacteroidetes (F:B) ratio is associated with inflammation and T2D, and this meta-analysis suggests that a comparatively decreased F:B ratio is far more typical in patients with DR. This provides insight into the hypothesis that leaky gut may play an important role in the pathogenesis of DR.

Hopefully, clinical trials with a constellation of specific health-promoting bacterial species that promote intestinal barrier function (eg, Akkermansia muciniphila) while providing SCFAs requisite for intestinal epithelial cell health, bacteriophages that selectively inhibit injurious species, and/or so-called postbiotics (thermally deactivated bacterial species that exhibit anti-inflammatory effects) will shed additional light on the practical benefits of modulating the gut microbiome in diabetes.

References:

1. Microbiome. US National Institute of Environmental Health Sciences. Updated July 7, 2025. Accessed September 11, 2025. https://www.niehs.nih.gov/health/topics/science/microbiome

2. Whipps J, Lewis K, Cooke RC. Mycoparasitism and plant disease control. In: Burge MN, ed. Fungi in Biological Control Systems. Manchester University Press; 1988:161-187.

3. Bull MJ, Plummer NT. Part 1: the human gut microbiome in health and disease. Integr Med (Encinitas). 2014;13(6):17-22.

4. Rosenberg E. Diversity of bacteria within the human gut and its contribution to the functional unity of holobionts. NPJ Biofilms Microbiomes. 2024;10(1):134. doi:10.1038/s41522-024-00580-y

5. Kang Y, Lin S, Ma X, et al. Strain heterogeneity, cooccurrence network, taxonomic composition and functional profile of the healthy ocular surface microbiome. Eye Vis (Lond). 2021;8(1):6. doi:10.1186/s40662-021-00228-4

6. Floyd JL, Grant MB. The gut-eye axis: lessons learned from murine models. Ophthalmol Ther. 2020;9(3):499-513. doi:10.1007/s40123-020-00278-2

7. Rosenbaum JT, Asquith M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat Rev Rheumatol. 2018;14(12):704-713. doi:10.1038/s41584-018-0097-2.

8. Liu M, Geng J, Liu T, Liu X. Gut microbiome dysregulation in noninfectious uveitis. Front Immunol. 2025;16:1614304. doi:10.3389/fimmu.2025.1614304

9. Asante Baadu F, Ahsan M, Hussain B, et al. Microbiome imbalance and pediatric type 1 diabetes mellitus: an updated systematic review of gut dysbiosis evidence. Cureus. 2025;17(8):e89279. doi:10.7759/cureus.89279

10. Chen Z, Radjabzadeh D, Chen L, et al. Association of insulin resistance and type 2 diabetes with gut microbial diversity: a microbiome-wide analysis from population studies. JAMA Netw Open. 2021;4(7):e2118811.

11. Gomes JMG, Costa JA, Alfenas RCG. Metabolic endotoxemia and diabetes mellitus: a systematic review. Metabolism. 2017;68:133-144. doi:10.1016/j.metabol.2016.12.009

12. Wu K, Xiao Y, Zhang T, Bai Y, Yan M. The role of the gut microbiota and its metabolites: a new predictor in diabetes and its complications. Eur J Med Res. 2025:30(1):601. doi:10.1186/s40001-025-02824-9

13. Zhao S, Yan Q, Xu W, Zhang J. Gut microbiome in diabetic retinopathy: a systematic review and meta-analysis. Microb Pathog. 2024;189:106590. doi:10.1016/j.micpath.2024.106590

14. Fusco W, Lorenzo MB, Cintoni M, et al. Short-chain fatty-acid-producing bacteria: key components of the human gut microbiota. Nutrients. 2023;15(9):2211. doi:10.3390/nu15092211