Bacterial Derived Metabolites in Diabetic Retinopathy

About This Grant

We are at a watershed moment in human biology were we have identified that we have an axillary microbial genome that affects how our cells function and we can leverage this genome to tackle complex diseases such as diabetic retinopathy (DR). Thus, the human host is inextricably linked to its microbiome and has coevolved with it resulting in the outsourcing of approximately 60% of human metabolism to microbiota. The gut provides the dominant microbiome in the body, representing approximately a 3000 microbial species that are responsible for the generation of biologically active metabolites that dramatically impact host health. Microbiota-derived metabolites such as tryptophan (Trp) metabolites, short-chain fatty acids, and bile acid derivatives are crucial for gut health, beneficially influencing gut barrier function, immune responses, energy metabolism and lipid digestion. We have identified specific beneficial microbe derived metabolites of Trp that are decreased and other deleterious metabolites that are increased in the plasma of diabetic individuals with retinopathy. Using liquid chromatography–mass spectrometry (LC-MS) for targeted metabolomics, we show that individuals with DR have markedly reduced levels of the protective Trp metabolite, indole 3- proprionic acid (IPA) and elevated levels of toxic metabolite Indole sulfate. Exogenous administration IPA prevented the development of DR in db/db mice, a model of type 2 diabetes. IPA administration activated pregnane X receptor (PXR) receptors to enhance intestinal and retinal barrier function. IPA suppressed NF-κB signaling and NLRP-3 activation and downregulated pro-inflammatory cytokines such as IL-6 and TNF-α in the retina and reduced Th17 cells migration from the gut to the retina. We propose the following hypothesis: Key beneficial microbial derived metabolites such as IPA generated by the gut microbes enter the systemic circulation and retina activating PXR receptors on retinal endothelial cells and retinal pigment epithelial cells to main integrity of blood retinal barrier and modulate local retinal immune responses. These protective mechanisms are lost in DR. We postulate that Trp supplementation in the form of Trp containing dipeptides and/or genetically modified bacteria that generate beneficial Trp metabolites will prevent DR. Impact: nutraceutical supplementation with Trp or Trp containing dipeptides or intake of food grade probiotics that generate beneficial bacterial metabolites represent novel strategies for prevention of DR and are timely approaches for this era of personalized medicine.