Postbiotic Metabolites from Indigenous Fermented Medicinal Plants as Candidate Modulators of the Gut–Retina Axis in Early Diabetic Retinopathy: A Mechanistic Review and Research Roadmap

Abstract

Approximately a quarter of the world’s diabetics suffer from DR, with 160 million patients anticipated by 2045, but there is no effective treatment beyond glycemic control for its earliest, non-proliferative form. In the last five years, another area of research has developed a view of a “gut-retina axis,” where gut dysbiosis, gut barrier dysfunction, and circulating bacterial metabolites contribute to retinal inflammation and vascular biology in the same way that the gut-brain axis influences neurological outcomes. Simultaneously, the notion of postbiotics, defined as inactive microorganisms and/or components with proven health benefits, has developed into an established, ISAPP-managed class of molecules, different from probiotics, prebiotics, and isolated metabolites. This review unites these two areas of research with a third, previously underappreciated line of research: the biochemistry of local fermented herbal medicines. Examples of the former include the Ayurvedic tradition of Asava-Arishta remedies and various regionally fermented drinks, such as Raabadi and Kanji, which have been used clinically for many centuries but never explored from a retinal perspective. From existing literature on the link between gut dysbiosis and diabetes and DR, the pathophysiology of NPDR driven by the oxidative stress and AGEs-RAGE interaction, and the categories of active metabolites formed through fermentation of medicinal plants, we appraise the literature and the mixed trial results concerning probiotics and synbiotics in glucose management, leading to the conclusion that a standardized postbiotic approach is more favorable compared to living organism methods. Based on all of the above, we develop an explicit five-step hypothesis about how postbiotic metabolites may help maintaining gut-retina axis homeostasis in early DR, and we propose a sequential in vitro, animal and human study to test the hypothesis. The article does not provide any new experimental data but provides an approach based on the literatures in different but mature fields that were not yet connected.