Highlight
– A translational study (Prasad et al., Gut 2025) links gut-derived indole-3-propionic acid (IPA) with protection of the retina in experimental type 2 diabetes and shows lower circulating IPA in people with diabetic retinopathy (DR).
– Two strategies that restored intestinal tryptophan (Trp) absorption—ACE2-preserving Lactobacillus paracasei expressing ACE2 and an ACE2-independent Trp dipeptide (isoleucine-tryptophan, IW)—prevented DR in db/db mice, improved metabolic control and gut barrier integrity, and enriched Trp-metabolizing bacteria.
– In humans with type 2 diabetes (T2D), DR was associated with biochemical evidence of endotoxemia and impaired gut barrier markers, lower serum IPA and higher indoxyl sulfate, suggesting a pathogenic gut-to-retina axis and a potential biomarker and therapeutic target.
Background: disease burden and rationale
Diabetic retinopathy (DR) remains the leading cause of vision loss in working-age adults worldwide. Global diabetes burden continues to rise: the International Diabetes Federation (IDF) estimates hundreds of millions living with diabetes and rising complications burden, including sight-threatening DR. Current preventive strategies—glycemic, blood pressure and lipid control plus screening and timely ophthalmic treatment—have reduced but not eliminated vision loss. New preventive and early-intervention approaches are needed, especially those that intervene upstream in disease pathogenesis.
Emerging evidence implicates gut microbiome alterations, intestinal barrier dysfunction and metabolite signaling in metabolic disease. Tryptophan (Trp) is metabolized both by host pathways (kynurenine) and by microbial routes to indoles and other small molecules. Some indole derivatives exert beneficial effects on mucosal integrity and systemic homeostasis, whereas others (for example indoxyl sulfate) are associated with toxicity. Understanding whether specific tryptophan-derived microbial metabolites influence DR could reveal biomarkers and novel therapeutic strategies that act far upstream of the retina.
Study design and methods
Prasad and colleagues used parallel preclinical and human observational approaches to test whether restoring Trp absorption or delivering Trp-derived metabolites affects DR.
Preclinical (db/db mouse model)
– Model: Leptin receptor-deficient db/db mice (a type 2 diabetes model) prone to metabolic dysfunction and retinal microvascular disease.
– Interventions: Two oral strategies were used to increase Trp bioavailability—(1) gavage with a genetically modified Lactobacillus paracasei engineered to preserve intestinal ACE2 and the sodium-coupled neutral amino acid transporter, thereby enhancing ACE2-dependent Trp uptake; (2) gavage with an ACE2-independent Trp dipeptide (isoleucine-tryptophan, IW) absorbed via the peptide transporter SLC15A1 (PEPT1).
– Treatment timelines: Both strategies were tested as prevention (6 months of treatment starting early) and as an intervention (3 months of treatment started later).
– Outcome measures: Intestinal histology and barrier function, gut microbiome composition, metabolic measures (glucose homeostasis, incretin secretion), retinal structure and function assessments including spatial mass spectrometry to map metabolites within retinal layers.
Human cohort
– Cross-sectional comparison of plasma biomarkers in adults: T2D with DR (n=30), T2D without DR (n=40), and healthy controls (n=35).
– Measurements: Plasma Trp metabolites (including IPA and indoxyl sulfate) and serologic markers of gut permeability and endotoxemia.
Key findings
Preclinical results — prevention and reversal of DR in db/db mice
– Prevention of retinal injury: Both Lactobacillus paracasei-ACE2 and IW dipeptide treatments prevented development of diabetic retinal changes in db/db mice when used as long-term preventive therapy and produced beneficial effects when given later as a shorter intervention.
– Restoration of intestinal physiology: Treatments corrected diabetes-associated dysbiosis, selectively enriched Trp-metabolizing taxa, and improved intestinal barrier integrity. Markers of gut permeability and endotoxemia were reduced.
– Metabolic effects: Treated mice had improved glucose homeostasis and increased incretin secretion, linking restored intestinal amino acid handling to systemic metabolic benefits.
– Retinal metabolite localization: Spatial mass spectrometry localized indole-3-propionic acid (IPA) within the retinal pigment epithelium (RPE) layer and at the posterior blood–retinal barrier, suggesting local accumulation where barrier integrity is critical.
– Mechanistic implication: IPA was identified as a candidate effector molecule mediating barrier protection at the level of the RPE. Although the study did not define a single receptor-mediated pathway, IPA’s known antioxidant and barrier-supportive properties provide a biologically plausible mechanism linking gut-derived metabolites to retinal protection.
Human observational findings
– Altered circulating metabolites in DR: People with T2D and DR had lower circulating IPA levels compared with T2D without DR and healthy controls, and higher levels of indoxyl sulfate, a metabolite associated with toxicity in other organ systems.
– Evidence of gut leak and endotoxemia: Individuals with DR showed elevated serum markers consistent with intestinal barrier disruption and endotoxemia compared with those without DR, supporting the translational relevance of the gut–retina connection observed in mice.
Safety and other observations
– No specific adverse-event profile is reported in this preclinical-to-human translational study summary; however, delivery of genetically modified probiotics and chronic peptide dosing raise predictable safety and regulatory considerations requiring rigorous evaluation prior to clinical use.
Expert commentary and interpretation
This work advances a compelling paradigm: a gut-derived microbial metabolite (IPA) may be both a biomarker and a mediator protecting the retinal barrier in diabetes. Several points merit emphasis:
– Biological plausibility: IPA is produced by specific gut bacteria from dietary Trp. IPA has documented antioxidant properties and has been linked to preservation of barrier integrity in other tissues. The spatial MS finding of IPA concentrated in the RPE provides direct tissue-level evidence consistent with a protective role.
– Two complementary strategies: The study demonstrates that restoring Trp handling can be achieved either by manipulating host–microbe interface (ACE2-preserving probiotic) or by bypassing host-dependent transport (peptide IW). Both approaches converged on beneficial outcomes, strengthening causal inference.
– Clinical signal in humans: The human biomarker data—lower IPA and higher indoxyl sulfate in DR—align with the preclinical findings and support IPA as a candidate circulating biomarker for risk stratification or therapeutic monitoring.
– Limitations and generalizability: The preclinical evidence is strong but remains in a single rodent model. Db/db mice recapitulate many metabolic features of T2D but cannot model all aspects of human DR. The human data are cross-sectional and cannot prove causation; confounding by medications (for example antibiotics, metformin), diet, renal function and other comorbidities could influence circulating metabolites. The sample sizes in the clinical cohort are modest and require replication in larger, prospective cohorts with careful control of confounders.
– Safety and translational pathway: Genetically modified probiotics that modulate host ACE2 or long-term peptide supplementation would need robust safety evaluation, containment strategies, and regulatory review. Alternatively, direct supplementation with purified IPA (as a nutraceutical or drug) may be an attractive, more controllable strategy but would require dosing, pharmacokinetic and toxicology studies.
Clinical and research implications
– Biomarker development: Circulating IPA has potential as a noninvasive biomarker to identify T2D patients at higher risk of DR or to monitor response to gut-targeted interventions. Prospective validation is needed.
– Therapeutic strategies: Several translational pathways emerge: (1) microbe-directed therapies designed to restore beneficial Trp metabolism (probiotics, prebiotics, fecal microbiota-directed approaches), (2) peptide or nutraceutical approaches to increase Trp bioavailability (for example IW), and (3) direct IPA supplementation. Each path requires tailored safety and efficacy testing.
– Trial design considerations: Randomized, placebo-controlled trials in people with early DR or high-risk T2D populations should measure retinal structural and functional endpoints (OCT, fundus photography, visual function), systemic metabolic outcomes, gut permeability markers and comprehensive metabolomics to establish causal effects and optimal dosing.
Conclusion
Prasad et al. provide convergent preclinical and human evidence that disrupted Trp metabolism and diminished levels of the microbially derived metabolite indole-3-propionic acid are linked to diabetic retinopathy. Restoring Trp handling—either via an ACE2-preserving probiotic or an ACE2-independent Trp dipeptide—prevented DR in a mouse model, improved systemic metabolism and gut barrier function, and enriched IPA at the retinal pigment epithelium. Cross-sectional human data showing lower IPA and higher indoxyl sulfate in DR support translational relevance. These findings identify IPA as a promising biomarker and nominate several gut-targeted therapeutic strategies for further development, but clinical translation will require prospective human trials, rigorous safety evaluation and clarification of mechanism.
Funding and clinicaltrials.gov
Funding and trial registration details are reported in the original publication: Prasad R et al., Gut. 2025 Nov 5. Readers should consult the published paper for specific grant and institutional support information. No registered human interventional trials testing IPA supplementation for DR are reported in this summary; future clinical development should register planned trials on ClinicalTrials.gov.
References
1. Prasad R, Adu-Rutledge Y, Ziani B, et al. Indole-3-propionic acid links gut dysfunction to diabetic retinopathy: a biomarker and novel therapeutic approach. Gut. 2025 Nov 5:gutjnl-2025-336180. doi:10.1136/gutjnl-2025-336180. PMID: 41198173.
2. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010 Jul 10;376(9735):124-36. doi:10.1016/S0140-6736(09)62124-3.
3. International Diabetes Federation. IDF Diabetes Atlas, 10th ed. 2021. (Access for epidemiology and burden estimates.)
4. Dodd D, et al. A gut bacterial pathway metabolizes aromatic amino acids into circulating metabolites. Cell Host Microbe. 2017;21(3):1-??. (Describes microbial aromatic amino-acid metabolism to indoles including IPA.)
Author note
This article synthesizes results from a recent translational study and places them in clinical context aimed at clinicians, researchers and health policy stakeholders. For details of experimental methods, raw data and supplementary analyses readers should consult the original Gut article and supporting materials.