Gut-derived metabolic reprogramming drives immune aging and tissue degeneration
. In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.
Authors
- Durgadas Cherukaraveedu (ORCID: https://orcid.org/0000-0002-2131-9083)
- Idris Adekale (ORCID: https://orcid.org/0000-0003-2857-0745)
- Rangaramanujam M. Kannan (ORCID: https://orcid.org/0000-0002-3712-7836)
- Srinivas R. Sripathi (ORCID: https://orcid.org/0000-0001-6834-553X)
- Padmanabhan P. Pattabiraman (ORCID: https://orcid.org/0000-0003-1902-0493)
- Ying Xin (ORCID: https://orcid.org/0000-0001-7591-9423)
- Victoria Koontz
- Stacey Hose
- James T. Handa (ORCID: https://orcid.org/0000-0003-1314-1745)
- Avinash Soundararajan (ORCID: https://orcid.org/0000-0001-9557-0038)
- Sheldon Rowan (ORCID: https://orcid.org/0000-0002-1123-6743)
- Vishnu Suresh Babu (ORCID: https://orcid.org/0000-0001-8104-8652)
- Jiang Qian (ORCID: https://orcid.org/0000-0002-0476-3596)
- Sayan Ghosh
- Dulal Bhaumik
- Haochen Wang
- Anupam K Mondal
- Jenny Nguyen
- Sridhar Bammidi
- Dominique Meyer
- Debasish Sinha
- Ji Yi
- Jagnnath Das
- Shreevadsaa A Mohanakrishnan
- Puja Dutta
Institutions
- Tufts University (US)
- Illinois Department of Public Health (US)
- Johns Hopkins University (US)
- Illinois College (US)
- Chicago Department of Public Health (US)
- University of Pittsburgh (US)
- University of Alabama (US)
- Johns Hopkins Medicine (US)
- University of Illinois Chicago (US)
- Retina Foundation of the Southwest (US)
- Indiana University – Purdue University Indianapolis (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-20
- DOI
- https://doi.org/10.64898/2026.04.14.718497
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- School of Medicine, Johns Hopkins University