Nicotinamide mononucleotide reduces metabolic-syndrome-associated lens stiffening and gut microbiota–metabolic–ocular changes in mice

Introduction Lens stiffening contributes to impaired accommodation and age-related optical dysfunction, but whether metabolic syndrome (MetS) accelerates this biomechanical change in association with microbiota-linked metabolic disturbances remains unclear. This study evaluated whether nicotinamide mononucleotide (NMN) reduces lens stiffening in mice with diet-induced metabolic syndrome and whether changes in gut microbial metabolites, systemic inflammatory markers, and ocular biochemical injury accompany this response. Methods Male and female C57BL/6J mice were fed a high-fat/high-sucrose regimen and assigned to vehicle, NMN dose, antibiotic-depletion, NMN plus antibiotic-depletion, and fecal microbiota transfer arms. A total of 96 mice were randomized, and 94 mice contributed valid week-16 lens stiffness measurements. The primary endpoint was lens apparent Young’s modulus. Secondary endpoints included Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), serum triglyceride, fecal microbiota diversity, fecal short-chain fatty acids, serum lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO), lens nicotinamide adenine dinucleotide (NAD+), oxidative and glycation-related injury, and molecular fibrosis-associated lens markers. Results Compared with controls, metabolic-syndrome mice showed higher HOMA-IR, serum triglyceride, serum LPS, serum TMAO, lens malondialdehyde (MDA), lens advanced glycation end-products (AGEs), and lens apparent Young’s modulus, with lower fecal butyrate and lens NAD+. Lens apparent Young’s modulus increased from 7.4 ± 1.3 kPa in controls to 17.9 ± 2.1 kPa in metabolic-syndrome mice. NMN reduced lens stiffness to 14.8 ± 2.0 kPa at 150 mg/kg/day and 11.9 ± 2.4 kPa at 300 mg/kg/day. Fecal butyrate increased from 8.1 ± 1.9 μmol/g in metabolic-syndrome mice to 12.0 ± 2.4 μmol/g and 13.7 ± 2.8 μmol/g in the two NMN groups, while lens NAD+ increased from 1.50 ± 0.28 to 1.96 ± 0.31 pmol/mg and 2.34 ± 0.35 pmol/mg, respectively. Antibiotic depletion weakened but did not abolish the high-dose NMN ocular response, and fecal transfer from NMN-treated donors partially shifted microbial metabolite and lens stiffness endpoints toward the direct NMN-treatment profile. Discussion These findings support an NMN-associated reduction in metabolic-syndrome-related lens stiffening accompanied by coordinated systemic metabolic, microbial-metabolite, and ocular biochemical changes; the microbiota-related component appeared contributory rather than sufficient to explain the ocular response.