Impact of novel aldose reductase inhibitor drug on gut microbiota composition and metabolic health in ZDF 'lean' rats

Abstract

A novel multi-target drug, cemtirestat, inhibiting aldose reductase (ALR2) has been developed to prevent secondary diabetic complications and act as an antioxidant against hyperglycemia-related processes. This study examines cemtirestat's impact on gut microbiome composition, drug metabolism, and therapeutic efficacy in male Zucker diabetic fatty (ZDF) "Lean" rats. Rats were divided into the control group (C) and the treated group (T), which received 7.7 mg/kg/day cemtirestat for two months, with weekly monitoring of food, fluid intake, and weight gain. Stool, urine, and plasma samples were analyzed biochemically, and fecal DNA was sequenced using Oxford Nanopore Technology. Treated rats exhibited less weight gain, likely due to cemtirestat's antioxidant effects. Biochemical analyses revealed no significant changes in glucose, liver enzymes, or cholesterol. Although there was a slight increase in alanine aminotransferase (ALT), our study found that levels of other liver enzymes such as aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin remained within normal limits, suggesting the observed increase in ALT was not indicative of drug-induced liver injury. LefSe microbiome analysis revealed an enrichment of beneficial bacteria like Blautia and Faecalibacterium in treated rats. Microbial community structure did not distinctly separate treated from control groups, but differences emerged over time. DeSeq2 analysis identified varying genera abundances over weeks, with treated samples enriched in beneficial bacteria by Week 8. Correlation analysis linked plasma insulin levels positively with Prevotella and negatively with Clostridium and Lactobacillus. Cemtirestat's impact on weight and microbiota suggests the potential to improve gut health. Further research is required to uncover cemtirestat's mechanism in diabetes management, drug metabolism, and therapeutic efficacy.