Microbiota-Targeted Chitooligosaccharides Intervention Restores Glucose Homeostasis After Islet Cell Transplantation in Rapamycin-Treated Mice

Islet cell transplantation (ICT) is an effective treatment for diabetes mellitus, but postoperative islet function recovery and inflammation are closely linked to immunosuppressants. Using multi-omics and fecal microbiota transplantation (FMT) in human microbiota-associated (HMA) mice, this study explored rapamycin-induced gut dysbiosis and its impacts on islet function and inflammation post-ICT. ICT significantly altered the gut microbiota of type 2 diabetes mellitus (T2DM) patients, and FMT from these patients to antibiotic-treated mice recapitulated metabolic disorders in the mice. These disorders included hyperglycemia, hepatic and pancreatic injury, and impaired intestinal barrier. Rapamycin decreased beneficial bacteria ( Akkermansia , Faecalibacterium ) and enriched Desulfovibrio in HMA-T2DM mice. Targeted microbial modulation by chitooligosaccharides (COS) ameliorated rapamycin-induced deficits in insulin and C-peptide secretion, as well as elevated glycated hemoglobin levels. COS also significantly reduced serum inflammatory markers IP-10 and MCP-1, while upregulating colonic barrier proteins ( Muc2 , Occludin ) in HMA-T2DM-ICT mice. COS additionally mitigated postoperative hyperglycemia via the PI3K/AKT/GSK3β/FOXO1 signaling pathway. This study identified COS as a microbiota-targeted adjunctive strategy to improve metabolic recovery and islet function under post-transplant immunosuppression.