Microbiota-Targeted Intervention in Pancreatic Islet Transplant Recipients: Remodeling Glucose-Metabolism Related Microbial Communities Restores Gut Microbiota Balance and Glucose Stability in Type 2 Diabetes

Islet cell transplantation (ICT) effectively treats type 2 diabetes mellitus (T2DM), but the use of adjunct immunosuppressants/antibiotics disrupts gut microbiota, thereby impairing glucose homeostasis. This study revealed how ICT-induced dysbiosis in functional microbes modulates islet function and glucose metabolism. T2DM patients exhibited marked gut microbiota dysbiosis after ICT, characterized by a significant enrichment of pro-inflammatory microbiota such as Streptococcus and Enterococcus. Conversely, glucose metabolism-related commensals, including Akkermansia, Faecalibacterium, Bacteroides, Fusobacterium, and Bifidobacterium, were significantly reduced. Using a humanized gut microbiota-associated T2DM-ICT mouse model (HMA-T2DM-ICT), intervention with the defined MicroAFB consortium (Akkermansia, Faecalibacterium, Bacteroides) was tested. MicroAFB intervention significantly improved postoperative antibiotic/medication-induced deficiencies in insulin (INS) and C-peptide (C-P) secretion and elevated glycated hemoglobin (HbA1c). It also significantly reduced serum levels of inflammation markers (IP-10, MCP-1) and upregulated intestinal barrier tight junction proteins (MUC2, Occludin, ZO-1). Importantly, microbiota-derived metabolites (bile acids, vitamins B/K) were not only involved in the improvement of glucose homeostasis but also significantly correlated with key biomarkers, including INS, C-P, HbA1c, and GLP-1. Mechanistically, MicroAFB activated insulin signaling via the IRS/PI3K/AKT and GSK-3β/FOXO1 pathways and regulated metabolites such as bile acids and B vitamins/vitamin K, thus suppressing gluconeogenesis and ultimately enhancing insulin sensitivity and glucose homeostasis. The gut microbiota-derived bile acid 3-sulfodeoxycholic acid restored host homeostasis by rebalancing the gut microbiota and activating the TGR5 receptor and its downstream PI3K/AKT/GSK3β pathway. This work pioneered microbial consortium therapy to rectify post-ICT dysbiosis, directly linking microbiota restoration to improved islet function for durable diabetes remission.