(P19-007-25) BCO2 Deficiency Exacerbates STZ-Induced Diabetes and Alters Gut Microbiota in Synergy With LepR Deficiency

Objectives: Beta-carotene oxygenase 2 (BCO2) is a mitochondrial protein involved in the asymmetric cleavage of carotenoids. Depletion of BCO2 has been linked to shifts in gut microbiota, inflammation, and metabolic dysfunction. Here, we investigated whether BCO2 depletion differentially impacts the microbiome and metabolic homeostasis in streptozotocin (STZ)-induced type 1 diabetes (T1D) and leptin receptor (LepR) knockout-associated type 2 diabetes (T2D) models.

Methods: BCO2 heterozygous/LepR heterozygous (Het/Het) mice in a C57BL/6J (WT) background were mated to generate various genotypes, including WT/WT, KO/WT, KO/Het, KO/KO, WT/KO, Het/KO, and KO/KO (double knockout). T1D was induced in 6-week-old male WT and KO/WT mice via a single STZ dose (200 mg/kg, intraperitoneally). Fasting blood glucose (FBG), body weight (BW), blood, and cecal content samples were collected at 7 days post-injection. T2D was studied in 8-week-old male WT, KO/WT, KO/Het, KO/KO, WT/KO, and Het/KO mice. Circulatory cytokines and microbiome 16S rRNA sequencing were analyzed.

Results: In T1D, BCO2 KO mice showed increased sensitivity to STZ with elevated FBG and pro-inflammatory cytokines. Gut microbiome profiling revealed a rise in Mucispirillum schaedleri in KO mice, further amplified with STZ, alongside increases in Anaerotruncus sp. G3 and Subdoligranulum sp. 4_3_54A2FAA, while Clostridium leptum decreased. Beneficial bacteria, such as Blautia coccoides, Clostridiales bacterium CIEAF 020, Bacteroides thetaiotaomicron, and Sphingomonas aerolata were reduced in STZ-treated KO mice but increased in WT. In T2D, KO/KO mice showed severe hyperglycemia, inflammation, and elevated Lactococcus abundance. Moderate changes in FBG, cytokines, and cecal microbiota in other genotypes revealed epistatic interactions between BCO2 and LepR.

Conclusions: BCO2 regulates metabolism and gut microbiota balance, buffering against metabolic and inflammatory insults. Genetic interactions between BCO2 and LepR exacerbate diabetes outcomes, highlighting their roles in metabolic dysfunction.

Funding Sources: NIH and USDA