24 Dietary Blueberries to Prevent Trimethylamine N-Oxide Induced Vascular Complications in Diabetes

Faculty Mentor: Anandh Babu Pon Velayutham (Nutrition and Integrative Physiology, University of Utah)

Cardiovascular disease (CVD) is a major health concern worldwide, and its prevalence is significantly higher among individuals with diabetes compared to the general population. One of the contributing factors to this elevated risk is gut dysbiosis, an imbalance in the gut microbiota that plays a critical role in the progression of diabetes-related cardiovascular complications. This connection is mediated, in part, by the production of the gut-derived microbial metabolite trimethylamine N-oxide (TMAO), which has been strongly associated with vascular dysfunction and cardiovascular disease. The formation of TMAO involves a two-step process: first, gut microbial enzyme trimethylamine lyase metabolizes dietary nutrients such as choline and phosphatidylcholine to produce trimethylamine (TMA). This TMA then enters the liver, where it is further oxidized by the hepatic enzyme flavin-containing monooxygenase 3 (FMO3) into TMAO. Elevated FMO3 activity and increased TMAO levels have been observed in diabetes, which may contribute to worsened cardiovascular outcomes.

Our lab has been exploring dietary strategies to mitigate these effects, and recent findings from our group demonstrated that supplementation with blueberries effectively lowers circulating TMAO levels and improves cardiovascular outcomes in diabetic (db/db) mice. Building on this observation, the present study was designed to investigate whether the bioactive phytochemicals in blueberries exert their beneficial effects on TMAO by modulating the activity or expression of FMO3. To test this, diabetic mice were fed either a standard diet or a diet supplemented with 2.46% freeze-dried blueberries (equivalent to one human serving) for a duration of eight weeks. Non-diabetic control mice were maintained on a standard diet for comparison. After the treatment period, we assessed liver FMO3 expression by Western Blot. Preliminary findings revealed that diabetic mice had markedly increased expression of FMO3 compared to controls. Notably, blueberry supplementation appeared to reduce this elevated expression, suggesting a potential regulatory effect of blueberry-derived compounds on this key enzyme. While these initial results are encouraging, they are based on a limited sample size. Therefore, our ongoing studies aim to expand the number of samples analyzed to confirm the reproducibility of these findings. In addition, we plan to further investigate the impact of blueberry phytochemicals on gut microbial enzymes, particularly trimethylamine lyase, to better understand how dietary interventions influence the gut-liver axis in diabetes.

Our ongoing studies will confirm whether dietary blueberries reduce TMAO by targeting FMO3 and identify novel dietary strategies to prevent or treat TMAO-induced cardiovascular complications in diabetes.

Bibliography

Saba Naghipour, Amanda J. Cox, Jason N. Peart, Eugene F. Du Toit and John P. Headrick. (2020). “Trimethylaminen-oxide: Heart of the microbiota–CVD nexus?” Nutrition Research Reviews, 34(1), pp. 125–146, https://doi.org/10.1017/s0954422420000177.

Chrissa Petersen, Divya Bharat, Umesh D. Wankhade, Ji-Seok Kim, Brett Ronald Cutler, Christopher Denetso, Samira Gholami, Samantha Nelson, Jessica Bigley, Aspen Johnson, Sree V. Chintapalli, Brian D. Piccolo, Adhini Kuppuswamy Satheesh Babu, Henry A. Paz, Kartik Shankar, J. David Symons, and Pon Velayutham Anandh Babu. (2022).  “Dietary blueberry ameliorates vascular complications in diabetic mice possibly through nox4 and modulates composition and functional diversity of gut microbes.” Molecular Nutrition and Food Research, 66(8), 25  https://doi.org/10.1002/mnfr.202100784.

Adhini Kuppuswamy Satheesh Babu, Chrissa Petersen, Lisard Iglesias-Carres, Henry A. Paz, Umesh D. Wankhade, Andrew P. Neilson, and Pon Velayutham Anandh Babu. (2023). “Blueberry intervention mitigates detrimental microbial metabolite trimethylamine n‐oxide by modulating gut microbes.” BioFactors, 50,(2), pp. 392–404, https://doi.org/10.1002/biof.2014.

Jing Zhen, Zhou Zhou, Meng He, Hai-Xiang Han, En-Hui Lv, Peng-Bo Wen, Xin Liu, Yan-Ting Wang, Xun-Chao Cai 4, Jia-Qi Tian, Meng-Ying Zhang, Lei Xiao and Xing-Xing Kang. (2023). “The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases.” Frontiers in Endocrinology, 14,  https://doi.org/10.3389/fendo.2023.1085041.