A recent study published in Engineering has shed new light on the potential therapeutic effects of berberine (BBR), a natural compound derived from traditional Chinese medicine, in treating diabetic encephalopathy (DE). The research, conducted by a team from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines at the Chinese Academy of Medical Sciences & Peking Union Medical College, reveals that BBR can significantly improve cognitive function and protect cerebral vessels in type 2 diabetic encephalopathy mice by modulating the gut microbiota.

Diabetic encephalopathy is a condition characterized by cognitive impairment due to chronic hyperglycemia, often leading to severe neurological disorders such as Alzheimer’s disease. The pathogenesis of DE is complex and involves factors like cerebrovascular inflammation, which can be exacerbated by the activation of inflammatory pathways such as Toll-like receptor-4 (TLR-4) and nuclear factor kappa B (NF-κB). The study investigates the role of BBR in mitigating these effects by targeting the gut microbiota, which has been increasingly recognized for its influence on neurological health.

The researchers used a type 2 diabetic encephalopathy KK-Ay (2DEK) mouse model to evaluate the efficacy of BBR. The mice were divided into three groups: a control group, a low-dose BBR group (100 mg/kg/day), and a high-dose BBR group (200 mg/kg/day). After ten weeks of treatment, the cognitive functions of the mice were assessed using novel object recognition and step-down tests. The results showed that BBR treatment significantly improved cognitive performance, with the high-dose group demonstrating the most substantial improvements.

High-resolution imaging via fluorescence micro-optical sectioning tomography (fMOST) revealed that BBR treatment enhanced the integrity of brain vessels. The average vessel diameter, vessel length density, and total vessel volume were significantly improved in the parietal association cortex (PtA) and the CA1 and CA3 regions of the hippocampus. These findings suggest that BBR can protect cerebral vessels from hyperglycemia-induced damage.

The study also explored the mechanism by which BBR exerts its protective effects. It was found that BBR inhibits the production of δ-valerobetaine (δ-VB), a metabolite produced by the gut microbiota that can cross the blood–brain barrier and activate the TLR-4/MyD88/NF-κB inflammatory pathway in blood vessel endothelial cells. By reducing δ-VB levels, BBR interrupts this inflammatory pathway, thereby protecting cerebral blood vessels and improving brain function.

To further validate the role of the gut microbiota, fecal microbiota transplantation (FMT) was performed using gut microbiota from BBR-treated mice. The results confirmed that the gut microbiota plays a crucial role in mediating the therapeutic effects of BBR. The transplanted microbiota significantly improved cognitive function and reduced inflammation in the recipient mice, similar to the effects observed with direct BBR treatment.

The study also analyzed the changes in the gut microbiota composition following BBR treatment. The results showed that BBR increased the abundance of beneficial bacteria, such as Bacteroides and Akkermansia, which are known to produce short-chain fatty acids (SCFAs). These SCFAs are known to have anti-inflammatory effects and may contribute to the overall therapeutic benefits of BBR. Conversely, BBR reduced the levels of harmful bacteria, such as Escherichia-Shigella and Klebsiella, which are associated with increased inflammation.

The study provides compelling evidence that BBR can protect cerebral vessels and alleviate diabetic encephalopathy by modulating the gut microbiota and reducing the production of harmful metabolites like δ-VB. These findings highlight the potential of BBR as a therapeutic agent for DE and underscore the importance of the gut-brain axis in managing neurological disorders. Future research should focus on clinical trials to further explore the therapeutic potential of BBR in human patients with DE.

The paper “Berberine Protects Cerebral Vessels and Alleviates Diabetic Encephalopathy by Inhibiting the Production of δ-Valerobetaine in the Gut Microbiota,” is authored by Zheng-Wei Zhang, Wei-Ping Wang, Jia-Chun Hu, Jin-Yue Lu, Ru Feng, Shao-Feng Xu, Ling Wang, Jie Fu, Hang Yu, Hui Xu, Hao-Jian Zhang, Xin-Yu Yang, Zhao Zhai, Jing-Yue Wang, Meng-Liang Ye, Heng-Tong Zuo, Jian-Ye Song, Yi Zhao, Xiang Hui, Xiao-Liang Wang, Jian-Dong Jiang, Yan Wang. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.04.018. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.