A research group led by Graduate Student Meng Zheng, Associate Professor Tomohiko Fukuda and Professor Jianguo Gu at the Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, in collaboration with Yaizu Suisankagaku Industry Co., Ltd., announced on August 20 that oral administration of the monosaccharide L-fucose, which is found in seaweed and other marine-derived foods, alleviates depression-like behavior and suppresses neuroinflammation in the hippocampus of mice. The researchers also found that L-fucose improved colon inflammation induced by chronic social defeat stress (CSDS), suggesting that L-fucose metabolism may play a role in stress responses through the gut-brain axis. The findings point to a potential new therapeutic strategy for depression. The study was published in Frontiers in Immunology on July 30.
Under physiological conditions, both the de novo and salvage pathways maintain intracellular GDP-fucose levels, supporting Fut8-mediated core fucosylation and normal neuroimmune and synaptic homeostasis.
After chronic social defeat stress (CSDS), salvage-associated biosynthesis is impaired, leading to hippocampal GDP-fucose depletion and reduced core fucosylation. Impaired core fucosylation is linked to heightened neuroinflammatory responses, increased JAK2/STAT3 signaling, microglial activation, synaptic dysfunction, and depressive-like behaviors. L-fucose administration significantly restores GDP-fucose levels and core fucosylation, alleviating stress-associated neuroinflammation and behavioral abnormalities. Furthermore, CSDS induces inflammatory responses in the distal colon. L-fucose or L-fucose-containing food ingredients, such as Marine Fucose®30 (MF30), also suppress these inflammatory responses. These findings may underscore the importance of the gut-brain axis.
Provided by Tohoku Medical and Pharmaceutical University
Chronic stress is known to reduce glycan expression in the brain and promote neuroinflammation, increasing the risk of depression. However, the relationship between abnormalities in brain fucose metabolism, which is involved in glycan synthesis, and depression had remained unclear. L-fucose is a naturally occurring hexose sugar, also known as 6-deoxy-galactose. It is a major component of fucoidan, a polysaccharide found in brown algae.
Previously, the research group used mice lacking α1,6-fucosyltransferase (Fut8), a glycosyltransferase responsible for core fucosylation, to demonstrate that reduced levels of core-fucosylated glycans increase susceptibility to inflammatory responses, including excessive activation of microglia, the brain's resident immune cells. They also found that mice with reduced core fucosylation developed depression-like behavior significantly faster than wild-type mice, and that this effect could be ameliorated by L-fucose administration.
The mechanisms underlying fucose metabolism, however, remained largely unclear. To further investigate them, the researchers examined the effects of CSDS on the brain and peripheral tissues, as well as the impact of L-fucose treatment. The CSDS model is a widely used animal model of depression that exploits the territorial behavior of male mice and is considered to reproduce social stressors such as interpersonal conflict, social defeat, and bullying-like experiences in humans.
The researchers found that increasing levels of core-fucosylated glycans through L-fucose administration suppressed neuroinflammation in the brain. The treatment also restored levels of synaptic proteins, including AMPA receptor subunit and PSD95, which are believed to play important roles in the neural mechanisms underlying depression. Furthermore, CSDS reduced GDP-fucose levels in the hippocampus, thereby impairing fucosylation. This was associated with reduced expression of enzymes involved in the GDP-fucose biosynthetic pathway, including FUK and FPGT. These abnormalities in fucose metabolism were improved by L-fucose administration. In contrast, treatment with the fucosylation inhibitor 2FF reduced GDP-fucose levels and suppressed expression of the associated enzymes, leading to worsening depression-like behavior and neuroinflammation.
The researchers also investigated the gut-brain axis. They found that CSDS increased the expression of inflammatory cytokines in the distal colon, where large numbers of immune cells reside and maintain immune tolerance to prevent excessive inflammation, indicating that peripheral inflammation is induced alongside brain inflammation. In contrast, oral administration of MF30, a seaweed-derived food ingredient, suppressed inflammation in both the hippocampus and the colon.
Gu commented, "Fut8 was purified and cloned more than 20 years ago in the laboratory of Professor Naoyuki Taniguchi at Osaka University School of Medicine, where I was working at the time, and Fut8-deficient mice were subsequently generated. Later, at Tohoku Medical and Pharmaceutical University, we demonstrated that reduced Fut8 expression causes chronic inflammation in the brain. In the present study, we showed that oral administration of L-fucose has both preventive and therapeutic effects in a mouse model of depression. We will continue to investigate the detailed molecular mechanisms underlying these findings with the goal of future clinical applications. L-fucose is abundant in seaweeds such as mozuku. These findings raise expectations for the development of new functional foods and pharmaceutical products that could contribute to the prevention and treatment of depression."
Journal Information
Publication: Frontiers in Immunology
Title: L-fucose administration ameliorates chronic social defeat stress-induced depressive-like behaviors by restoring GDP-fucose biosynthetic activation and core fucosylation
DOI: 10.3389/fimmu.2026.1909378
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.