Elucidation of a New Mechanism by Which Lactyl-Phenylalanine in Fermented Foods Exerts Mental Stress Reduction in Animals

A research group consisting of Associate Professor Kentaro Kaneko (School of Agriculture, Meiji University), Shiho Suzuki (2nd-year Master's student, Graduate School of Agriculture, Meiji University), Associate Professor Yoshiya Seto, Professor Takahiro J. Nakamura (School of Agriculture, Meiji University), Professor Asuka Inoue, and Assistant Professor Ryoji Kise (Graduate School of Pharmaceutical Sciences, Kyoto University) has discovered that the oral ingestion of the metabolite 'lactyl-phenylalanine' (Lac-Phe)—which is produced in the body during exercise and is also found in fermented foods—exerts a mental stress-relieving effect in mice (Figure 1). While Lac-Phe was previously reported to be associated with exercise-induced appetite suppression and metabolic regulation, this study is the first to demonstrate a link between Lac-Phe and anxiety-related behaviors. This research outcome suggests that components derived from fermented foods may act on brain functions and stress responses, potentially leading to new insights bridging 'food' and the 'brain'. Furthermore, developing this achievement is expected to lead to the creation of new functional foods utilizing endogenous metabolites and stress-relief strategies that are easy to incorporate into daily life.

This outcome was published on May 29, 2026, in the international academic journal 'Translational Psychiatry' issued by Springer Nature.

Paper title: Lac-Phe elicits anxiolytic-like effects associated with monoaminergic signaling in mice

Additionally, three researchers—Kentaro Kaneko, Yoshiya Seto, and Asuka Inoue—are selected for the FOREST program. This research was supported by the Meiji University Institute of Science and Technology Focal Research A, JST FOREST Program, JSPS KAKENHI, AMED-CREST, the Lotte Foundation, and the Uehara Memorial Foundation.

Research Background

Chronic stress is one of the factors causing mental health issues such as anxiety disorders and depression, representing a significant health challenge in modern society. Stress is known to affect the emotional control mechanisms in the brain, leading to decreased motivation and quality of life. Currently, treatments targeting monoaminergic nervous systems, such as serotonin and dopamine, are used for anxiety disorders. However, issues such as insufficient efficacy, side effects, and dependence have been pointed out. Therefore, there is a demand for the discovery of new functional components with mechanisms of action different from conventional ones.

Lac-Phe, the focus of this study, is a metabolite in which lactic acid and phenylalanine are linked by an amide bond, known to be produced in the body during exercise. Previous studies reported its involvement in exercise-induced appetite suppression, weight loss, and metabolic regulation, but its impact on brain function and emotional behavior remained largely unknown.

Furthermore, Lac-Phe has been reported to be present in fermented foods such as parmesan cheese and soy sauce, and some lactic acid bacteria are known to produce it during the fermentation process. However, there were almost no reports on whether Lac-Phe derived from fermented foods exhibits mental stress-relieving effects in animal models.

Research Results

To verify whether Lac-Phe exhibits a mental stress-relieving effect (anxiolytic-like effect) in mice, the research team used the Elevated Plus Maze (EPM) test and the Novelty Suppressed Feeding Test (NSFT), which are recognized as standard test systems for anxiety-like behavior (emotional behavior).

In the EPM test, mice orally administered Lac-Phe showed increased time spent and frequency of entries in the open arms, revealing that Lac-Phe has an anxiolytic-like effect (Figure 2). The same effect was not observed with the administration of lactic acid alone, phenylalanine alone, or a mixture of both, indicating that the bonded state of Lac-Phe is crucial. Furthermore, similar anxiolytic-like effects were observed with intraperitoneal and intracerebroventricular administration. In the NSFT, the Lac-Phe administration group showed an increase in the time spent and frequency of entries in the center area, confirming anxiolytic-like effects across multiple behavioral evaluation systems.

Serotonin and dopamine are known neurotransmitters involved in the regulation of emotional behavior in the central nervous system. Therefore, to investigate the underlying mechanisms of the anxiolytic-like effect of Lac-Phe, the team focused on the dopamine and serotonin systems.

Analysis was conducted using the dopamine D1 receptor antagonist SCH23390 and the serotonin 5-HT1A receptor antagonist WAY100135. The results revealed that administering these inhibitors suppressed the anxiolytic-like effects induced by Lac-Phe. This indicated that the dopamine and serotonin systems are likely involved in the anxiolytic-like effects of Lac-Phe.

Additionally, an increase in dopamine levels was observed in the hypothalamus and striatum following Lac-Phe administration (Figure 3). Furthermore, a decrease in the expression levels of inflammatory cytokines IL-1β and IL-6 in the hippocampus, along with a decrease in blood corticosterone levels after acute stress loading, were confirmed. From these results, it was suggested that Lac-Phe may exert mental stress-relieving effects through monoaminergic nervous systems and the control of brain inflammation.

Future Outlook

This study is the first to demonstrate that oral administration of Lac-Phe, contained in fermented foods, induces anxiolytic-like effects in mice. This outcome indicates the possibility that components derived from fermented foods act on brain functions and stress responses, which is thought to lead to new insights connecting 'food' and the 'brain'. Because Lac-Phe is a metabolite produced in the body during exercise, further research advancements are expected regarding its association with the maintenance of mental health through exercise. Moreover, since it is also contained in fermented foods, the team plans to proceed with investigating its involvement in stress response control through daily diet. Expanding on this research in the future is expected to lead to the development of new functional foods utilizing endogenous metabolites and stress-relief strategies that are easily incorporated into daily life.